Literature DB >> 25429559

Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

Juan David Guzman1.   

Abstract

Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships.

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Year:  2014        PMID： 25429559      PMCID： PMC6271800          DOI： 10.3390/molecules191219292

Source DB:  PubMed          Journal:  Molecules        ISSN： 1420-3049            Impact factor:   4.411


1. Introduction

Cinnamic acids are a group of aromatic carboxylic acids (C6–C3) appearing naturally in the plant kingdom. They are formed in the biochemical route that yields lignin, the polymeric material that provides mechanical support to the plant cell wall [1]. Cinnamic acids occur in all green plants [2], although in minute quantities covalently bound to cell walls [3], but also in the reproductive organs of flowering plants [4]. Cinnamic acids are formed in the biosynthetic pathway leading to phenyl-propanoids, coumarins, lignans, isoflavonoids, flavonoids, stilbenes, aurones, anthocyanins, spermidines, and tannins [5]. These secondary metabolites play key physiological roles in plant growth, development, reproduction and disease resistance [6,7]. The first step of this pathway is catalyzed by the phenylalanine ammonia lyase (PAL), a widely distributed phenylpropanoid enzyme present in green plants, algae, fungi, and even in some prokaryotes [8]. This enzyme deaminates l-phenylalanine to yield (E)-cinnamic acid, which undergoes other enzymatic transformations, yielding a diversity of related products [5]. The term “cinnamic” derives from the spice cinnamon (Cinnamomum zeilanicum) which has been used since antiquity as a flavoring agent and for its stimulant, carminative, antiseptic and insecticide properties [9]. The bark of several species of Cinnamomum contain considerable amounts of (E)-cinnamaldehyde, a volatile aldehyde responsible for the pungent, sweet and hot flavor of cinnamon [10,11]. Cinnamaldehyde and the essential oils of the species of Cinnamomum have antimicrobial activity both against bacteria and fungi [12,13]. Cinnamic acids are also readily available from coffee beans, tea, mate, cocoa, apples and pears, berries, citrus, grape, brassicas vegetables, spinach, beetroot, artichoke, potato, tomato, celery, faba beans, and cereals [14]. Cinnamic acids often appear as ester conjugates with quinic acid, known as the chlorogenic acids, but they can also form esters with other acids, sugars or lipids, or form amides with aromatic and aliphatic amines. In the last ten years, the interest of researchers on the cinnamic acid moiety has notably increased. The number of published reports having the word “cinnamic” in the title, has almost doubled, from 341 in the years 1993–2003 to 633 in the period 2004–2014 according to the Scopus database (until mid-November 2014). If both “cinnamic” and “antimicrobial” keywords are used, the number of published articles increased from 1 in the period 1993–2003, to 7 in the period 2004–2014. There is no doubt that the cinnamic acids currently attracts the attention of chemists from different perspectives. Ozagrel (Figure 1), a thromboxane A2 synthase inhibitor, is in fact an imidazole para-substituted cinnamic acid that is employed therapeutically for treating acute ischemic stroke [15]. Cinromide (Figure 1) is an antiepileptic experimental drug studied in clinical trials during the 80 decade with a favorable profile to suppress generalized convulsions, but however displayed considerable toxicity [16]. Piplartine (Figure 1) is another cinnamic-related molecule showing an attractive biological horizon [17]. This cinnamic amide was first-time isolated from the roots of Piper tuberculatum [18], and later proved to be a promising anti-cancer scaffold [19,20].
Figure 1

Chemical structures of some therapeutically important cinnamic acid-containing molecules: ozagrel, cinromide and piplartine.

Several reviews and studies have appeared in the literature focusing on a particular medicinal application of cinnamic-related molecules, for example on anticancer [21], antituberculosis [22], antimalarial [23], antifungal [24], antimicrobial [25], antiatherogenic [26] and antioxidant [25] activities. In addition a number of reviews directed towards the synthetic methods used to prepare cinnamic acids and related molecules have appeared in the literature [27,28,29]. Cinnamic acids have also been used by medicinal chemists to alter the potency, permeability, solubility or other parameters of a selected drug or pharmacophore. Chemical structures of some therapeutically important cinnamic acid-containing molecules: ozagrel, cinromide and piplartine. Infectious diseases caused by bacteria, fungi and viruses are still a prominent global health problem, particularly in developing, low-income countries [30,31]. Every year in the whole planet, around 4 million persons die from acute respiratory infections, around 3 million individuals die from enteric infections, around 1.8 persons die from human immunodeficiency virus (HIV), around 1.3 million die from tuberculosis (TB), and 0.7 million die from malaria [32,33,34]. Other thousand people deeply suffer the consequences of being infected by neglected tropical pathogens Schistosoma mansoni, Onchocerca volvulus, Trypanosoma spp., Leishmania spp., Mycobacterium ulcerans, Mycobacterium leprae, Wucheria spp., and others. Although some of these diseases are caused by parasites, many are caused by bacteria and fungi. Anti-bacterial and anti-fungal drugs, which are broadly known as antimicrobials, started to be used in chemotherapy since the 1940 decade [35]. New antimicrobial classes were discovered in the 1940–1970 period, and were successfully introduced to clinical practice. However as soon as the new drugs were employed, the first drug-resistant strains started to appear [36,37]. In addition the widespread use of antibiotics for animal feed and human consumption during the last forty years, has fostered the emergence of resistance in several pathogenic organisms. Infection with drug-resistant strains is typically associated with longer treatment times, higher toxicity and higher costs. Nowadays some infections are extremely difficult to treat such as extensively drug-resistant tuberculosis (XDR-TB) [38], community-associated methicillin-resistant Staphylococcus aureus (MRSA) [39] and pan-resistant Klebsiella and Escherichia coli strains [40], and they pose an enormous challenge to clinicians. The presence of these “superbugs” call for drugs with novel mechanisms of action [41]. The cinnamic skeleton is considered an interesting scaffold for the development of novel antimicrobials, however little is known about its antimicrobial mechanism of action. A recent report proposed that cinnamic acids caused fungal growth inhibition by interacting with benzoate 4-hydroxylase, an enzyme responsible for aromatic detoxification [42]. However this enzyme occurs in fungi but not in prokaryotes, and because the cinnamic acids have proven anti-bacterialeffects [43,44,45,46], other targets may be implicated in their biological effects. This review intends to bring the attention of scientists on the antimicrobial potential of the cinnamic acids. The focus is brought to the chemical entities containing the cinnamic skeleton, displaying fungal or bacterial growth inhibition. Emphasis is placed on whole-cell inhibitory potency, structure-activity relationships and mechanism of action studies. The review is organized in different sections according to the functional groups decorating the C6–C3 cinnamic skeleton. The first section deals with natural and synthetic cinnamic acids, the second section is concerned with cinnamic esters and amides, the third section deals with cinnamic aldehydes and alcohols, and finally the fourth section covers the hybrid covalently-bound molecules between a cinnamic acid and any other biologically-relevant molecule.

2. Natural and Synthetic Cinnamic Acids

Honey and propolis are both bee (Apis mellifera) products made from the nectar of the flowers, and they have long been used for their antimicrobial properties [47,48]. We should recall that a report from 1978, postulated the presence of cinnamic amides in the reproductive organs of flowers [4]. Propolis and honey contain hundreds of different organic compounds, and the cinnamic acids and their esters are typically present in these natural bees products [49,50,51,52]. Cinnamic acids with varied substitution on the aryl ring, and their esters have been identified in Iranian propolis showing minimum inhibitory concentration (MIC) values between 125 and 500 mg/L against bacteria and fungi [52]. Other studies have confirmed the antimicrobial potential of propolis [53,54]. Although secondary metabolites such as flavonoids, sesquiterpenoids present in propolis may have antimicrobial activity, cinnamic acids are likely to contribute to the observed effect. The minimum inhibitory concentration (MIC) values for the natural cinnamic acids against different bacteria, as determined by different researchers using different methods, are shown in Table 1. It was surprising to find huge differences in the MIC values for the same compounds against the same species as reported by different authors. The existence of controversial results was already noted by Wen et al., in the seminal work of the antilisterial effect of natural phenolic acids [46]. The differences may be attributed to the diversity of experimental methods for MIC determination, often measuring distinct end-points, using different inoculum sizes, different culture media, and using particular strains with varying susceptibilities [55]. Although these discrepancies obscure the antimicrobial potential of the cinnamic acid class, there is clear tendency of the molecules to inhibit the growth of a wide variety of microorganisms by molecular mechanisms that are still unknown.
Table 1

Minimum inhibitory concentration values of natural and synthetic cinnamic acids 1–24.

