The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: 'Talented' Taxa from the Amaryllidaceae.

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer's disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.

1. Introduction

Amaryllidaceae belongs to the order Asparagales and consists of bulbous flowering plants separated into three infrageneric ranks: Agapanthoideae, Allioideae and Amaryllidoideae, as delineated by the Angiosperm Phylogeny Group [1]. The term “Amaryllidaceae” is frequently used in either phytochemical or pharmacological literature to refer to plants or alkaloids originating from the subfamily Amaryllidoideae [2,3]. Monocotyledonous plants constitute seventy-nine genera (including Allium, Crinum, Cyrtanthus, and Tulbaghia) with over 1000 species [4]. Aside from their broad pantropical distribution, Amaryllidaceae are located in Africa, the Mediterranean Coast and South America, and have high adaptation and speciation [5]. The genus Allium is distributed in temperate, arid, semi-arid and subtropical areas such as the Mediterranean region, central Asia, Africa and parts of Europe. As herbaceous geophyte perennials, Allium comprises a plethora of species with pungent linear leaves that may or may not arise from a bulb or rhizome [6,7]. The Tulbaghia genus, popularly called “sweet garlic”, “wild garlic”, or “pink agapanthus”, is crown shaped with outgrowth or appendages of the perianth and predominantly colonizes the Eastern cape belt of South Africa, and is adapted for growth in areas such as Europe and America [8,9]. The genus Crinum encompasses 104 species and appear as showy flowers on leafless stems, which thrive in the tropics and warm temperate parts, specifically Asia, Africa, America, and Australia [10]. Cyrtanthus is popularly known as “fire lily” due to its unique rapidly flowering response to natural bush fires. Most species are found in South Africa and play an important role in South African traditional medicine [11].

Amaryllidaceous plants are known for their ornamental, nutritional, and medicinal value. Given their attractive flowering plant-like features, Crinum species are prized for their umbel lily-like blossoms in China and Japan [3]. Concurrently, Amaryllidaceae are known for their longstanding exploitation in medicinal therapy owing to their inherent biosynthesis of chemically diverse bioactive compounds with peculiar biological properties. The use of proximate and mineral composition analysis enabled the identification of phytoconstituents [10,12], while in vitro, in vivo, and in silico model systems have permitted the unravelling of intrinsic pharmacological activities of the natural products and other alkaloids isolated from this source [13,14,15]. Of note, bioactive compounds from Amaryllidaceae possesses a wide range of bioactivities ranging from antioxidant [16,17], anti-inflammatory [16,18], antimicrobial [17], antifungal [19], antiviral [20,21], antiplasmodial [22,23,24], anticarcinogenic [18,25,26], antispasmodic [1,27], antiplatelet [28], antiasthmatic [29], antithrombotic [30,31], antitumor [25], antihyperlipidemic [25], antihyperglycemic [25,32,33], antiarthritic [25], antimutagenic [16], immunomodulatory [16] and several others [34].

Given the aforementioned biological activities, Allium, Tulbaghia, Cyrtanthus and Crinum are utilized in traditional medicinal therapy for varying diseases and conditions [35,36,37,38,39,40,41]. For example, Allium is used as concoctions, decoctions, extracts, and herbal preparations to treat angina, amoebic dysentery, arthritis, cardiovascular diseases, cholera, catarrh, dysmenorrhea, fever, headaches, hepatitis, stomach disorders, throat infections, and prostatic hypertrophy [30,31,35,36,37,38]. The genus Tulbaghia has unique pharmacotherapeutic properties and is utilized to manage ailments such as earache, pyrexia, tuberculosis, and rheumatism [9,42]. Crinum species are used to treat haemorrhoids, malaria, osteoarthritis, varicosities, wounds, urinary tract infections, and gynaecological remedies [40,41]. Cyrtanthus are also employed in the management of ailments associated with pregnancy, as well as cystitis, age-related dementia, leprosy, scrofula, headaches, chronic coughs, among others [43,44]. In modern clinical practice, galanthamine from Amaryllidaceae is a primary choice of drug in managing symptomatic neurological disorders such as Alzheimer’s disease due to its selective inhibitory action on the acetylcholine biosynthetic enzyme, acetylcholinesterase [45]. The pancratistatin phenanthridone class of alkaloids are also promising chemotherapeutic drug candidates with unique cell line-specific antiproliferative properties, conferring a selective advantage for clinical development [46].

Although Amaryllidaceae represents a source of valuable bioactive compounds, developing promising drug candidates into clinically relevant therapeutics has been slow. Similarly, other genera in this family, including Cyrtanthus, Crinum and Tulbaghia, are untapped reservoirs and could serve as an alternative window for novel drug targets and warrant further investigation. This review consolidates evidence on the bioactive compounds from Allium, Tulbaghia, Crinum and Cyrtanthus and ascertains their traditional and pharmacological applications. Specifically, bibliographic searches were conducted on multiple standard databases (such as, Scopus, Web of Science, MEDLINE, Sci verse, Embase, Google scholar among others) using MESH and non-MESH terms to retrieve and synthesize relevant publications over the 3-month search period. This review highlights panoply of promising biomolecules from the taxa Amaryllidaceae and their prominent medicinal values. The evidence from this study could hasten drug discovery among the pharmaceutical industries. An update on the natural products from these lesser explored genera could also augment the lean pipeline of novel therapeutics.