CompoundMicrobial StrainMICRefs.
cinnamic acid (1)Aeromonas hydrophila MTCC 6467.7 mM[59]
Aeromonas salmonicida MTCC 15225.6 mM[59]
Aspergillus flavus UBA2941.7 mM[65]
Aspergillus niger ATCC 11394844 µM[65]
Aspergillus terreus INM 0317831.7 mM[65]
Candida albicans405 µM[66]
Edwardiella tarda MTCC 24007.0 mM[59]
Enterococcus faecalis6.75 mM[12]
Escherichia coli6.75 mM[12]
Escherichia coli5.0 mM[56]
Escherichia coli>6.75 mM[58]
Escherichia coli ATCC 259229.0 mM[57]
Listeria monocytogenes13.5 mM[46]
Morganella morganni>6.75 mM[58]
Mycobacterium tuberculosis H37Rv270 µM[60]
Mycobacterium tuberculosis H37Rv675 µM[62]
Neisseria gonorrhoeae6.75 mM[58]
Pasteurella multocida>6.75 mM[58]
Proteus mirabilis>6.75 mM[58]
Pseudomonas aeruginosa6.75 mM[12]
Salmonella sp.6.75 mM[12]
Salmonella typhimurium LT27.5 mM[56]
Staphylococcus aureus6.75 mM[12]
Staphylococcus epidermis6.75 mM[12]
Streptococcus pyogenes 10535844 µM[77]
Vibrio parahaemolyticus6.75 mM[12]
4-coumaric acid (3)Aspergillus flavus UBA2941.5 mM[65]
Aspergillus niger ATCC 11394761 µM[65]
Aspergillus terreus INM 0317831.5 mM[65]
Bacillus cereus No-82.44 mM[70]
Bacillus subtilis NCIMB 86492.0 mM[68]
Bacillus subtilis 9372122 µM[67]
Escherichia coli NCIMB 122102.0 mM[68]
Escherichia coli6.09 mM[58]
Escherichia coli #9163.04 mM[69]
Escherichia coli O157:H72.74 mM[70]
Escherichia coli ATCC 25922490 µM[67]
Fusarium oxysporum3.5 mM[73]
Fusarium verticillioides2.2. mM[73]
Lactobacillus brevis6.09 mM[72]
Lactobacillus collinoides6.09 mM[72]
Lactobacillus hilgardii IFI-CA 496.09 mM[71]
Lactobacillus rhamnosus #2993.04 mM[69]
Listeria monocytogenes13.4 mM[46]
Morganella morganni>6.09 mM[58]
Mycobacterium tuberculosis H37Rv244 µM[60]
Neisseria gonorrhoeae6.09 mM[58]
Pasteurella multocida6.09 mM[58]
Pediococcus pentosaceus IFI-CA 854.87 mM[71]
Proteus mirabilis>6.09 mM[58]
Pseudomonas syringae NCIMB 6492.0 mM[68]
Saccharomyces cerevisiae 019 391>8.0 mM[68]
Salmonella typhimurium #4503.04 mM[69]
Salmonella typhimurium NRRL E44632.44 mM[70]
Salmonella typhimurium 50013122 µM[67]
Schizosaccharomyces pombe 039 9178.0 mM[68]
Shigella disenteriae 5130261 µM[67]
Sporobolomyces roseus 043 5298.0 mM[68]
Staphylococcus aureus # 917761 µM[69]
Staphylococcus aureus NCTC 10657>3.65 mM[70]
Staphylococcus aureus 6538122 µM[67]
Streptococcus pneumoniae ATCC 49619122 µM[67]
Streptococcus pyogenes 10535761 µM[77]
3-coumaric acid (4)Aspergillus flavus UBA2941.5 mM[65]
Aspergillus niger ATCC 113941.5 mM[65]
Aspergillus terreus INM 0317831.5 mM[65]
Mycobacterium tuberculosis H37Rv366 µM[60]
2-coumaric acid (5)Bacillus cereus No-82.44 mM[70]
Escherichia coli #9161.5 mM[69]
Escherichia coli O157:H72.74 mM[70]
Lactobacillus rhamnosus #2991.5 mM[69]
Morganella morganni>6.09 mM[58]
Mycobacterium tuberculosis H37Rv122 µM[60]
Neisseria gonorrhoeae>6.09 mM[58]
Pasteurella multocida>6.09 mM[58]
Proteus mirabilis>6.09 mM[58]
Salmonella typhimurium NRRL E44632.44 mM[70]
Salmonella typhimurium #4501.5 mM[69]
Staphylococcus aureus NCTC 10657>3.65 mM[70]
Staphylococcus aureus # 917760 µM[69]
caffeic acid (6)Aspergillus flavus UBA294>1.39 mM[65]
Aspergillus flavus>5.5 mM[73]
Aspergillus fumigatus>5.5 mM[73]
Aspergillus niger ATCC 11394>1.39 mM[65]
Aspergillus terreus INM 031783>1.39 mM[65]
Bacillus cereus No-81.94 mM[70]
Bacillus subtilis NCIMB 86494.0 mM[68]
Campylobacter jejuni KC40>1.0 mM[93]
Candida albicans 62694 µM[77]
Candida albicans biofilm1.42 mM[78]
Candida albicans planktonic710 µM[78]
Escherichia coli>5.5 mM[58]
Escherichia coli #9162.78 mM[69]
Escherichia coli1.78 mM[57]
Escherichia coli NCIMB 122108.0 mM[68]
Escherichia coli O157:H71.94 mM[70]
Fusarium oxysporum>5.5 mM[73]
Fusarium verticilioides>5.5 mM[73]
Lactobacillus hilgardii IFI-CA 494.44 mM[71]
Lactobacillus rhamnosus #299<1.39 mM[69]
Listeria monocytogenes16.1 mM[46]
Morganella morganni>5.5 mM[58]
Neisseria gonorrhoeae>5.5 mM[58]
Pasteurella multocida5.5 mM[58]
Pediococcus pentosaceus IFI-CA 853.89 mM[71]
Penicillium brevicompactum>5.5 mM[73]
Penicillium expansum>5.5 mM[73]
Proteus mirabilis>5.5 mM[58]
Pseudomonas syringae NCIMB 6494.0 mM[68]
Saccharomyces cerevisiae 019 391>8.0 mM[68]
Salmonella typhimurium #4502.78 mM[69]
Salmonella typhimurium NRRL E44631.94 mM[70]
Schizosaccharomyces pombe 039 917>8.0 mM[68]
Sporobolomyces roseus 043 529>8.0 mM[68]
Staphylococcus aureus 209694 µM[77]
Staphylococcus aureus # 917694 µM[69]
Staphylococcus aureus NCTC 106572.22 mM[70]
Streptococcus pyogenes 10535694 µM[77]
ferulic acid (7)Aspergillus flavus>5.15 mM[73]
Aspergillus flavus UBA294161 µM[65]
Aspergillus fumigatus>5.15 mM[73]
Aspergillus niger>10 mM[80]
Aspergillus niger ATCC 11394322 µM[65]
Aspergillus terreus INM 031783>1.3 mM[65]
Bacillus cereus No-82.06 mM[70]
Bacillus subtilis6.0 mM[80]
Bacillus subtilis NCIMB 86492.0 mM[68]
Candida albicans>10 mM[80]
Candida albicans ATCC 10231659 µM[81]
Candida krusei ATCC 6258659 µM[81]
Enterococcus faecalis ATCC 29212659 µM[81]
Escherichia coli>5.15 mM[58]
Escherichia coli ATCC 259221.3 mM[81]
Escherichia coli O157:H72.32 mM[70]
Escherichia coli CECT 434515 µM[79]
Escherichia coli IFO13275>5.0 mM[94]
Escherichia coli NCIMB 122102.0 mM[68]
Fusarium oxysporum>5.15 mM[73]
Fusarium verticilioides>5.15 mM[73]
Klebsiella pneumoniae RSKK 5741.3 mM[81]
Listeria monocytogenes13.9 mM[46]
Listeria monocytogenes ATCC 153136.44 mM[79]
Morganella morganni>5.15 mM[58]
Neisseria gonorrhoeae5.15 mM[58]
Pasteurella multocida5.15 mM[58]
Pediococcus pentosaceus IFI-CA 854.63 mM[71]
Penicillium brevicompactum>5.15 mM[73]
Penicillium expansum>5.15 mM[73]
Proteus mirabilis>5.15 mM[58]
Pseudomonas aeruginosa ATCC 10145515 µM[79]
Pseudomonas syringae NCIMB 6492.0 mM[68]
Saccharomyces cerevisiae6.0 mM[80]
Saccharomyces cerevisiae 019 3914.0 mM[68]
Salmonella enteriditis IFO3133>5.0 mM[94]
Salmonella typhimurium NRRL E44632.06 mM[70]
Schizosaccharomyces pombe 039 9178.0 mM[68]
Sporobolomyces roseus 043 5292.0 mM[68]
Staphylococcus aureus6.0 mM[80]
Staphylococcus aureus 209644 µM[77]
Staphylococcus aureus ATCC 292131.3 mM[81]
Staphylococcus aureus CECT 9765.7 mM[79]
Staphylococcus aureus IFO 127322.0 mM[94]
Staphylococcus aureus NCTC 106573.09 mM[70]
Streptococcus pyogenes 10535644 µM[77]
sinapic acid (8)Bacillus subtilis NCIMB 86492.0 mM[68]
Bacillus subtilis FAD 1101.3 mM[83]
Escherichia coli NCIMB 122102.0 mM[68]
Escherichia coli IFO132752.2 mM[94]
Escherichia coli AW 1.73.1 mM[83]
Listeria innocua ATCC 3309091.3 mM[83]
Listeria monocytogenes ATCC 7644900 µM[83]
Pseudomonas fluorescens ATCC 135252.7 mM[83]
Pseudomonas syringae NCIMB 6494.0 mM[68]
Saccharomyces cerevisiae 019 391>8.0 mM[68]
Salmonella enteriditis IFO31332.0 mM[94]
Schizosaccharomyces pombe 039 917>8.0 mM[68]
Sporobolomyces roseus 043 529>8.0 mM[68]
Staphylococcus aureus 209558 µM[77]
Staphylococcus aureus IFO 127321.8 mM[94]
Staphylococcus aureus ATCC 65381.3 mM[83]
Streptococcus pyogenes 10535558 µM[77]
4-methoxycinnamic acid (9)Aspergillus niger50.4 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans50.4 µM[44]
Escherichia coli164 µM[44]
Escherichia coli281 µM[84]
Micrococcus luteus449 µM[84]
Salmonella enteriditis337 µM[84]
Staphylococcus aureus337 µM[84]
Staphylococcus aureus203 µM[44]
3,4-methylenedioxy-cinnamic acid (10)Mycobacterium tuberculosis H37Rv312 µM[60]
Mycobacterium tuberculosis H37Rv>520 µM[85]
4-nitrocinnamic acid (11)Bacillus subtilis IFO 3009891 µM[86]
Escherichia coli IFO 3301794 µM[86]
3-nitrocinnamic acid (12)Aspergillus niger43.5 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans43.5 µM[44]
Escherichia coli252 µM[44]
Staphylococcus aureus252 µM[44]
4-aminocinnamic acid (13)Bacillus subtilis IFO 3009602 µM[86]
Escherichia coli IFO 3301708 µM[86]
4-chlorocinnamic acid (14)Bacillus subtilis IFO 3009708 µM[86]
Escherichia coli IFO 3301708 µM[86]
4-O-prenylcoumaric acid (16)Mycobacterium tuberculosis H37Rv86.1 µM[60]
4-O-geranylcoumaric acid (17)Mycobacterium tuberculosis H37Rv66.8 µM[60]
3-O-prenylcoumaric acid (18)Mycobacterium tuberculosis H37Rv172 µM[60]
2-O-prenylcoumaric acid (19)Mycobacterium tuberculosis H37Rv258 µM[60]
3-prenyl-4-coumaric acid (= drupanin) (20)Aspergillus fumigatus ATCC 26934>1.1 mM[92]
Aspergillus flavus ATCC 9170>1.1 mM[92]
Aspergillus niger ATCC 9029>1.1 mM[92]
Candida albicans ATCC 102311.1 mM[92]
Candida tropicalis CEREMIC 131>1.1 mM[92]
Cryptococcus neoformans ATCC 322641.1 mM[92]
Epidermophyton floccosum C114215 µM[92]
Escherichia coli ATCC 25922>1.1 mM[92]
Microsporum canis C112431 µM[92]
Microsporum gypseum C115431 µM[92]
Staphylococcus aureus LMS>1.1 mM[92]
Methicillin-resistant Staphylococcus aureus>1.1 mM[92]
Trichophyton mentagrophytes ATCC 9972431 µM[92]
Trichophyton rubrum C113431 µM[92]
4-acetyl-3-prenyl-4-coumaric acid (21)Aspergillus fumigatus ATCC 26934>912 µM[92]
Aspergillus flavus ATCC 9170>912 µM[92]
Aspergillus niger ATCC 9029>912 µM[92]
Candida albicans ATCC 10231>912 µM[92]
Candida tropicalis CEREMIC 131>912 µM[92]
Cryptococcus neoformans ATCC 32264>912 µM[92]
Epidermophyton floccosum C114364 µM[92]
Escherichia coli ATCC 25922>912 µM[92]
Microsporum canis C112>912 µM[92]
Microsporum gypseum C115912 µM[92]
Staphylococcus aureus LMS>912 µM[92]
Methicillin-resistant Staphylococcus aureus>912 µM[92]
Trichophyton mentagrophytes ATCC 9972456 µM[92]
Trichophyton rubrum C113456 µM[92]
3,5-diprenyl-4-coumaric acid (22)Aspergillus fumigatus ATCC 26934>833 µM[92]
Aspergillus flavus ATCC 9170>833 µM[92]
Aspergillus niger ATCC 9029>833 µM[92]
Candida albicans ATCC 10231833 µM[92]
Candida tropicalis CEREMIC 131>833 µM[92]
Cryptococcus neoformans ATCC 32264>833 µM[92]
Epidermophyton floccosum C114166 µM[92]
Escherichia coli ATCC 25922>833 µM[92]
Microsporum canis C112>833 µM[92]
Microsporum gypseum C115>833 µM[92]
Staphylococcus aureus LMS833 µM[92]
Methicillin-resistant Staphylococcus aureus833 µM[92]
Trichophyton mentagrophytes ATCC 9972>833 µM[92]
Trichophyton rubrum C113416 µM[92]
4-acetyl-3,5-diprenyl-4-coumaric acid (23)Aspergillus fumigatus ATCC 26934>731 µM[92]
Aspergillus flavus ATCC 9170>731 µM[92]
Aspergillus niger ATCC 9029>731 µM[92]
Candida albicans ATCC 10231>731 µM[92]
Candida tropicalis CEREMIC 131>731 µM[92]
Cryptococcus neoformans ATCC 32264>731 µM[92]
Epidermophyton floccosum C114292 µM[92]
Escherichia coli ATCC 25922>731 µM[92]
Microsporum canis C112>731 µM[92]
Microsporum gypseum C115>731 µM[92]
Staphylococcus aureus LMS>731 µM[92]
Methicillin-resistant Staphylococcus aureus>731 µM[92]
Trichophyton mentagrophytes ATCC 9972731 µM[92]
Trichophyton rubrum C113365 µM[92]
O-acetylferulic acid (24)Candida albicans ATCC 10231540 µM[81]
Candida krusei ATCC 6258540 µM[81]
Enterococcus faecalis ATCC 29212540 µM[81]
Escherichia coli ATCC 259221.1 mM[81]
Klebsiella pneumoniae RSKK 5741.1 mM[81]
Staphylococcus aureus ATCC 292131.1 mM[81]
Cinnamic acid (1, Figure 2) showed a weak antibacterial effect against most of Gram-negative and Gram-positive species of bacteria, with MIC values higher than 5.0 mM [12,46,56,57,58] (Table 1). The same level of potency was observed against the fish pathogens Aeromonas hydrophila, Aeromonas salmonicida and Edwardiella tarda with MIC values between 5.6 and 7.7 mM [59]. However cinnamic acid was found to be much more active against the tuberculosis-causing bacteria, Mycobacterium tuberculosis H37Rv, with an MIC values of 270–675 µM using the SPOTi and the radiometric Bactec assays [60,61,62]. The free carboxylic acid and the presence of the α,β-unsaturation were both required for the anti-TB activity [60]. Rastogi et al., reported an MIC value of 675 µM against the H37Rv strain and varying values between 337 µM and 1.4 mM for multiple drug-resistant (MDR) clinical M. tuberculosis isolates [62]. The study found that 1 enhanced synergistically the effect of anti-TB drugs such as amikacin, ofloxacin and clofazimine. In addition its geometric isomer, cis-cinnamic acid (2) (Figure 2), was approximately 120 times more active than the trans isomer, with minimum bactericidal concentrations (MBC) values of 16.9 µM for 2, compared to 2.0 mM for 1, against an MDR M. tuberculosis strain [63]. The specific anti-TB effect of cinnamic acid may explain the traditional use of storax (Liquidambar orientalis) and cinnamon for treating TB in the 19th century [64]. Cinnamic acid also demonstrated anti-fungal activity with MIC values of 1.7 mM against Aspergillus terreus and Aspergillus flavus, being more active against Aspergillus niger with an MIC value of 844 µM [65]. Against Candida albicans, an MIC value of 405 µM has been found [66], which is comparable to the potency against M. tuberculosis.
Figure 2

Chemical structures of trans- and cis-cinnamic acids

Chemical structures of trans- and cis-cinnamic acids The widely distributed natural phenol 4-hydroxycinnamic acid (3, Figure 3), also known as 4-coumaric acid, has been found to be comparatively more potent bacterial growth inhibitor compared to cinnamic acid (1) (Table 1). However the reported MIC values of 4-coumaric acid vary to great extent from one species or strain to another. The MIC values against some Gram-negative bacteria such as Shigella disenteriae 51302 was low (MIC = 61 µM) [67], but however against Neisseria gonorrhoeae or Listeria monocytogenes or E. coli, the MIC was high (MIC > 6.0 mM) [46,58]. The same was true against Gram-positive species, with some studies reporting low MIC values for strains of Staphylococcus aureus and Bacillus subtilis whereas other reports have published higher MIC values [67,68,69,70]. A study showed that 3 disrupted the outer membrane of the Gram-negative bacteria S. disenteriae increasing the permeabilization, and in addition, the compound interacted with DNA and thus it may inhibit essential biochemical processes related to nucleic acids [67]. 4-Coumaric acid (3) completely inhibited M. tuberculosis H37Rv growth at 244 µM concentration [60], being therefore slightly more active than cinnamic acid. The compound had weak inhibition of lactic acid bacteria with MIC values of 6.09 mM [71,72] but was however relatively more active against the economically important phytopathogenic fungi Fusarium oxysporum and Fusarium verticillioides, with MIC values of 3.5 mM and 2.2 mM respectively [73]. Against Aspergillus spp MIC values have been reported between 1.5 mM and 760 µM [65].
Figure 3

Chemical structures of differently substituted natural and synthetic cinnamic acids.

The structural isomers 3-coumaric acid (4) and 2-coumaric acid (5) (Figure 3 and Table 1) are less common in nature [74,75] compared to the 4-isomer, and have been less studied. In particular, reports of the antimicrobial activity of the 3-coumaric acid are scarce. 3-Coumaric acid (4) was less active (MIC = 366 µM) compared with the 4-isomer against M. tuberculosis H37Rv, while 2-coumaric acid (5) was the isomer with the highest activity (MIC = 122 µM) [60]. Similarly, 2-coumaric acid showed stronger antimicrobial activity against E. coli, S. aureus, Salmonella typhimurium and Lactobacillus rhamnosus in comparison with 4-coumaric acid, with MIC values between 1.5 mM and 760 µM [69]. However another report published the same MIC values against S. aureus (MIC > 3.6 mM), Bacillus cereus (MIC = 2.4 mM), E. coli (MIC = 2.7 mM) and S. typhimurium (MIC = 2.7 mM) [70]. The 3-isomer (4) displayed moderate antifungal activity (MIC > 1.5 mM) against A. terreus, A. flavus and A. niger [65]. The other abundant cinnamic acids in nature are caffeic acid (6), ferulic acid (7) and sinapic acid (8) (Figure 3), which have been studied for their antimicrobial activities [58,68,73]. A similar pattern was observed for these three natural cinnamic acids, showing a weak growth inhibition against Gram-negative bacteria compared to Gram-positive bacteria and fungi (Table 1). The pH of the media has been reported to exert influence on growth inhibition, with lower pH values increasing the activity of the acids [76] by probably favoring a greater proportion of un-dissociated acid. The lowest MIC values for caffeic acid (6) were found against some strains of S. aureus and Streptococcus pyogenes 10535 (MIC = 694 µM) [69,77]. Caffeic acid showed significant growth inhibition of planktonic C. albicans with MIC between 694 and 710 µM [77,78]. Other species of bacteria and fungi were less susceptible to caffeic acid. Ferulic acid (7) demonstrated significant antibacterial activity against S. aureus 209 and Streptococcus pyogenes 10535 with MIC values of 644 µM [77]. Pseudomonas aeruginosa ATCC 10145 and E. coli CECT 434 were also susceptible to ferulic acid (MIC = 515 µM) [79]. In addition the strain A. niger ATCC 11394 showed a low MIC value (MIC = 322 µM) [65], however the MIC value against another strain of A. niger was found to be higher than 10 mM [80]. Interestingly A. flavus UBA 294 was the microorganism with the lowest MIC value for ferulic acid (MIC = 161 µM) [65]. A similar pattern was noticed for C. albicans, one strain being reported as susceptible with an MIC value of 659 µM [81], whereas another report showed an MIC value higher than 10 mM [80]. Sinapic acid (8), which is the most substituted of the common naturally-occurring cinnamic acids, showed significant activity against S. aureus 209 and Streptococcus pyogenes 10535 (MIC = 558 µM) [77]. The acid also demonstrated anti-Campylobacter activity with MIC values ranging from 696 µM to 1.40 mM [82]. Sinapic acid was fairly active against L. monocytogenes ATCC 7644 with an MIC value of 900 µM [83]. Sinapic acid (8) was completely inactive at a concentration of 4.46 mM against the phytopathogenic fungi F. oxysporum, A. flavus, Penicillium brevicompactum and others [73], in contrast with caffeic and ferulic acid. Some cinnamic acids with a particular substitution pattern on the aryl ring have been prepared and examined for their antimicrobial activity. The compound 4-methoxycinnamic acid (9) was isolated from the Argentinian medicinal plant Baccharis grisebachii and its antimicrobial activity was evaluated [84]. This acid showed a potent antibacterial and antifungal effect with MIC values ranging between 50.4 and 449 µM (Table 1) [44,84]. Interestingly, the acid (9) showed higher growth inhibition against fungal species compared to bacteria, and Gram-negative and Gram-positive bacteria were equally inhibited by the compound. The acid 3,4-methylenedioxycinnamic acid (10) has been reported to inhibit Mycobacterium tuberculosis H37Rv with one report displaying an MIC value of 312 µM [60] and the other an MIC value higher than 520 µM [85]. The effect of the position of the nitro group on antimicrobial activity suggest that 4-nitrocinnamic acid (11) is more active than 3-nitrocinnamic acid (12), however the comparison data results from two different studies [44,86]. The seminal report from 1940, found that none of the positional isomers of nitrocinnamic acid inhibited S. aureus or E. coli at the highest dilution tested [87]. A noteworthy MIC value was found for 12 against the fungal species A. niger and C. albicans (MIC = 43.5 µM) [44]. Although the nitro groups can be readily reduced to amino groups, only 4-aminocinnamic (13) acid has been evaluated for its antimicrobial properties. This acid showed inhibitory activity of B. subtilis and E. coli with respective MIC values of 602 and 708 µM [86]. No information on the antimicrobial properties of the positional isomers of 4-aminocinnamic acid could be found. Although most of the halogen derivatives of cinnamic acid have been prepared [88,89], no information about their antimicrobial profile of activity was found in literature, except for 4-chlorocinnamic acid (14). This acid showed MIC values of 708 µM against both E. coli and B. subtilis [86]. Zosteric acid (15) which is naturally present in the eelgrass Zostera marina, has been found to display powerful antifouling properties by preventing bacterial biofilm formation on the surface of water-submerged objects [90]. Zosteric acid did not show any growth inhibitory activity against M. tuberculosis H37Rv [60], however the compound inhibited biofilm formation of C. albicans at 41 µM [91], but no MIC values were found in the literature search. Chemical structures of differently substituted natural and synthetic cinnamic acids. Among the prenylated coumaric acids, 4-O-prenylcoumaric acid (16) showed potent inhibition of M. tuberculosis H37Rv with an MIC value of 86 µM [60]. The MIC values for 4-O-geranylcoumaric acid (17), 3-O-prenylcoumaric acid (18) and 2-O-prenylcoumaric acid (19) against the same bacterial species were found to be respectively 69, 172 and 258 µM [60]. If we compare the anti-TB activity of the coumaric acids with the O-prenylcoumaric acids, it is clear that O-prenylation increases the activity for the 4- and 3-isomers, whereas for the 2-isomer, O-prenylation reduces the anti-TB activity. The C-prenylated coumaric acid drupanin (20), also known as 3-prenyl-4-coumaric acid, showed fungal growth inhibition particularly against dermatophytes species such as Epidermophyton floccosum C114, Microsporum gypseum C115, Microsporum canis C112, Trichophyton mentagrophytes ATCC 9972 and Trichophyton rubrum C113 with respective MIC values of 215, 431, 431, 431 and 431 µM [92]. Against the bacterial species, drupanin was weakly active with MIC values higher than 1.1 mM. The O-acetyl derivative of drupanin, 4-acetyl-3-prenyl-4-coumaric acid (21) showed a similar pattern of activity, being able to inhibit the dermatophyte E. floccosum C114 with an MIC value of 364 µM [92]. It was therefore slightly less active than the non-acetylated compound. Minimum inhibitory concentration values of natural and synthetic cinnamic acids 1–24. The compound 3,5-diprenyl-4-coumaric acid (22) was comparatively more active growth inhibitor of E. floccosum C114 achieving an MIC values of 166 µM [92]. Its O-acetyl derivative (23) was again slightly less active than the non-acetylated compound (Table 1), suggesting that the free phenolic OH is essential for potent activity of this class of molecules. The 4-O-acetyl derivative of ferulic acid, namely 4-O-acetylferulic acid (24), prepared by synthesis, inhibited the growth of C. albicans, Candida krusei and Enterococcus faecalis at 540 µM, but was less active against S. aureus, E. coli and Klebsiella pneumoniae [81]. Its activity was found to be comparatively similar to the antimicrobial effect of ferulic acid.

3. Natural and Synthetic Cinnamic Esters and Amides

3.1. Esters

The chlorogenic acids are a family of natural esters of hydroxycinnamic acids (coumaric, caffeic, ferulic and sinapic acids) with (−)-quinic acid [14]. The most common chlorogenic acid is 5-O-caffeoylquinic acid (25, Figure 4), which is abundant in coffee, black tea and mate but is also present in apples, pears and berries [95]. This chlorogenic acid isolated from artichoke, displayed MIC values of 564 µM against B. subtilis, S. aureus, E. coli, S. typhimurium, P. aeruginosa and S. cerevisiae, and lower MIC values of 282 µM against Micrococcus luteus, Agrobacterium tumefaciens, Aspergillus niger, Penicillium oxalicum and Mucor mucedo [96]. It was even more active against the fungi Candida albicans, Candida lusitaniae, Saccharomyces carlsbergencis and Cladosporium cucumerinum with an MIC value of 141 µM [96]. MIC values for the natural cinnamic esters are summarized in Table 2. However the effect of (25), isolated from roasted coffee beans, against S. aureus and Streptococcus mutans was much less marked in the study of Daglia et al., with MIC values of 17.8 and 7.62 mM respectively [97]. The study of Xia et al., isolated the three position isomers of caffeoylquinic acid from the Prunus mume seeds, and evaluated their antimicrobial activity against a panel of microorganisms, finding for (25) MIC values of 282 µM against S. aureus, 423 µM against E. coli and C. albicans, 564 µM against S. enterica, S. cerevisiae and A. niger, and an MIC value of 705 µM against Vibrio parahaemolyticus [98]. This natural product isolated from Artemisia absinthium inhibited completely the growth of S. aureus at a concentration of 361 µM, being even more active against B. cereus, E. faecalis with an MIC value 181 µM [99]. In addition 5-O-caffeoylquinic acid demonstrated biofilm formation inhibition in S. aureus and E. faecalis. Controversial results have also been reported for 25, as the study of Alves et al. reported MIC values higher than 2.8 mM against all the evaluated microorganisms including E. coli [58]. The study of Lou et al., published in 2011, showed MIC values ranging from 54 µM against Streptococcus pneumoniae and Shigella disenteriae to 226 µM against E. coli [100]. The methyl ester of 25, namely methyl 5-O-caffeoylquinate isolated from the invasive plant Ageratina adenophora, inhibited the growth of S. aureus, Bacillus thuringensis, E. coli and S. enterica at a concentration of 89 µM [101], and was therefore comparatively more active than the parent chlorogenic acid. Transmission electron microscopy, membrane potential and nucleotide leakage studies on Shigella disenteriae led to the conclusion that the chlorogenic acid disrupted cell wall permeability and then depolarized the bacterial cell wall membrane causing cytoplasmic leakage [100].
Figure 4

Chemical structures of cinnamic esters displaying antimicrobial activity.

Table 2

Minimum inhibitory concentration values of natural and synthetic cinnamic esters 25–77.

CompoundMicroorganism StrainMICRefs.
5-O-caffeoylquinic acid (25)Agrobacterium tumefaciens CGMCC 1.1415282 µM[96]
Aspergillus niger ATCC 10553564 µM[98]
Aspergillus niger CGMCC 3.316282 µM[96]
Bacillus subtilis CGMCC 1.1849564 µM[96]
Bacillus subtilis 9372108 µM[100]
Candida albicans ATCC 10231141 µM[96]
Candida albicans ATCC 14053423 µM[98]
Candida albicans DAY185181 µM[99]
Candida lusitaniae ATCC 2201141 µM[96]
Cladosporium cucumerinum ATCC 11279141 µM[96]
Enterococcus faecalis OGRF1181 µM[99]
Escherichia coli ATCC 25922216 µM[100]
Escherichia coli ATCC 25922423 µM[98]
Escherichia coli CGMCC 1.90564 µM[96]
Micrococcus luteus CGMCC 1.880282 µM[96]
Mucor mucedo CGMCC 3.15282 µM[96]
Penicillium oxalicum CGMCC 3.4022282 µM[96]
Pseudomonas aeruginosa CG-MCC 1.2031564 µM[96]
Saccharomyces carlsbergensis ATCC 2166141 µM[96]
Saccharomyces cerevisiae ATCC 36858564 µM[98]
Saccharomyces cerevisiae IFFI 1611564 µM[96]
Salmonella enterica ATCC 13076564 µM[98]
Salmonella typhimurium CGMCC 1.1190564 µM[96]
Salmonella typhimurium 50013108 µM[100]
Shigella disenteriae 5130254 µM[100]
Staphylococcus aureus17.8 mM[97]
Staphylococcus aureus 8325-4361 µM[99]
Staphylococcus aureus 6538108 µM[100]
Staphylococcus aureus ATCC 25923282 µM[98]
Staphylococcus aureus ATCC 6358P564 µM[96]
Streptococcus mutans7.62 mM[97]
Streptococcus pneumoniae ATCC 4961954 µM[100]
Vibrio parahaemolyticus ATCC 17802705 µM[98]
4-O-caffeoylquinic acid (26)Aspergillus niger ATCC 10553564 µM[98]
Candida albicans ATCC 14053564 µM[98]
Escherichia coli ATCC 25922423 µM[98]
Saccharomyces cerevisiae ATCC 36858705 µM[98]
Salmonella enterica ATCC 13076705 µM[98]
Staphylococcus aureus ATCC 25923423 µM[98]
3-O-caffeoylquinic acid (27)Aspergillus niger ATCC 10553423 µM[98]
Candida albicans ATCC 14053423 µM[98]
Escherichia coli ATCC 25922282 µM[98]
Saccharomyces cerevisiae ATCC 36858564 µM[98]
Salmonella enterica ATCC 13076564 µM[98]
Staphylococcus aureus ATCC 25923282 µM[98]
Vibrio parahaemolyticus ATCC 17802564 µM[98]
1,3-di-O-caffeoylquinic acid (28)Agrobacterium tumefaciens CGMCC 1.1415194 µM[96]
Aspergillus niger CGMCC 3.316194 µM[96]
Bacillus subtilis CGMCC 1.1849387 µM[96]
Candida albicans ATCC 10231194 µM[96]
Candida lusitaniae ATCC 2201194 µM[96]
Cladosporium cucumerinum ATCC 11279194 µM[96]
Escherichia coli CGMCC 1.90194 µM[96]
Micrococcus luteus CGMCC 1.880194 µM[96]
Mucor mucedo CGMCC 3.15194 µM[96]
Penicillium oxalicum CGMCC 3.4022194 µM[96]
Pseudomonas aeruginosa CG-MCC 1.2031194 µM[96]
Saccharomyces carlsbergensis ATCC 2166194 µM[96]
Saccharomyces cerevisiae IFFI 1611387 µM[96]
Salmonella typhimurium CGMCC 1.1190387 µM[96]
Staphylococcus aureus ATCC 6358P387 µM[96]
3,5-di-O-caffeoylquinic acid (29)Agrobacterium tumefaciens CGMCC 1.1415387 µM[96]
Aspergillus niger CGMCC 3.316194 µM[96]
Bacillus subtilis CGMCC 1.1849387 µM[96]
Candida albicans ATCC 10231387 µM[96]
Candida lusitaniae ATCC 2201387 µM[96]
Cladosporium cucumerinum ATCC 11279194 µM[96]
Escherichia coli CGMCC 1.90387 µM[96]
Micrococcus luteus CGMCC 1.880194 µM[96]
Mucor mucedo CGMCC 3.15194 µM[96]
Penicillium oxalicum CGMCC 3.4022194 µM[96]
Saccharomyces carlsbergensis ATCC 2166387 µM[96]
Saccharomyces cerevisiae IFFI 1611387 µM[96]
Salmonella typhimurium CGMCC 1.1190>387 µM[96]
Staphylococcus aureus ATCC 6358P387 µM[96]
4,5-di-O-caffeoylquinic acid (30)Agrobacterium tumefaciens CGMCC 1.1415387 µM[96]
Aspergillus niger CGMCC 3.316387 µM[96]
Bacillus subtilis CGMCC 1.1849387 µM[96]
Candida lusitaniae ATCC 2201387 µM[96]
Cladosporium cucumerinum ATCC 11279194 µM[96]
Escherichia coli CGMCC 1.90194 µM[96]
Micrococcus luteus CGMCC 1.88097 µM[96]
Mucor mucedo CGMCC 3.15194 µM[96]
Penicillium oxalicum CGMCC 3.4022194 µM[96]
Saccharomyces carlsbergensis ATCC 2166387 µM[96]
Saccharomyces cerevisiae IFFI 1611387 µM[96]
Staphylococcus aureus ATCC 6358P194 µM[96]
Acteoside (31)Enterobacter cloacae P991.2 mM[102]
Escherichia coli 507E4.8 mM[102]
Klebsiella oxytosa 1082E1.2 mM[102]
Klebsiella aerogenes 1522E2.4 mM[102]
Pseudomonas aeruginosa 90271.2 mM[102]
Staphylococcus aureus3.2 mM[102]
Staphylococcus aureus SG511600 µM[102]
Streptococcus pyogenes A3081.2 mM[102]
Campneoside I (32)Enterobacter cloacae P99>917 µM[102]
Escherichia coli 507E>917 µM[102]
Klebsiella oxytosa 1082E>917 µM[102]
Klebsiella aerogenes 1522E>917 µM[102]
Pseudomonas aeruginosa 9027>917 µM[102]
Staphylococcus aureus200 µM[102]
Staphylococcus aureus SG511229 µM[102]
Streptococcus pyogenes A308229 µM[102]
Campneoside II (33)Staphylococcus aureus2.0 mM[102]
Caffeic acid ester (34)Phomopsis longicolla19 µM[103]
Rosmarinic acid (35)Aspergillus niger ATCC 164042.8 mM[106]
Bacillus cereus ATCC 109871.8 mM[105]
Bacillus subtilis ATCC 110601.8 mM[105]
Candida albicans ATCC 14053694 µM[106]
Corynebacterium T25-176.9 mM[104]
Enterococcus faecalis C159-6833 µM[104]
Escherichia coli ATCC 87391.4 mM[106]
Listeria monocytogenes ATCC 191151.8 mM[105]
Mycobacterium smegmatis 50033.3 mM[104]
Pseudomonas aeruginosa ATCC 275836.9 mM[104]
Pseudomonas aeruginosa ATCC 278531.8 mM[105]
Staphylococcus aureus ATCC 29213888 µM[105]
Staphylococcus aureus ATCC 297371.4 mM[106]
Staphylococcus epidermis 5001833 µM[104]
Staphylococcus lugdunensis T26A31.6 mM[104]
Staphylococcus warneri T12A123.3 mM[104]
Stenotrophomonas maltophilia833 µM[104]
Methyl rosmarinate (36)Bacillus cereus ATCC 10987>3.4 mM[105]
Bacillus subtilis ATCC 11060>3.4 mM[105]
Corynebacterium T25-173.2 mM[104]
Enterococcus faecalis C159-6801 µM[104]
Listeria monocytogenes ATCC 19115>3.4 mM[105]
Mycobacterium smegmatis 50031.6 mM[104]
Pseudomonas aeruginosa ATCC 275833.2 mM[104]
Pseudomonas aeruginosa ATCC 27853>3.4 mM[105]
Staphylococcus aureus ATCC 29213>3.4 mM[105]
Staphylococcus epidermis 5001801 µM[104]
Staphylococcus lugdunensis T26A31.6 mM[104]
Staphylococcus warneri T12A12801 µM[104]
Stenotrophomonas maltophilia801 µM[104]
Caffeic acid phenethyl ester (37)Escherichia coli ATCC 25922>800 µM[108]
Staphylococcus aureus ATCC 6538P100 µM[108]
Enterococcus faecalis ATCC 29212400 µM[108]
Listeria monocytogenes ATCC 7644400 µM[108]
Methyl cinnamate (40)Aspergillus flavus UBA 294>1.5 mM[65]
Aspergillus niger61 µM[44]
Aspergillus niger ATCC 11394>1.5 mM[65]
Aspergillus terreus INM 031783>1.5 mM[65]
Bacillus subtilis301 µM[44]
Candida albicans50 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus252 µM[44]
Ethyl cinnamate (41)Aspergillus niger61 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans50 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus252 µM[44]
Propyl cinnamate (42)Aspergillus niger43 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans59 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus301 µM[44]
Isopropyl cinnamate (43)Aspergillus niger43 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans43 µM[44]
Escherichia coli139 µM[44]
Staphylococcus aureus139 µM[44]
Butyl cinnamate (44)Aspergillus niger36 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans61 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus203 µM[44]
Isobutyl cinnamate (45)Aspergillus niger12 µM[44]
Bacillus subtilis43 µM[44]
Candida albicans14 µM[44]
Escherichia coli43 µM[44]
Staphylococcus aureus50 µM[44]
Octyl cinnamate (46)Aspergillus niger43 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans43 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus203 µM[44]
Phenyl cinnamate (47)Aspergillus niger61 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans43 µM[44]
Escherichia coli252 µM[44]
Staphylococcus aureus203 µM[44]
Benzyl cinnamate (48)Aspergillus niger50 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans43 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus252 µM[44]
8-Hydroxyquinolyl cinnamate (49)Aspergillus niger50 µM[44]
Bacillus subtilis252 µM[44]
Candida albicans61 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus164 µM[44]
Methyl 4-coumarate (50)Aspergillus flavus UBA 294702 µM[65]
Aspergillus niger ATCC 11394702 µM[65]
Aspergillus niger MTCC 8189247 µM[111]
Aspergillus terreus INM 031783702 µM[65]
Bacillus subtilis MTCC 2063247 µM[111]
Candida albicans MTCC 227247 µM[111]
Escherichia coli MTCC 1652247 µM[111]
Staphylococcus aureus MTCC 2901247 µM[111]
Ethyl 4-coumarate (51)Aspergillus niger MTCC 8189176 µM[111]
Bacillus subtilis MTCC 2063176 µM[111]
Candida albicans MTCC 227176 µM[111]
Escherichia coli MTCC 1652176 µM[111]
Staphylococcus aureus MTCC 2901176 µM[111]
Propyl 4-coumarate (52)Aspergillus niger MTCC 81892.3 mM[111]
Bacillus subtilis MTCC 2063137 µM[111]
Candida albicans MTCC 227137 µM[111]
Escherichia coli MTCC 1652137 µM[111]
Staphylococcus aureus MTCC 2901137 µM[111]
Isopropyl 4-coumarate (53)Aspergillus niger MTCC 81892.3 mM[111]
Bacillus subtilis MTCC 2063137 µM[111]
Candida albicans MTCC 227137 µM[111]
Escherichia coli MTCC 16522.3 mM[111]
Staphylococcus aureus MTCC 2901137 µM[111]
Butyl 4-coumarate (54)Aspergillus niger MTCC 81891.9 mM[111]
Bacillus subtilis MTCC 2063107 µM[111]
Candida albicans MTCC 227107 µM[111]
Escherichia coli MTCC 16521.9 mM[111]
Staphylococcus aureus MTCC 2901107 µM[111]
Isopentyl 4-coumarate (55)Aspergillus niger MTCC 818992 µM[111]
Bacillus subtilis MTCC 206392 µM[111]
Candida albicans MTCC 22792 µM[111]
Escherichia coli MTCC 16521.4 mM[111]
Staphylococcus aureus MTCC 290192 µM[111]
Cyclohexyl 4-coumarate (56)Aspergillus niger MTCC 818978 µM[111]
Bacillus subtilis MTCC 20639.1 µM[111]
Candida albicans MTCC 2271.1 mM[111]
Escherichia coli MTCC 165241 mM[111]
Staphylococcus aureus MTCC 290178 µM[111]
Menthyl 4-coumarate (57)Aspergillus niger MTCC 81891.9 mM[111]
Bacillus subtilis MTCC 2063107 µM[111]
Candida albicans MTCC 227107 µM[111]
Escherichia coli MTCC 16521.9 mM[111]
Staphylococcus aureus MTCC 2901107 µM[111]
Phenyl 4-coumarate (58)Aspergillus niger MTCC 81891.2 mM[111]
Bacillus subtilis MTCC 206385 µM[111]
Candida albicans MTCC 22710 µM[111]
Escherichia coli MTCC 165247 mM[111]
Staphylococcus aureus MTCC 290185 µM[111]
4-aminophenyl 4-coumarate (59)Aspergillus niger MTCC 818967 µM[111]
Bacillus subtilis MTCC 20638.5 µM[111]
Candida albicans MTCC 22767 µM[111]
Escherichia coli MTCC 1652905 µM[111]
Staphylococcus aureus MTCC 290167 µM[111]
4-nitrophenyl 4-coumarate (60)Aspergillus niger MTCC 8189558 µM[111]
Bacillus subtilis MTCC 206346 µM[111]
Candida albicans MTCC 22746 µM[111]
Escherichia coli MTCC 165246 µM[111]
Staphylococcus aureus MTCC 290146 µM[111]
Benzyl 4-coumarate (61)Aspergillus niger MTCC 8189905 µM[111]
Bacillus subtilis MTCC 206367 µM[111]
Candida albicans MTCC 22767 µM[111]
Escherichia coli MTCC 1652905 µM[111]
Staphylococcus aureus MTCC 290167 µM[111]
Methyl caffeate (62)Aspergillus flavus UBA 294>1.3 mM[65]
Aspergillus niger ATCC 11394>1.3 mM[65]
Aspergillus terreus INM 031783>1.3 mM[65]
Candida albicans ATCC 10231MIC50 = 659 µM[78]
Ethyl caffeate (63)Candida albicans ATCC 10231MIC50 = 615 µM[78]
Propyl caffeate (64)Candida albicans ATCC 10231MIC50 = 576 µM[78]
Isopropyl caffeate (65)Candida albicans ATCC 10231MIC50 = 576 µM[78]
3-fluoro-4-methoxyphenyl caffeate (66)Candida albicans ATCC 10231MIC50 = 421 µM[78]
(5-nitrofuran-2-yl)methyl caffeate (67)Candida albicans ATCC 10231MIC50 = 52 µM[78]
Methyl ferulate (68)Aspergillus flavus UBA 294>1.2 mM[65]
Aspergillus niger4.0 mM[80]
Aspergillus niger ATCC 11394>1.2 mM[65]
Aspergillus terreus INM 031783>1.2 mM[65]
Bacillus subtilis6.0 mM[80]
Candida albicans4.0 mM[80]
Saccharomyces cerevisiae4.0 mM[80]
Staphylococcus aureus6.0 mM[80]
Ethyl ferulate (69)Aspergillus niger4.0 mM[80]
Bacillus subtilis2.0 mM[80]
Candida albicans4.0 mM[80]
Saccharomyces cerevisiae4.0 mM[80]
Staphylococcus aureus4.0 mM[80]
Butyl ferulate (70)Aspergillus niger>10 mM[80]
Bacillus subtilis500 µM[80]
Candida albicans10 mM[80]
Saccharomyces cerevisiae500 µM[80]
Staphylococcus aureus500 µM[80]
Hexyl ferulate (71)Aspergillus niger>10 mM[80]
Bacillus subtilis63 µM[80]
Candida albicans>10 mM[80]
Saccharomyces cerevisiae>10 mM[80]
Staphylococcus aureus125 µM[80]
2-methyl-1-butyl ferulate (72)Aspergillus niger>10 mM[80]
Bacillus subtilis125 µM[80]
Candida albicans>10 mM[80]
Saccharomyces cerevisiae250 µM[80]
Staphylococcus aureus125 µM[80]
4-t-butylphenyl ferulate (73)Candida albicans ATCC 10231391 µM[81]
Candida krusei ATCC 6258391 µM[81]
Enterococcus faecalis ATCC 29212391 µM[81]
Escherichia coli ATCC 25922782 µM[81]
Klebsiella pneumoniae RSKK 574782 µM[81]
Staphylococcus aureus ATCC 29213782 µM[81]
4-isopropylphenyl ferulate (74)Candida albicans ATCC 10231204 µM[81]
Candida krusei ATCC 6258204 µM[81]
Enterococcus faecalis ATCC 2921251 µM[81]
Escherichia coli ATCC 25922818 µM[81]
Klebsiella pneumoniae RSKK 574409 µM[81]
Staphylococcus aureus ATCC 29213409 µM[81]
4-chloro-3-methylphenyl ferulate (75)Candida albicans ATCC 10231201 µM[81]
Candida krusei ATCC 6258201 µM[81]
Enterococcus faecalis ATCC 2921250 µM[81]
Escherichia coli ATCC 25922812 µM[81]
Klebsiella pneumoniae RSKK 574401 µM[81]
Staphylococcus aureus ATCC 29213<25 µM[81]
4-methoxyphenyl ferulate (76)Candida albicans ATCC 10231425 µM[81]
Candida krusei ATCC 6258425 µM[81]
Enterococcus faecalis ATCC 29212850 µM[81]
Escherichia coli ATCC 25922850 µM[81]
Klebsiella pneumoniae RSKK 574850 µM[81]
Staphylococcus aureus ATCC 29213850 µM[81]
4-acetamidophenyl ferulate (77)Candida albicans ATCC 10231390 µM[81]
Candida krusei ATCC 6258390 µM[81]
Enterococcus faecalis ATCC 29212390 µM[81]
Escherichia coli ATCC 25922780 µM[81]
Klebsiella pneumoniae RSKK 574780 µM[81]
Staphylococcus aureus ATCC 29213780 µM[81]
4-O-Caffeoylquinic acid (26) (Figure 4 and Table 2) was found to be slightly less active than the 5-O-isomer with MIC values of 423 µM against both S. aureus and E. coli, 564 µM against both fungi C. albicans and A. niger, and 705 µM against S. enterica and S. cerevisiae [98]. In contrast with 5-O-caffeoylquinic acid, 3-O-caffeoylquinic acid (27) displayed more pronounced growth inhibitory activity against bacteria than fungi (Table 2), achieving MIC values of 282 µM against E. coli and S. aureus [98]. The literature reports of the antimicrobial activity of the 3-O- and 4-O-isomers are scarce, in contrast with the 5-O-isomer. The fact that the esters 25, 26 and 27 have a different antimicrobial profile suggests that they have antimicrobial activity on their own, and the hydrolysis products caffeic and quinic acids, which could be released in the same amount, are not responsible for the antimicrobial activity of the three esters. Chemical structures of cinnamic esters displaying antimicrobial activity. Among the chlorogenic acids formed by two caffeic acids residues, 1,3-di-O-caffeoylquinic acid (28), 3,5-di-O-caffeoylquinic acid (29) and 4,5-di-O-caffeoylquinic acid (30), the presence of caffeic residue in the position 3 of quinic acid increased the antifungal spectrum of activity, with 28 achieving MIC values below 200 µM against almost all fungi tested (Table 2), whereas the esterification in the position 5 of quinic acid increased the antibacterial potency of the acid, displaying MIC values of 194 µM against E. coli and S. aureus for 30 and even inhibiting completely the growth of Micrococcus luteus at 97 µM [96]. However discrepant MIC have also been reported. A report from 2011, published MIC values higher than 248 µM against S. aureus, B. cereus and higher than 496 µM against E. coli and C. albicans for 28, 29 and 30 [99]. Moreover the study found an impressive synergism (FICI < 0.002) between 30 and several fluoroquinolone antibiotics against S. aureus. Four caffeic acid glycosides isolated from Paulownia tomentosa displayed antibacterial activity [102]. Campneoside I (32) demonstrated the highest activity against Gram-positive bacteria achieving MIC values around 200 µM against different species of S. aureus, while both acteoside (31) and campneoside II (33) showed less antistaphylococcal activity [102]. The caffeic acid ester 34 (Figure 4) isolated from Zuccagnia punctata, showed antifungal activity against the phytopathogenic fungi Phomopsis longicolla with an MIC value of only 19 µM, being less active against other fungi [103]. Another caffeic acid ester known as rosmarinic acid (35), and its methyl ester 36 showed growth inhibition of several species of bacteria with MIC values ranging between 801 µM and 6.94 mM [104]. In the study, the methyl ester 36 was slightly more active than the free acid 35. However both rosmarinic acid (35) and its methyl ester 36 isolated from Rabdosia serra, were reported to have significantly higher MIC values against Gram-positive and Gram-negative bacteria [105], and surprisingly the methyl ester was found to be completely inactive with MIC values higher than 3.4 mM, whereas rosmarinic acid showed some activity [105] (Table 2). Moreover the study of Gohari et al., showed that Candida albicans was more susceptible to rosmarinic acid with an MIC value of 694 µM, in comparison with S. aureus, E. coli and Aspergillus niger [106]. Caffeic acid phenethyl ester (37) is a biologically active component of propolis showing interesting anticancer activity [107]. This ester demonstrated antibacterial activity against S. aureus, E. faecalis and L. monocytogenes with MIC values ranging between 100 and 400 µM, but did not show growth inhibition against P. aeruginosa and E. coli up to a concentration of 800 µM [108]. Trilepisiumic acid (38) is an ester of caffeic acid and protocatechuic acid, isolated from Trilepisium madagascariense, that shows antifungal activity against Candida albicans ATCC 9002 (MIC = 202 µM) while being less active against other fungi and bacteria [109]. Two cinnamic esters were isolated from the root of Ehretia longiflora, and identified as ehretiolide (39) and arachidyl ferulate [110]. Ehretiolide (39) showed growth inhibitory activity against M. tuberculosis H37Rv (MIC = 41 µM), which is impressive for an unmodified natural product. All the reported esters of cinnamic acid 40–49, showed potent antifungal activity against A. niger and C. albicans, particularly isobutyl cinnamate (45) achieving MIC values of 12 and 14 µM respectively [44]. The MIC values of 40–49 against A. niger and C. albicans ranged between 12 and 61 µM, and between 14 and 61 µM respectively (Table 2). The MIC values of 40–49 were higher against Gram-positive and Gram-negative bacteria, ranging between 43 and 301 µM [44]. Isobutyl cinnamate (45), also showed the highest growth inhibitory activity against the bacterial species with MIC values between 43 and 50 µM. The esters of 4-coumaric acid 50–61 were comparatively less active compared to the esters of cinnamic acid, achieving MIC values between 67 µM and 2.3 mM against A. niger, and between 10 µM and 1.1 mM against C. albicans [111] (Table 2). The most active ester of 4-coumaric acid was 4-nitrophenyl 4-coumarate (60) showing MIC values of 46 µM against B. subtilis, C. albicans, E. coli and S. aureus [111]. The ester ethyl 4-methoxycinnamate, isolated from the plant Kaempferia galanga, showed anti-TB activity (MIC = 485 µM) against the virulent H37Rv and drug-resistant strains [112]. The esters of caffeic acid 62–67 were not assayed against different microorganisms, but only against some fungal species. Methyl caffeate (62) showed little antimicrobial activity against Aspergillus species with MIC values higher than 1.3 mM [65], however it was more active against C. albicans (MIC50 = 659 µM) [77,78]. Minimum inhibitory concentration values of natural and synthetic cinnamic esters 25–77. The esters of caffeic acid showed moderate activity against C. albicans, and the most active was (5-nitrofuran-2-yl)methyl caffeate (67) with an MIC50 value of 52 µM against C. albicans [77,78]. The esters of ferulic acid 68–77 have been evaluated against different bacteria and fungi, and comparatively they have lower growth inhibitory activity compared to cinnamate and 4-coumarate esters. The MIC values of the ferulate esters 68–77 ranged between 201 µM and >10 mM against C. albicans, and between <25 µM and 6.0 mM against S. aureus [80,81]. The most active ferulate ester was identified to be 4-chloro-3-methylphenyl ferulate (75) achieving MIC values of 201 µM against C. albicans and C. krusei, of 50 µM against E. faecalis, 812 µM against E. coli, 401 µM against K. pneumoniae, and <25 µM against S. aureus [81].

3.2. Amides

The simplest cinnamic amide is cinnamide (78) (Figure 5 and Table 3) which displayed growth inhibition against both fungi A. niger and C. albicans at a concentration of 60.8 µM, while being less active against bacteria, showing an MIC value of 252 µM against B. subtilis, E. coli and S. aureus [44]. All the cinnamoyl amides 79–94 were found to have a more potent effect against fungi compared to bacteria, except cinnamoyl dopamine (94) which showed little antimicrobial activity (MIC = 1.76 mM) [77]. Among the screened cinnamoyl amides, the compound with the highest antifungal activity was identified to be cinnamoyl N,N-diethylamide (84) achieving MIC values of 14.3 and 36.3 µM against A. niger and C. albicans respectively [44]. The most potent antibacterial cinnamoyl amide was cinnamoyl 2-methylphenylamine (90) with MIC values of 114, 139 and 139 µM against B. subtilis, E. coli and S. aureus respectively.
Figure 5

Chemical structures of the cinnamic amides 78–131 with antimicrobial activity

Table 3

Minimum inhibitory concentration values of cinnamic amides 78–131.

CompoundMicroorganism StrainMICRefs.
Cinnamide (78)Aspergillus niger60.8 µM[44]
Bacillus subtilis252 µM[44]
Candida albicans60.8 µM[44]
Escherichia coli252 µM[44]
Staphylococcus aureus252 µM[44]
Cinnamoyl isopropylamine (79)Aspergillus niger60.8 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans50.4 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus252 µM[44]
Cinnamoyl butylamine (80)Aspergillus niger43.5 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans43.5 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus164 µM[44]
Cinnamoyl morpholine (81)Aspergillus niger60.8 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans60.8 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus203 µM[44]
Cinnamoyl piperidine (82)Aspergillus niger43.5 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans50.4 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus139 µM[44]
Cinnamoyl N,N-dimethylamine (83)Aspergillus niger50.4 µM[44]
Bacillus subtilis139 µM[44]
Candida albicans43.5 µM[44]
Escherichia coli139 µM[44]
Staphylococcus aureus139 µM[44]
Cinnamoyl N,N-diethylamine (84)Aspergillus niger14.3 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans36.3 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus252 µM[44]
Cinnamoyl N,N-diethanolamine (85)Aspergillus niger60.8 µM[44]
Bacillus subtilis301 µM[44]
Candida albicans86 µM[44]
Escherichia coli301 µM[44]
Staphylococcus aureus301 µM[44]
Cinnamoyl phenylamine (86)Aspergillus niger73.6 µM[44]
Bacillus subtilis301 µM[44]
Candida albicans86 µM[44]
Escherichia coli301 µM[44]
Staphylococcus aureus203 µM[44]
Cinnamoyl 2-chlorophenylamine (87)Aspergillus niger50.4 µM[44]
Bacillus subtilis301 µM[44]
Candida albicans60.8 µM[44]
Escherichia coli301 µM[44]
Staphylococcus aureus301 µM[44]
Cinnamoyl 3-chlorophenylamine (88)Aspergillus niger43.5 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans60.8 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus203 µM[44]
Cinnamoyl 4-chlorophenylamine (89)Aspergillus niger50.4 µM[44]
Bacillus subtilis301 µM[44]
Candida albicans60.8 µM[44]
Escherichia coli301 µM[44]
Staphylococcus aureus301 µM[44]
Cinnamoyl 2-methylphenylamine (90)Aspergillus niger73.6 µM[44]
Bacillus subtilis114 µM[44]
Candida albicans86 µM[44]
Escherichia coli139 µM[44]
Staphylococcus aureus139 µM[44]
Cinnamoyl 4-methoxyphenylamine (91)Aspergillus niger50.4 µM[44]
Bacillus subtilis203 µM[44]
Candida albicans50.4 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus164 µM[44]
Cinnamoyl 2-nitrophenylamine (92)Aspergillus niger86 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans73.6 µM[44]
Escherichia coli203 µM[44]
Staphylococcus aureus139 µM[44]
Cinnamoyl 2,4-dinitrophenylamine (93)Aspergillus niger50.4 µM[44]
Bacillus subtilis164 µM[44]
Candida albicans86 µM[44]
Escherichia coli164 µM[44]
Staphylococcus aureus164 µM[44]
Cinnamoyl dopamine (94)Bacillus subtilis 1A951.76 mM[77]
Candida albicans 621.76 mM[77]
Listeria monocytogenes C121.76 mM[77]
Staphylococcus aureus 2091.76 mM[77]
Streptococcus pyogenes 10535441 µM[77]
4-coumaroyl hexanamine (95)Aspergillus niger MTCC 818972.5 µM[111]
Bacillus subtilis MTCC 20639.1 µM[111]
Candida albicans MTCC 22772.5 µM[111]
Escherichia coli MTCC 165272.5 µM[111]
Staphylococcus aureus MTCC 290172.5 µM[111]
4-coumaroyl 2-naphtylamine (96)Aspergillus niger MTCC 8189558 µM[111]
Bacillus subtilis MTCC 206346.2 µM[111]
Candida albicans MTCC 22715.5 mM[111]
Escherichia coli MTCC 165246.2 µM[111]
Staphylococcus aureus MTCC 29015.9 µM[111]
4-coumaroyl morpholine (97)Aspergillus niger MTCC 81891.4 mM[111]
Bacillus subtilis MTCC 206391.6 µM[111]
Candida albicans MTCC 22791.6 µM[111]
Escherichia coli MTCC 165291.6 µM[111]
Staphylococcus aureus MTCC 29011.4 mM[111]
4-coumaroyl N,N-dimethylamine (98)Aspergillus niger MTCC 8189191 µM[111]
Bacillus subtilis MTCC 2063191 µM[111]
Candida albicans MTCC 227191 µM[111]
Escherichia coli MTCC 16523.6 mM[111]
Staphylococcus aureus MTCC 29013.6 mM[111]
4-coumaroyl N,N-dibutylamine (99)Aspergillus niger MTCC 8189676 µM[111]
Bacillus subtilis MTCC 206353.6 µM[111]
Candida albicans MTCC 22753.6 µM[111]
Escherichia coli MTCC 1652676 µM[111]
Staphylococcus aureus MTCC 290153.6 µM[111]
4-coumaroyl N,N-diphenylamine (100)Aspergillus niger MTCC 8189386 µM[111]
Bacillus subtilis MTCC 20635.0 µM[111]
Candida albicans MTCC 22734.6 µM[111]
Escherichia coli MTCC 16525.0 µM[111]
Staphylococcus aureus MTCC 290134.6 µM[111]
4-coumaroyl N,N-diethanolamine (101)Aspergillus niger MTCC 818972.5 µM[111]
Bacillus subtilis MTCC 20639.1 µM[111]
Candida albicans MTCC 22772.5 µM[111]
Escherichia coli MTCC 165272.5 µM[111]
Staphylococcus aureus MTCC 290172.5 µM[111]
4-coumaroyl phenylamine (102)Aspergillus niger MTCC 81891.2 mM[111]
Bacillus subtilis MTCC 206384.7 µM[111]
Candida albicans MTCC 22784.7 µM[111]
Escherichia coli MTCC 165284.7 µM[111]
Staphylococcus aureus MTCC 290110.3 µM[111]
4-coumaroyl 2'-nitrophenylamine (103)Aspergillus niger MTCC 818946.2 µM[111]
Bacillus subtilis MTCC 206346.2 µM[111]
Candida albicans MTCC 2276.3 µM[111]
Escherichia coli MTCC 165246.2 µM[111]
Staphylococcus aureus MTCC 290146.2 µM[111]
4-coumaroyl 3'-chlorophenylamine (104)Aspergillus niger MTCC 8189676 µM[111]
Bacillus subtilis MTCC 20637.1 µM[111]
Candida albicans MTCC 22753.6 µM[111]
Escherichia coli MTCC 165253.6 µM[111]
Staphylococcus aureus MTCC 29017.1 µM[111]
4-coumaroyl 4'-chlorophenylamine (105)Aspergillus niger MTCC 8189676 µM[111]
Bacillus subtilis MTCC 20637.1 µM[111]
Candida albicans MTCC 22753.6 µM[111]
Escherichia coli MTCC 165253.6 µM[111]
Staphylococcus aureus MTCC 290153.6 µM[111]
4-coumaroyl 3'-nitrophenylamine (106)Aspergillus niger MTCC 818946.2 µM[111]
Bacillus subtilis MTCC 206346.2 µM[111]
Candida albicans MTCC 22746.2 µM[111]
Escherichia coli MTCC 1652558 µM[111]
Staphylococcus aureus MTCC 290146.2 µM[111]
4-coumaroyl 4'-nitrophenylamine (107)Aspergillus niger MTCC 818918 mM[111]
Bacillus subtilis MTCC 206346.2 µM[111]
Candida albicans MTCC 22746.2 µM[111]
Escherichia coli MTCC 165246.2 µM[111]
Staphylococcus aureus MTCC 290146.2 µM[111]
4-coumaroyl 2'-aminophenylamine (108)Aspergillus niger MTCC 8189905 µM[111]
Bacillus subtilis MTCC 206367.2 µM[111]
Candida albicans MTCC 22767.2 µM[111]
Escherichia coli MTCC 165267.2 µM[111]
Staphylococcus aureus MTCC 290167.2 µM[111]
4-coumaroyl 2'-methoxyphenylamine (109)Aspergillus niger MTCC 8189744 µM[111]
Bacillus subtilis MTCC 20637.5 µM[111]
Candida albicans MTCC 22757.7 µM[111]
Escherichia coli MTCC 165257.7 µM[111]
Staphylococcus aureus MTCC 290157.7 µM[111]
4-coumaroyl 3',4'-dichlorophenylamine (110)Aspergillus niger MTCC 8189422 µM[111]
Bacillus subtilis MTCC 206337.1 µM[111]
Candida albicans MTCC 22737.1 µM[111]
Escherichia coli MTCC 165237.1 µM[111]
Staphylococcus aureus MTCC 290137.1 µM[111]
4-coumaroyl 2'-chloro-4'-nitrophenylamine (111)Aspergillus niger MTCC 8189352 µM[111]
Bacillus subtilis MTCC 2063929 nM[111]
Candida albicans MTCC 22732.2 µM[111]
Escherichia coli MTCC 165232.2 µM[111]
Staphylococcus aureus MTCC 2901352 µM[111]
4-coumaroyl 3'-chloro-4'-nitrophenylamine (112)Aspergillus niger MTCC 818932.2 µM[111]
Bacillus subtilis MTCC 20634.7 µM[111]
Candida albicans MTCC 22732.2 µM[111]
Escherichia coli MTCC 16524.7 µM[111]
Staphylococcus aureus MTCC 290132.2 µM[111]
4-coumaroyl 2'-methyl-5'-nitrophenylamine (113)Aspergillus niger MTCC 818939.9 µM[111]
Bacillus subtilis MTCC 206339.9 µM[111]
Candida albicans MTCC 22739.9 µM[111]
Escherichia coli MTCC 1652463 µM[111]
Staphylococcus aureus MTCC 290139.9 µM[111]
4-coumaroyl 2',4'-dimethylphenylamine (114)Aspergillus niger MTCC 8189744 µM[111]
Bacillus subtilis MTCC 20637.55 µM[111]
Candida albicans MTCC 22757.7 µM[111]
Escherichia coli MTCC 1652744 µM[111]
Staphylococcus aureus MTCC 290157.7 µM[111]
4-coumaroyl dopamine (115)Bacillus subtilis 1A951.67 mM[77]
Candida albicans 621.67 mM[77]
Listeria monocytogenes C121.67 mM[77]
Staphylococcus aureus 209418 µM[77]
Streptococcus pyogenes 10535418 µM[77]
Caffeoyl phenylethylamine (116)Bacillus subtilis 1A951.76 mM[77]
Candida albicans 62882 µM[77]
Listeria monocytogenes C12441 µM[77]
Staphylococcus aureus 209882 µM[77]
Streptococcus pyogenes 10535882 µM[77]
Caffeoyl dopamine (117)Bacillus subtilis 1A95793 µM[77]
Candida albicans 62396 µM[77]
Listeria monocytogenes C12793 µM[77]
Staphylococcus aureus 209793 µM[77]
Streptococcus pyogenes 10535793 µM[77]
Caffeoyl tyramine (118)Bacillus subtilis 1A95836 µM[77]
Candida albicans 62418 µM[77]
Listeria monocytogenes C12836 µM[77]
Staphylococcus aureus 209836 µM[77]
Streptococcus pyogenes 10535836 µM[77]
Caffeoyl tryptamine (119)Bacillus subtilis 1A951.55 mM[77]
Candida albicans 621.55 mM[77]
Listeria monocytogenes C121.55 mM[77]
Staphylococcus aureus 209388 µM[77]
Streptococcus pyogenes 10535194 µM[77]
Feruloyl dopamine (120)Bacillus subtilis 1A95759 µM[77]
Candida albicans 621.52 mM[77]
Listeria monocytogenes C121.52 mM[77]
Staphylococcus aureus 209190 µM[77]
Streptococcus pyogenes 10535380 µM[77]
Feruloyl tyramine (121)Bacillus subtilis 1A95798 µM[77]
Candida albicans 621.59 mM[77]
Listeria monocytogenes C121.59 mM[77]
Staphylococcus aureus 209199 µM[77]
Streptococcus pyogenes 10535399 µM[77]
Feruloyl tryptamine (122)Bacillus subtilis 1A95743 µM[77]
Candida albicans 621.49 mM[77]
Listeria monocytogenes C121.49 mM[77]
Staphylococcus aureus 209372 µM[77]
Streptococcus pyogenes 10535372 µM[77]
Sinapoyl phenylethylamine (123)Bacillus subtilis 1A951.53 mM[77]
Candida albicans 621.53 mM[77]
Listeria monocytogenes C121.53 mM[77]
Staphylococcus aureus 209382 µM[77]
Streptococcus pyogenes 10535382 µM[77]
Sinapoyl dopamine (124)Bacillus subtilis 1A951.39 mM[77]
Candida albicans 621.39 mM[77]
Listeria monocytogenes C121.39 mM[77]
Staphylococcus aureus 209696 µM[77]
Streptococcus pyogenes 10535696 µM[77]
Sinapoyl tyramine (125)Bacillus subtilis 1A951.46 mM[77]
Candida albicans 621.46 mM[77]
Listeria monocytogenes C121.46 mM[77]
Staphylococcus aureus 209182 µM[77]
Streptococcus pyogenes 10535182 µM[77]
Sinapoyl tryptamine (126)Bacillus subtilis 1A951.36 mM[77]
Candida albicans 621.36 mM[77]
Listeria monocytogenes C121.36 mM[77]
Staphylococcus aureus 209682 µM[77]
Streptococcus pyogenes 10535171 µM[77]
3',4',5'-trimethoxycinnamoyl pyrrolidine (127)Mycobacterium tuberculosis H37Ra600 µM[118]
Toussaintine A (128)Escherichia coli DSM 110334 µM[119]
Staphylococcus aureus ATCC 25923>136 µM[119]
Toussaintine B (129)Escherichia coli DSM 110367 µM[119]
Staphylococcus aureus ATCC 2592367 µM[119]
Toussaintine C (130)Escherichia coli DSM 110334 µM[119]
Staphylococcus aureus ATCC 25923>136 µM[119]
Toussaintine D (131)Escherichia coli DSM 1103>136 µM[119]
Staphylococcus aureus ATCC 2592317 µM[119]
Chemical structures of the cinnamic amides 78–131 with antimicrobial activity The 4-coumaroyl amides 95–115 were tested for antimicrobial activity, and the MIC results suggest that they are comparatively more active inhibitors of microbial growth than the cinnamoyl amides (Table 3). The 4-coumaroyl amides do not show a higher specificity for fungi compared to bacteria as was observed for the cinnamoyl amides. The MIC values of the 4-coumaroyl amides 95–115 ranged between 929 nM and 3.6 mM against bacteria, and between 6.3 µM and 18 mM against fungal species [77,111]. The 4-coumaroyl amide displaying the lowest MIC value against bacteria, was found to be 4-coumaroyl 2'-chloro-4'-nitrophenylamine (111) achieving an MIC value of 929 nM against B. subtilis MTCC 2063 [111], while the lowest MIC value against fungi was 6.3 µM attained by 4-coumaroyl 2'-nitrophenylamine (103) against C. albicans MTCC 227 [111]. Most of the 4-coumaroyl amides displayed higher activity against B. subtilis and S. aureus bacteria compared to E. coli (Table 3). The caffeoyl amides 116–119 (Figure 5) showed moderate antimicrobial activity (Table 3) with MIC values ranging between 194 µM and 1.76 mM [77]. The lowest MIC value (194 µM) was reported for caffeoyl tryptamine (119) against S. pyogenes 10535, however the MIC values for the same amide against other bacteria were comparatively higher, being 1.55 mM against B. subtilis 1A95, C. albicans 62 and L. monocytogenes C12 [77]. The amides caffeoyl dopamine (117) and caffeoyl tyramine (118) showed growth inhibition against Gram-positive, Gram-negative and fungal species with MIC values between 396 and 793 µM, and 418 and 836 µM respectively, whereas the other caffeoyl amides displayed MIC values higher than 1.0 mM against at least one microorganism (Table 3). The three evaluated feruloyl amides 120–122 showed a very similar pattern of antimicrobial activity [77]. The feruloyl amides showed to be growth inhibitors of S. aureus 209 with MIC values between 190 and 372 µM. They were equally active against S. pyogenes but much less against B. subtilis (MIC around 743–798 µM), and C. albicans and L. monocytogenes. Interestingly all the sinapoyl amides 123–126 showed selective growth inhibition of Gram-positive cocci bacteria (MIC between 171 and 696 µM), while being much less effective inhibitors of B. subtilis, L. monocytogenes or C. albicans (MIC between 1.36 and 1.53 mM) [77]. The Piper amides, which are one of the major phytochemicals present in the medicinally important Piper species displayed a broad variety of biological activities [113]. The carboxylic acid residues of some Piper amides are in fact substituted cinnamic acids. Piplartine (Figure 1), originally isolated from the roots of Piper tuberculatum [18], demonstrated antibacterial activity against K. pneumoniae, P. aeruginosa and S. aureus, however no MIC values were reported [114]. Among the amides isolated from the seeds of Piper tuberculatum, piplartine showed antifungal activity against Cladosporium sphaerospermun but no MIC value was determined [115,116]. The amide 3',4',5'-trimethoxycinnamoyl pyrrolidine (127), which is related to piplartine, was isolated from Piper sarmentosum, and showed MIC values higher than 600 µM against M. tuberculosis H37Ra [117,118]. The toussaintines are amides of cinnamic acid with indolidinones or benzofuranones, obtained from the African plant Toussaintia orientalis [119]. The toussaintine B (129) inhibited both S. aureus and E. coli with a low MIC value of 67 µM, while toussaintine A (128) inhibited E. coli at 34 µM but did not inhibit S. aureus, and toussaintine D (131) inhibited S. aureus at 17 µM but did not inhibit E. coli [119]. Reports of natural cinnamic amides displaying antimicrobial activity were very scarce in the literature. Minimum inhibitory concentration values of cinnamic amides 78–131.

4. Natural and Synthetic Cinnamic Aldehydes and Alcohols

Cinnamaldehyde (132) (Figure 6, Table 4) which is abundantly obtained from the essential oils of cinnamon [12,120], has demonstrated a significant antimicrobial activity particularly against Gram-negative bacteria. The aldehyde was found to be very active against Helicobacter pylori and E. coli with MIC values of 15 and 7.6 µM respectively [121]. Similar MIC values of 10.6 µM and < 1.5 µM have been reported against P. aeruginosa and E. coli respectively [122]. However controversial results have appeared for this compound, as other reports published higher MIC values against E. coli [12,123,124,125]. Against the Clostridium difficile bacteria, the aldehyde showed complete growth inhibition at a concentration of 605 µM [13]. A similar MIC value was observed against Legionella pneumophila, the causative bacteria of Legionnaire’s disease [126]. Cinnamaldehyde has also found to be more active against S. aureus than Gram-negative bacteria [124], and interestingly the MIC values against a susceptible S. aureus and a methicillin-resistant S. aureus (MRSA) were exactly the same. The antibiotic clindamycin actually was found to be synergistic with cinnamaldehyde, with a FICI value of 0.3125 [124]. In addition, cinnamaldehyde showed interaction with the FtsZ cell division protein using isothermal titration calorimetry, and inhibited the formation of FtsZ assembly in a dose-dependent manner, which phenotypically translated into elongated cells [124]. A report from 2003, showed that cinnamic aldehyde prevented Bacillus cereus daughter cells separation during division, forming filamentous cells [127], a result correlating with inhibition of FtsZ. Against S. aureus clinical isolates the reported MIC values were 5.0 and 10 mM, however cinnamaldehyde was found to inhibit biofilm formation at concentration five times higher than the MIC [128]. Cinnamaldehyde (25) showed an MIC value of 358 µM against Fusarium verticillioides, the phytopathogenic fungi infecting maize that can also produce mycotoxins during the storage of grains [129]. Treatment of F. verticillioides with the aldehyde produced morphological alterations of the hyphae and the cell wall, which resulted in cytoplasmic leakage. Cinnamaldehyde showed weak antifungal activity against C. albicans and Candida tropicalis with MIC values of 3.0 and 3.8 mM respectively [130], however lower MIC values have been reported [131,132]. Against wood decay fungi, Laetiporus betulina and Laetiporus sulphureus the potency was comparable, with MIC values around 750 µM [133,134].
Figure 6

Chemical structures of the cinnamic aldehydes, alcohols and related natural products.

Table 4

Minimum inhibitory concentration values of cinnamic aldehydes, alcohols and their derivatives (132–151).

CompoundMicroorganism StrainMICRefs.
Cinnamaldehyde (132)Aspergillus niger MTCC 4041.89 mM[139]
Aspergillus sydowii MTCC 43353.78 mM[139]
Aspergillus parasiticus MTCC 27973.78 mM[139]
Bacillus cereus ATCC 117783.2 mM[127]
Bacillus subtilis7.6 mM[124]
Bacillus subtilis MTCC 1211.89 mM[139]
Burkholderia cepacea MTCC 4381.89 mM[139]
Candida albicans ATCC 20911.1 mM[131]
Candida albicans ATCC 90028459 µM[132]
Candida albicans MTCC 3017470 µM[139]
Candida albicans STD-11413.0 mM[130]
Candida tropicalis STD-11183.8 mM[130]
Clostridium difficile PHTCC 107605 µM[13]
Enterobacter cloacae MTCC 5091.89 mM[139]
Enterococcus faecalis1.89 mM[12]
Escherichia coli3.78 mM[124]
Escherichia coli3.78 mM[12]
Escherichia coli ATCC 111053.78 mM[125]
Escherichia coli CGMCC 1.4872.0 mM[123]
Escherichia coli MTCC 431.89 mM[139]
Escherichia coli NCIM-20897.6 µM[121]
Escherichia coli NTCT 8196< 1.5 µM[122]
Escherichia coli O157:H71.89 mM[125]
Fusarium verticillioides358 µM[129]
Gloeophyllum trabeum BCRC 316142.3 mM[134]
Helicobacter pylori ATCC 2669515 µM[121]
Issatchenkia orientalis MTCC 231470 µM[139]
Klebsiella pneumoniae MTCC 1093.78 mM[139]
Laetiporus betulina750 µM[133]
Legionella pneumophila JCM 7571620 µM[126]
Lenzites betulina BCRC 35296757 µM[134]
Laetiporus sulphureus700 µM[133]
Laetiporus sulphurous BCRC 35305757 µM[134]
Malassezia furfur IP305757 µM[131]
Micrococcus luteus MTCC 24703.78 mM[139]
Pseudomonas aeruginosa7.57 mM[12]
Pseudomonas aeruginosa MTCC 4241.89 mM[139]
Pseudomonas aeruginosa NCTC 902710.6 µM[122]
Sclerotinia sclerotiorum1.94 mM[146]
Staphylococcus aureus1.89 mM[12]
Staphylococcus aureus MTCC 1211.89 mM[139]
Methicillin-resistant Staphylococcus aureus1.89 mM[124]
Tametes versicolor BCRC 352532.3 mM[134]
Trychophyton rubrum MTCC 296470 µM[139]
Caffeic aldehyde (133)Mycobacterium tuberculosis H37Rv154 µM[135]
Coniferaldehyde (134)Streptococcus mitis ATCC 49456T351 µM[137]
Streptococcus mutans DMST 260951.4 mM[137]
Streptococcus pyogenes DMST 17020351 µM[137]
Sinapaldehyde (135)Streptococcus mitis ATCC 49456T601 µM[137]
Streptococcus mutans DMST 26095601 µM[137]
Streptococcus pyogenes DMST 17020150 µM[137]
2-Methoxycinnamaldehyde (136)Aspergillus fumigatus Kuboyama617 µM[138]
Aspergillus niger stA-21.2 mM[138]
Candida albicans stT-1308 µM[138]
Cryptococcus neoformans stY-877 µM[138]
Escherichia coli E-2602>1.2 mM[138]
Microsporum canis stT-619 µM[138]
Salmonella typhimurium 75-276>1.2 mM[138]
Staphylococcus aureus 209P1.2 mM[138]
4-Methoxycinnamaldehyde (137)Aspergillus niger MTCC 4043.08 mM[139]
Aspergillus sydowii MTCC 43353.08 mM[139]
Aspergillus parasiticus MTCC 27973.08 mM[139]
Bacillus subtilis MTCC 1216.16 mM[139]
Candida albicans MTCC 3017770 µM[139]
Enterobacter cloacae MTCC 5093.08 mM[139]
Escherichia coli MTCC 433.08 mM[139]
Issatchenkia orientalis MTCC 231770 µM[139]
Klebsiella pneumoniae MTCC 1093.08 mM[139]
Micrococcus luteus MTCC 24703.08 mM[139]
Pseudomonas aeruginosa MTCC 424770 µM[139]
Staphylococcus aureus MTCC 1213.08 mM[139]
Trychophyton rubrum MTCC 296770 µM[139]
3,4-dimethoxy-cinnamaldehyde (138)Aspergillus niger MTCC 4045.20 mM[139]
Aspergillus sydowii MTCC 43355.20 mM[139]
Aspergillus parasiticus MTCC 27972.60 mM[139]
Bacillus subtilis MTCC 1215.20 mM[139]
Burkholderia cepacea MTCC 4385.20 mM[139]
Candida albicans MTCC 30172.60 mM[139]
Enterobacter cloacae MTCC 50910.4 mM[139]
Escherichia coli MTCC 4310.4 mM[139]
Issatchenkia orientalis MTCC 2312.60 mM[139]
Klebsiella pneumoniae MTCC 10910.4 mM[139]
Micrococcus luteus MTCC 24702.60 mM[139]
Pseudomonas aeruginosa MTCC 4242.60 mM[139]
Staphylococcus aureus MTCC 1215.20 mM[139]
Trychophyton rubrum MTCC 296160 µM[139]
3,4,6-trimethoxy-cinnamaldehyde (139)Aspergillus sydowii MTCC 43354.50 mM[139]
Candida albicans MTCC 30178.99 mM[139]
Issatchenkia orientalis MTCC 2318.99 mM[139]
Micrococcus luteus MTCC 24702.25 mM[139]
Trychophyton rubrum MTCC 296280 µM[139]
3,4-methylenedioxy-cinnamaldehyde (140)Aspergillus niger MTCC 4041.42 mM[139]
Aspergillus sydowii MTCC 4335350 µM[139]
Aspergillus parasiticus MTCC 2797710 µM[139]
Bacillus subtilis MTCC 1212.84 mM[139]
Burkholderia cepacea MTCC 438710 µM[139]
Candida albicans MTCC 3017350 µM[139]
Enterobacter cloacae MTCC 5091.42 mM[139]
Escherichia coli MTCC 432.84 mM[139]
Issatchenkia orientalis MTCC 231350 µM[139]
Klebsiella pneumoniae MTCC 1091.42 mM[139]
Micrococcus luteus MTCC 24702.84 mM[139]
Pseudomonas aeruginosa MTCC 424350 µM[139]
Staphylococcus aureus MTCC 1212.84 mM[139]
Trychophyton rubrum MTCC 29640 µM[139]
3-methoxy-4-ethoxy-cinnamaldehyde (141)Aspergillus niger MTCC 4044.85 mM[139]
Aspergillus sydowii MTCC 43354.85 mM[139]
Aspergillus parasiticus MTCC 27972.42 mM[139]
Bacillus subtilis MTCC 1214.85 mM[139]
Burkholderia cepacea MTCC 4384.85 mM[139]
Candida albicans MTCC 30172.42 mM[139]
Enterobacter cloacae MTCC 5099.70 mM[139]
Escherichia coli MTCC 439.70 mM[139]
Issatchenkia orientalis MTCC 2314.85 mM[139]
Klebsiella pneumoniae MTCC 1099.70 mM[139]
Micrococcus luteus MTCC 24704.85 mM[139]
Pseudomonas aeruginosa MTCC 4244.85 mM[139]
Staphylococcus aureus MTCC 1212.42 mM[139]
Trychophyton rubrum MTCC 296600 µM[139]
2-bromo-3,4-dimethoxy-cinnamaldehyde (142)Trychophyton rubrum MTCC 296460 µM[139]
N,N-dimethyl-4-amino-cinnamaldehyde (143)Enterobacter cloacae MTCC 50911.4 mM[139]
Micrococcus luteus MTCC 247011.4 mM[139]
Trychophyton rubrum MTCC 296180 µM[139]
2-nitro-4-methyl-cinnamaldehyde (144)Bacillus subtilis MTCC 1212.61 mM[139]
Burkholderia cepacea MTCC 4382.61 mM[139]
Enterobacter cloacae MTCC 50910.5 mM[139]
Escherichia coli MTCC 432.61 mM[139]
Klebsiella pneumoniae MTCC 10910.5 mM[139]
Micrococcus luteus MTCC 24702.61 mM[139]
Pseudomonas aeruginosa MTCC 4242.61 mM[139]
Staphylococcus aureus MTCC 12110.5 mM[139]
Trychophyton rubrum MTCC 296160 µM[139]
Cinnamyl alcohol (145)Aspergillus niger 1017 mM[143]
Aspergillus oryzae 1028 mM[143]
Bacillus subtilis IFO 1372110 mM[143]
Candida albicans IFO 05977 mM[143]
Epidermophyton floccosum IFO 90453 mM[143]
Escherichia coli7.5 mM[12]
Escherichia coli IFO 35459 mM[143]
Enterococcus faecalis7.5 mM[12]
Klebsiella pneumonia IFO 1354110 mM[143]
Legionella pneumophila JCM 75717.6 mM[126]
Pseudomonas aeruginosa7.5 mM[12]
Rhizopus sp. 1033 mM[143]
Saccharomyces cerevisiae Kyokai no. 88 mM[143]
Staphylococcus aureus3.7 mM[12]
Trichophyton rubrum IFO 91854 mM[143]
Trichophyton violaceum IFO 310644 mM[143]
4-Coumaryl alcohol (146)Bacillus subtilis 86498.0 mM[68]
Escherichia coli 12210>8.0 mM[68]
Pseudomonas syringae 649>8.0 mM[68]
Saccharomyces cerevisiae 019391>8.0 mM[68]
Schizosaccharomyces pombe 039917>8.0 mM[68]
Sporobolomyces roseus 0435298.0 mM[68]
Coniferyl alcohol (147)Bacillus subtilis 8649>8.0 mM[68]
Escherichia coli 12210>8.0 mM[68]
Pseudomonas syringae 649>8.0 mM[68]
Saccharomyces cerevisiae 019391>8.0 mM[68]
Schizosaccharomyces pombe 039917>8.0 mM[68]
Sporobolomyces roseus 043529>8.0 mM[68]
Sinapyl alcohol (148)Bacillus subtilis 8649>8.0 mM[68]
Escherichia coli 12210>8.0 mM[68]
Pseudomonas syringae 649>8.0 mM[68]
Saccharomyces cerevisiae 019391>8.0 mM[68]
Schizosaccharomyces pombe 039917>8.0 mM[68]
Sporobolomyces roseus 043529>8.0 mM[68]
Cinnamyl benzoate (149)Aspergillus niger 101>10 mM[143]
Aspergillus oryzae 102>10 mM[143]
Bacillus subtilis IFO 13721>10 mM[143]
Candida albicans IFO 0597>10 mM[143]
Epidermophyton floccosum IFO 904520 µM[143]
Escherichia coli IFO 3545>10 mM[143]
Klebsiella pneumoniae IFO 13541>10 mM[143]
Rhizopus sp. 103>10 mM[143]
Saccharomyces cerevisiae Kyokai no. 8>10 mM[143]
Trichophyton rubrum IFO 918520 µM[143]
Trichophyton violaceum IFO 3106420 µM[143]
4-coumaryl acetate (150)Candida albicans ATCC 102315.2 mM[144]
Microsporum canis ATCC 3629910.4 mM[144]
Staphylococcus aureus ATCC 259236.5 mM[144]
Staphylococcus aureus VISA 24203 µM[144]
Tricophyton rubrum ATCC 2818810.4 mM[144]
4-coumaryl diacetate (151)Candida albicans ATCC 102312.7 mM[144]
Microsporum canis ATCC 362992.7 mM[144]
Mycobacterium smegmatis mc2 155215 µM[145]
Staphylococcus aureus ATCC 259232.7 mM[144]
Staphylococcus aureus VISA 24672 µM[144]
Tricophyton rubrum ATCC 281882.7 mM[144]
From the medicinal plant Piper taiwanense, caffeic aldehyde (133) (Figure 6) was isolated and found to have significant antitubercular properties (MICH37Rv = 154 µM) [135]. The other natural brothers of cinnamaldehyde, coniferaldehyde (134) and sinapaldehyde (135) displayed moderate anticandidal activity [136]. More than 60 strains and clinical Candida isolates were evaluated for their susceptibility to the three aldehydes. Sinapaldehyde was found to exert the most potent effect with a MIC values between 480 and 960 µM, while the MIC value of coniferaldehyde and cinnamaldehyde varied between 914 µM and 1.83 mM, and between 1.14 and 3.78 mM respectively [136]. Phenotypic characterization of C. albicans treated with sub-inhibitory concentrations of the aldehydes showed alterations in cell morphology and the cell wall, as well as damage to the plasma membrane resulting in cell lysis and cytoplasmic leakage. The study suggested inhibition of membrane ATPases, by examination of H+ efflux rates in presence of the aldehydes and known ATPase inhibitors [136]. Both coniferaldehyde (134) and sinapaldehyde (135) showed growth inhibitory properties against three species of Streptococcus with MIC ranging from 150 µM to 1.4 mM, being 135 more active against S. pyogenes and S. mutans, while 134 was more active against S. mitis [137]. Interestingly the most active antifungal compound present in cinnamon was identified to be 2-methoxycinnamaldehyde (136), achieving MIC values as low as 19 µM against Microsporum canis [138], a fungi causing ringworms in pets and tinea capitis in humans. This aldehyde was also active against other fungi including C. albicans, with an MIC value of 308 µM, but was however less active against A. niger and different species of bacteria [138]. The positional isomer 4-methoxycinnamaldehyde (137) was less active with MIC values of 770 µM against C. albicans MTCC 3017, Issatchenkia orientalis MTCC 231, P. aeruginosa MTCC 424 and Trichophyton rubrum MTCC 296, and higher values (MIC > 3 mM) against other microorganisms [139]. Clearly, as observed for the cinnamic acids, the substitution on position 2 of the cinnamic skeleton, confer an increase in the antimicrobial effect. The presence of another methoxy groups in position 3, did not provide a substantial effect, as 3,4-dimethoxycinnamaldehyde (138) showed MIC values higher than 2.5 mM for all the evaluated microorganisms (Table 4), except against T. rubrum MTCC 296 (MIC = 160 µM) [139]. The aldehyde having three methoxyl groups, 3,4,6-trimethoxycinnamaldehyde (139), showed a similar profile of activity, being a weak growth inhibitor of species of Aspergillus, Candida, Issatchenkia and Micrococcus (MIC > 1.4 mM) but being active against the dermatophyte T. rubrum MTCC 296 with an MIC value of 280 µM [139]. The compound 3,4-methylenedioxycinnamaldehyde (140) showed to be a potent inhibitor of T. rubrum fungi (MIC = 40 µM), with moderate activity against A. sydowii, C. albicans, I. orientalis and P. aeruginosa with an MIC value of 350 µM [139]. The aldehyde was less active against other bacteria and fungi. The replacement of a methoxy group in position 4 of 138 for an ethoxy group, as in 3-methoxy-4-ethoxycinnamaldehyde (141), slightly decreased the MIC values for most of the compounds, however the specificity against T. rubrum and I. orientalis decreased substantially. Introduction of a bromide to 138, as in 2-bromo-3,4-dimethoxycinnamaldehyde (142) decreased the antifungal activity against T. rubrum, increasing the MIC value to 460 µM [139]. The compound N,N-dimethyl-4-aminocinnamaldehyde (143) was the only tested cinnamaldehyde having an amino group, and displayed an MIC of 180 µM against T. rubrum, but was inactive against the bacteria Enterobacter cloacae and Micrococcus luteus (MIC > 11 mM). The cinnamaldehyde having a nitro substituent 2,2-nitro-4-methylcinnamaldehyde (144) showed a similar antimicrobial profile as the other cinnamaldehydes, with a potent growth inhibitory effect against T. rubrum (MIC = 160 µM) but with low activity against several species of bacteria (MIC > 2.5 mM) [139]. Chemical structures of the cinnamic aldehydes, alcohols and related natural products. Cinnamyl alcohol (145) is a component of several essential oils, particularly those of Cinnamomum species and other Lauraceae plants [140,141,142]. Cinnamyl alcohol showed little inhibitory effect against all the evaluated bacterial and fungal species (Table 4) [12,126,143]. The study of Barber et al. published in 2000, reported the antimicrobial activities of 4-coumaryl alcohol (146), coniferyl alcohol (147) and sinapyl alcohol (148) [68]. Comparatively the alcohols were found to be less active than their corresponding aldehydes, showing MIC values equal or higher than 8.0 mM against bacteria and yeasts. Cinnamyl benzoate (149) showed little activity against Gram-negative and Gram-positive bacteria (MIC > 10 mM), however it was higly active against dermatophyte fungi Trycophyton sp. and Epidermophyton floccosum IFO 9045 (MIC = 20 µM) [143]. Two acetate esters of coumaryl alcohol displayed growth inhibition of some fungi and S. aureus [144]. 4-Coumaryl acetate (150) displayed MIC values higher than 5 mM against C. albicans and other fungi, but was however more active against a vancomycin intermediate S. aureus (VISA) with an MIC value of 203 µM [144]. The diester 4-coumaryl diacetate (151) showed higher anti-fungal activity in comparison with 150, and additionally the diacetate demonstrated significant antimycobacterial activity with an MIC value of 215 µM against Mycobacterium smegmatis mc2-155 [145]. Minimum inhibitory concentration values of cinnamic aldehydes, alcohols and their derivatives (132–151).

5. Synthetic Cinnamic Hybrids

The interest in making hybrids molecules result from the idea of combining the biological properties of two active molecules to yield a third molecule (chimera or mermaid) with a stronger effect [147]. The conjugation can be used to modulate selectivity, spectrum of activity, potency, and physicochemical parameters. Theoretically the hybrid molecule once administered to biological systems could be lysed to yield in situ the two active molecules with atomic economy, or the hybrid molecule could be made sterically flexible enough to act on the two domains of the biological targets as a single piece [148]. Several cinnamic hybrids have been prepared [149,150,151,152,153] but only a few of them have been evaluated for their antimicrobial properties. The studied cephem hybrids 152–155 (Figure 6 and Table 5) are cephalosporin moieties linked covalently to a 2,5-dichlorocinnamic (Figure 4). These hybrids showed a potent growth inhibitory effect against Staphylococcus epidermidis A24548, Staphylococcus haemolyticus A21638 and S. pneumoniae A28272 with MIC values in the nanomolar range [154]. The cephem 155 having a cinnamic aldehyde and a 2-hydroxy-3-propylamine N-substitution on the pyridine ring, was the most active against S. epidermidis A24548 (MIC = 22 nM) and S. haemolyticus A21638 (MIC = 87 nM). The oxazolidinone hybrid (156) showed strong antibacterial activity against E. faecalis ATCC 29212 (MIC = 194 nM), Enterococcus faecium ATTC 700221 (MIC = 388 nM) and S. aureus ATCC 29213 (MIC = 194 nM) [155]. Against the methicillin-resistant S. aureus ATCC 33591, the cinnamic hybrid (156) displayed an MIC value of 1.6 µM. A peptide hybrid based on the human cysteine protease inhibitor cystatin C has been prepared and evaluated for its antimicrobial properties [156]. The peptide cystapep 1 (157), having a cinnamic acid residue, showed MIC values of 25.2 µM against S. aureus and Streptococcus pyogenes and slightly higher MIC values against other Streptococcus species. This is the only antimicrobial peptide cinnamic hybrid known so far. The rifamycin hybrid SV (T9) (158) (Figure 6) having a cinnamic acid residue linked through amide bond with the piperazine ring, is slightly more potent than rifampin (MICT9 = 106 nM vs. MICRIF = 243 nM) [157]. The molecule has demonstrated to be useful in clinical application [158]. The MIC values of the hybrid molecule were in the nanomolar range against the pathogenic mycobacteria Mycobacterium avium complex, Mycobacterium leprae and M. tuberculosis [157,159,160]. However the hybrid T9 is not active against rifampin-resistant M. tuberculosis strains.
Table 5

Minimum inhibitory concentration values of cinnamic hybrids (152–184).

CompoundMicroorganism StrainMICRefs.
cephem (152)Streptococcus pneumoniae A28272200 nM[154]
Enterococcus faecalis A206881.6 µM[154]
Staphylococcus aureus MRSA A272233.2 µM[154]
Staphylococcus epidermidis A2454895 nM[154]
Staphylococcus haemolyticus A21638200 nM[154]
cephem (153)Streptococcus pneumoniae A28272760 nM[154]
Enterococcus faecalis A206881.5 µM[154]
Staphylococcus aureus MRSA A272233.0 µM[154]
Staphylococcus epidermidis A2454891 nM[154]
Staphylococcus haemolyticus A21638190 nM[154]
cephem (154)Streptococcus pneumoniae A28272350 nM[154]
Enterococcus faecalis A206881.4 mM[154]
Staphylococcus aureus MRSA A272232.8 mM[154]
Staphylococcus epidermidis A2454842 nM[154]
Staphylococcus haemolyticus A21638175 nM[154]
cephem (155)Streptococcus pneumoniae A28272727 nM[154]
Enterococcus faecalis A20688364 nM[154]
Staphylococcus aureus MRSA A27223364 nM[154]
Staphylococcus epidermidis A2454822 nM[154]
Staphylococcus haemolyticus A2163887 nM[154]
oxazolidinone hybrid (156)Enterococcus faecalis ATCC 29212194 nM[155]
Enterococcus faecium ATTC 700221 (VRE)388 nM[155]
Staphylococcus aureus ATCC 29213194 nM[155]
Staphylococcus aureus ATCC 33591 (MRSA)1.6 µM[155]
cystapep 1 (157)Staphylococcus aureus ATCC 2921325.2 µM[156]
Streptococcus agalactiae NTCC 818150.5 µM[156]
Streptococcus anginosus CCUG 2729850.5 µM[156]
Streptococcus pneumoniae ATCC 4961950.5 µM[156]
Streptococcus pyogenes type M125.2 µM[156]
rifamycin T9 (158)Mycobacterium avium 10115.9 nM[159]
Mycobacterium avium N-260831 nM[157]
Mycobacterium tuberculosis H37Rv31.9 nM[159]
Mycobacterium tuberculosis H37Rv106 nM[157]
Mycobacterium tuberculosis MTB9 (RIF-R)8.5 µM[159]
isoniazid hybrid (159)Mycobacterium tuberculosis H37Rv300 nM[161]
isoniazid hybrid (160)Mycobacterium tuberculosis H37Rv1.1 µM[161]
isoniazid hybrid (161)Mycobacterium tuberculosis H37Rv1.3 µM[161]
isoniazid hybrid (162)Mycobacterium tuberculosis H37Rv2.2 µM[161]
isoniazid hybrid (163)Mycobacterium tuberculosis H37Rv2.3 µM[161]
isoniazid hybrid (164)Mycobacterium tuberculosis H37Rv1.9 µM[161]
cycloserine hybrid (165)Mycobacterium tuberculosis H37Rv950 µM[161]
triazophtalazine hybrid (166)Mycobacterium tuberculosis H37Rv1.4 µM[161]
guanylhydrazone hybrid (167)Mycobacterium tuberculosis H37Rv40.5 µM[164]
guanylhydrazone hybrid (168)Mycobacterium tuberculosis H37Rv8.9 µM[164]
Fenchol hybrid (169)Mycobacterium tuberculosis H37Rv6.7 µM[165]
Fenchol hybrid (170)Mycobacterium tuberculosis H37Rv6.7 µM[165]
Fenchol hybrid (171)Mycobacterium tuberculosis H37Rv2.4 µM[165]
Fenchol hybrid (172)Mycobacterium tuberculosis H37Rv540 nM[165]
oleanolic acid hybrid (173)Mycobacterium tuberculosis H37Rv85.2 µM[166]
oleanolic acid hybrid (174)Mycobacterium tuberculosis H37Rv10.4 µM[166]
oleanolic acid hybrid (175)Mycobacterium tuberculosis H37Rv323 µM[166]
oleanolic acid hybrid (176)Mycobacterium tuberculosis H37Rv19.8 µM[166]
ursolic acid hybrid (177)Mycobacterium tuberculosis H37Rv>341 µM[166]
ursolic acid hybrid (178)Mycobacterium tuberculosis H37Rv10.4 µM[166]
ursolic acid hybrid (179)Mycobacterium tuberculosis H37Rv323 µM[166]
ursolic acid hybrid (180)Mycobacterium tuberculosis H37Rv4.95 µM[166]
betulinic acid hybrid (181)Mycobacterium tuberculosis H37Rv>341 µM[166]
betulinic acid hybrid (182)Mycobacterium tuberculosis H37Rv10.4 µM[166]
betulinic acid hybrid (183)Mycobacterium tuberculosis H37Rv323 µM[166]
betulinic acid hybrid (184)Mycobacterium tuberculosis H37Rv316 µM[166]
Cinnamic acid hybrids have also been prepared with other antitubercular drugs including isoniazid 159–164 and cycloserine (165) (Figure 7).
Figure 7

Chemical structures of the cinnamic hybrids 152–184.

The isoniazid 4-methoxycinnamoyl hybrid (159) was the most active (MIC = 300 nM) among the screened hybrids [161], but was however slightly less active than isoniazid itself (MIC = 182 nM) [162]. The presence of larger substituents on the 4-O-position, decreased anti-TB activity. Among the prepared 4-coumaric hybrids from the same comprehensive study, the cycloserine hybrid 165 displayed an MIC value of 950 µM [161], while the literature MIC value of cycloserine is 245 µM [161,163]. Nonetheless the study identified the triazolophtalazine cinnamic derivative 166 with a significant MIC value of 1.4 µM against the H37Rv strain and a selectivity index around 320 in comparison to THP-1 cells [161]. Guanyl hydrazone hybrids have also been prepared and examined for antimycobacterial activity [164]. Hydroxy substitution of the benzaldehyde hydrazone increased the anti-TB activity, with the hybrid 167 having a hydroxyl in position 4 displaying an MIC value of 40.5 µM against the virulent H37Rv strain [164]. The presence of 3,4-dimethoxy substitution on the benzaldehyde hydrazone, as in the hybrid 168, increased growth inhibition (MIC = 8.9 µM). Thirty-one fenchol hybrids were prepared with different substitutions on the cinnamic ring, and four hybrids 169–172 resulted with potent activity against M. tuberculosis H37Rv [165]. The fenchol hybrids 169 and 170 having respectively a 3,4-methylenedioxy and a 2-nitro substituents (170) on the aryl ring of the cinnamic moiety, displayed an MIC value of 6.7 µM (Table 5). The fenchol hybrid 171 with 3,4,5-trimethoxy substitution on the cinnamic acid showed higher potency (MIC = 2.4 µM), while the hybrid 172 having 4-dimethylamine substitution was the most active (MIC = 540 nM) against the H37Rv pathogenic strain [165]. Chemical structures of the cinnamic hybrids 152–184. Minimum inhibitory concentration values of cinnamic hybrids (152–184). In a study from 2008, three triterpenes, betulinic, oleanolic and ursolic acids, were esterified in the 3-hydroxyl position, with different cinnamic acids with the aim of generating novel molecules which could potentially inhibit the M. tuberculosis H37Rv bacteria [166]. The cinnamic acids employed for the preparation of the esters were cinnamic, 4-coumaric, caffeic and ferulic acids. The esters having the 4-coumaroyl moiety, 3-O-(4'-coumaroyl) oleanolic acid (174), 3-O-(4'-coumaroyl) ursolic acid (178) and 3-O-(4'-coumaroyl) betulinic acid (182) were among the esters with the highest anti-TB activity, achieving MIC values of 10.4 µM. The MIC values of the free triterpenoids were 109 µM for oleanolic and betulinic acids, and 27.4 µM for ursolic acid [166], and therefore conjugation with 4-coumaric acid increased the anti-TB potency. Moreover the ester with the highest activity, 3-O-feruloyl ursolic acid (180), was able to inhibit completely the growth of M. tuberculosis at a concentration of 4.95 µM. The cinnamate and caffeate esters showed moderate to little anti-TB activity, with MIC values higher than those obtained for the free triterpenoids.

6. Conclusions

This review summarizes the in vitro antimicrobial activity of several cinnamic-related molecules by collating the reported MICs in a comprehensive list. Because the MIC data included in this review was extracted from several studies (using different experimental methods), it is far from ideal to compare the MIC as absolute values, but rather the MICs should be used as relative numbers indicating the tendency of the compounds to inhibit certain microorganisms. This review primarily serves as a framework to quickly identify the cinnamic acids and related molecules that have been tested for their antimicrobial properties. Among the cinnamic-related molecules with the highest antimicrobial activity, the hybrids between antibiotics and cinnamic acids, such as the rifamycin T9 (158) and the oxazolidinone 156 with MIC values in the nanomolar range, were the champions. However the activity of these hybrids is mostly due to the potent effect of the antibiotic component. It is unknown whether the conjugates actually hydrolyze in vivo to yield two active molecules with potential synergism, or it is the whole molecule responsible for the observed biological effect. Among the non-hybrid cinnamic-related molecules with the lowest MIC values 4-methoxycinnamic acid (9), 3-nitrocinnamic acid (11), all the caffeoyl quinic acids 25–30, most of the cinnamate and 4-coumarate esters 40–61, and most of the cinnamoyl and 4-coumaroyl amides 78–115 are worth mentioning. A remarkable antimicrobial activity was detected for isobutyl cinnamate (45) achieving a broad spectrum of activity against yeasts, Gram-positive and Gram-negative bacteria, with MIC values between 43 and 12 µM. Further studies need to confirm the potent antimicrobial activity observed, expanding the screening to other microorganisms and drug resistant-isolates, and finally evaluating its toxicity. This example illustrate how a simple substitution, for instance comparing isobutyl cinnamate (45) with butyl cinnamate (44), can have a significant impact on the biological properties of the molecules (4-fold MIC change against some microorganisms). There is no doubt that the cinnamic acids, their derivatives and hybrid molecules display marked antimicrobial effects. Some microorganisms are more sensitive to a chemical class than others. For instance, fungal organisms are generally more susceptible to the cinnamic aldehydes, while the cinnamic acids, esters and amides tend to affect more importantly the bacteria. A noteworthy effect was observed for the cinnamic molecules against Mycobacterium tuberculosis. The growth of the TB-causing bacteria was repeatedly inhibited by micromolar concentrations of molecules containing the cinnamic acid moiety. However very little is known about the mechanism of action of cinnamic acid, and the essential structural features required for anti-TB activity. Detailed molecular studies of the biological targets of the cinnamic acids may help to design high-affinity cinnamic-based ligands which may be important for developing future therapeutic alternatives to the growing problem of drug-resistant microbial pathogens.
  117 in total

1.  Antibacterial, antifungal and antiviral activity of propolis of different geographic origin.

Authors:  A Kujumgiev; I Tsvetkova; Y Serkedjieva; V Bankova; R Christov; S Popov
Journal:  J Ethnopharmacol       Date:  1999-03       Impact factor: 4.360

2.  Supercritical carbon dioxide extraction and characterization of Laurus nobilis essential oil.

Authors:  Alessandra Caredda; Bruno Marongiu; Silvia Porcedda; Carla Soro
Journal:  J Agric Food Chem       Date:  2002-03-13       Impact factor: 5.279

3.  Chlorogenic acid and caffeic acid are absorbed in humans.

Authors:  M R Olthof; P C Hollman; M B Katan
Journal:  J Nutr       Date:  2001-01       Impact factor: 4.798

4.  Antifungal amides from Piper hispidum and Piper tuberculatum.

Authors:  H M Navickiene; A C Alécio; M J Kato; V D Bolzani; M C Young; A J Cavalheiro; M Furlan
Journal:  Phytochemistry       Date:  2000-11       Impact factor: 4.072

5.  In vitro antimicrobial activity of propolis and Arnica montana against oral pathogens.

Authors:  H Koo; B P Gomes; P L Rosalen; G M Ambrosano; Y K Park; J A Cury
Journal:  Arch Oral Biol       Date:  2000-02       Impact factor: 2.633

6.  Antibacterial activity of leaf essential oils and their constituents from Cinnamomum osmophloeum.

Authors:  S T Chang; P F Chen; S C Chang
Journal:  J Ethnopharmacol       Date:  2001-09       Impact factor: 4.360

7.  Structure-activity relationships of novel anti-malarial agents. Part 2: cinnamic acid derivatives.

Authors:  J Wiesner; A Mitsch; P Wissner; H Jomaa; M Schlitzer
Journal:  Bioorg Med Chem Lett       Date:  2001-02-12       Impact factor: 2.823

8.  Antimicrobial intermediates of the general phenylpropanoid and lignin specific pathways.

Authors:  M S Barber; V S McConnell; B S DeCaux
Journal:  Phytochemistry       Date:  2000-05       Impact factor: 4.072

9.  Antifungal amides from Piper arboreum and Piper tuberculatum.

Authors:  Renata Vasques da Silva; Hosana M Debonsi Navickiene; Massuo J Kato; Vanderlan da S Bolzani; Christiane I Méda; Maria Claudia M Young; Maysa Furlan
Journal:  Phytochemistry       Date:  2002-03       Impact factor: 4.072

10.  Antibacterial phenylpropanoid glycosides from Paulownia tomentosa Steud.

Authors:  K H Kang; S K Jang; B K Kim; M K Park
Journal:  Arch Pharm Res       Date:  1994-12       Impact factor: 4.946
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  65 in total

1.  Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.

Authors:  Girish A Hampannavar; Rajshekhar Karpoormath; Mahesh B Palkar; Mahamadhanif S Shaikh; Balakumar Chandrasekaran
Journal:  ACS Med Chem Lett       Date:  2016-05-13       Impact factor: 4.345

Review 2.  Addressing Facts and Gaps in the Phenolics Chemistry of Winery By-Products.

Authors:  Nelson F L Machado; Raúl Domínguez-Perles
Journal:  Molecules       Date:  2017-02-14       Impact factor: 4.411

3.  Structural and Biochemical Analyses Reveal that Chlorogenic Acid Inhibits the Shikimate Pathway.

Authors:  Neetu Neetu; Madhusudhanarao Katiki; Aditya Dev; Stuti Gaur; Shailly Tomar; Pravindra Kumar
Journal:  J Bacteriol       Date:  2020-08-25       Impact factor: 3.490

4.  Bioactive compounds from mangrove derived rare actinobacterium Saccharomonospora oceani VJDS-3.

Authors:  Manideepa Indupalli; Vijayalakshmi Muvva; Ushakiranmayi Mangamuri; Rajesh Kumar Munaganti; Krishna Naragani
Journal:  3 Biotech       Date:  2018-01-29       Impact factor: 2.406

5.  Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening.

Authors:  Leigh M Matano; Heidi G Morris; B McKay Wood; Timothy C Meredith; Suzanne Walker
Journal:  Bioorg Med Chem       Date:  2016-08-16       Impact factor: 3.641

6.  Synthesis, characterization, and computational study of the supramolecular arrangement of a novel cinnamic acid derivative.

Authors:  S S Oliveira; L G Santin; L R Almeida; L A Malaspina; C Lariucci; J F Silva; W B Fernandes; G L B Aquino; R Gargano; A J Camargo; H B Napolitano
Journal:  J Mol Model       Date:  2017-01-24       Impact factor: 1.810

Review 7.  Natural products from Photorhabdus and Xenorhabdus: mechanisms and impacts.

Authors:  Harun Cimen; Mustapha Touray; Sebnem Hazal Gulsen; Selcuk Hazir
Journal:  Appl Microbiol Biotechnol       Date:  2022-06-20       Impact factor: 4.813

Review 8.  Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer's disease.

Authors:  Nasimudeen R Jabir; Fayaz Rahman Khan; Shams Tabrez
Journal:  CNS Neurosci Ther       Date:  2018-05-16       Impact factor: 5.243

9.  Evaluating the Antifungal Potential of Botanical Compounds to Control Botryotinia fuckeliana and Rhizoctonia solani.

Authors:  Francisca Sempere-Ferre; Jordi Asamar; Vicente Castell; Josefa Roselló; M Pilar Santamarina
Journal:  Molecules       Date:  2021-04-23       Impact factor: 4.411

Review 10.  Honey as an Ecological Reservoir of Antibacterial Compounds Produced by Antagonistic Microbial Interactions in Plant Nectars, Honey and Honey Bee.

Authors:  Katrina Brudzynski
Journal:  Antibiotics (Basel)       Date:  2021-05-09
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