2. The Genus Tulbaghia

2.1. Botanical Description

Tulbaghia is made up of monocotyledonous species with herbaceous perennial bulbs covered by brown scales and are mostly found in Africa [8]. South African species possess bulb-like corms or rhizomes which are swollen, irregularly shaped and wrapped in dry, fibrous leaves [8]. Members of this genus usually possess a raised crown-like structure or ring at the center of their flower tube [8]. Their seeds are black, flat and elongated with the mature ones having embryos [8]. Examples of species of this genus are Tulbaghia violacea (T. violacea), Tulbaghia acutiloba Harv. (T. acutiloba), Tulbaghia capensis L. (T. capensis) and Tulbaghia cepacea L.f (T. cepacea) [8].

2.2. Geographical Distribution and Traditional Uses of Tulbaghia Species

With approximately 66 species (https://www.kew.org/science accessed on 22 February 2022) [47], Tulbaghia is the second-most species-rich genus within Amaryllidaceae. Tulbaghia is a monocotyledonous genus comprised morphologically of herbaceous perennial bulbous species, which produce a variety of volatile sulfur compounds, hence resulting in a distinct pungent garlic odor released by bruised plants [8,48]. The genus was named by Carl Linnaeus after Ryk Tulbagh (1699–1771), a former governor of the Cape of Good Hope in South Africa, where most of the native species are to be found, particularly in the Eastern Cape Province [49]. In addition to South Africa, the genus is widely distributed across southern African countries including Botswana, Lesotho, Swaziland, and Zimbabwe, where the plant is revered in folk medicine being used for the treatment of a plethora of infectious and non-infectious diseases [9] as highlighted in Table 1.

Table 1

Geographical distribution and traditional uses of Tulbaghia species.

Plant Species	Geographical Distribution	Traditional Uses	References
T. violacea	Indigenous to the Eastern Cape, KwaZulu-Natal, Gauteng, Free State and Mpumalanga Provinces of South Africa.	The leaves and bulbs are used in the management of fever and colds, tuberculosis, asthma, and stomach problems. The leaves are eaten as vegetables and for the management of oesophageal cancer. It is also used as a snake repellent.	[8,50]
T. alliacea	Native to South Africa and grows mostly in the Eastern Cape and southern KwaZulu-Natal Provinces of South Africa.	Its bruised rhizome is used locally in bathwater to relieve fever, rheumatism, and paralysis, and in small doses as a laxative. T. alliacea is used for the management of stomach problems, asthma, and pulmonary tuberculosis. Its rhizome infusion is administered as an enema.	[8,51]
T. simmleri	Native to the South African Drakensberg mountains growing as isolated plants on rocky ledges.	Bulbs and leaves are used as a remedy for gastrointestinal ailments, enemas, high blood pressure, heart problems, chest complaints, high cholesterol, constipation, rheumatism, asthma, fever, pulmonary tuberculosis, earache, human immunodeficiency virus (HIV), paralysis, and cardiovascular diseases.	[50,52]
T. acutiloba	Found in the rainfall regions of southern Africa, occurring in the Eastern Cape, KwaZulu-Natal, Limpopo, Free State, Gauteng, North West, and Mpumalanga Provinces of South Africa, as well as in Lesotho, Swaziland and Botswana.	T. acutiloba leaves are used as a culinary herb and snake repellent. It is used to treat barrenness, flu, bad breath, and as an aphrodisiac. It is also cultivated to keep snakes away from the homestead.	[8]
T. natalensis	Although native to South Africa, but is now grown worldwide.	It is used as a culinary herb and snake repellent.	[53]
T. cernua	Commonly found in the Eastern Cape, Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, North West and Western Cape Provinces of South Africa.	It is used for ornamental purposes.	[8]
T. leucantha	Widely distributed in southern Africa including Botswana, Lesotho, South Africa, Swaziland, Zambia, and Zimbabwe.	Its rhizome is scraped clean and boiled in stews or roasted as a vegetable. Its leaves and stems are used as a culinary herb and protective charm.	[53]
T. ludwigiana	Commonly found in the Eastern Cape, KwaZulu-Natal, Northern Provinces of South Africa and in Swaziland.	It is traditionally used as a love charm.	[53]

2.3. Phytochemistry of Tulbaghia

Tulbaghia produces many different classes of compounds with diverse chemical structures dominated by sulfur-containing natural products (Figure 1; Table S1).

Figure 1

Chemical space of compounds identified from T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. PCA analysis carried out using DataWarrior [54].

Most compounds reported have a small molecular weight (<500) and are of a broad lipophilicity (Figure 2).

Figure 2

Analysis of cLogP and molecular weight space occupied by compounds identified in T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. Plot generated using DataWarrior [54].

Tulbaghia violacea has been the most widely investigated for its phytochemistry and pharmacological properties. To date, close to 100 compounds have been tentatively identified, largely using gas chromatography techniques, from different parts of this species (Supplementary File S1) [55]. Most prominent are the sulfur compounds with reported broad-spectrum pharmacological activity. The thiosulfinate marasmicin (1) is the most prolific antimicrobial compound reported thus far from this genus [56]. This compound is formed from its precursor compound marasmin (2), by the enzyme c-lyase. Marasmicin is responsible for the characteristic garlic odor generated by damaged plants [48]. Other notable compounds produced by this species include phenols, tannins and flavonoids [55], which are also responsible for several observed biological activities. Phytochemical characterization has been carried out, albeit minimally for other Tulbaghia species particularly T. alliacea and T. acutiloba. Unlike other genera in Amaryllidaceae, Tulbaghia is so far devoid of any alkaloids [57,58]. Despite the extensive in vitro pharmacological screening of extracts of Tulbaghia, it is possible that less effort has been made to isolate and identify their active principles. Hence, the phytochemistry of the genus Tulbaghia largely remains understudied. The chemicals structurers of noteworthy compounds isolated from T. violacea have been represented in Figure 3.

Figure 3

Chemical structures of compounds identified in T. violacea. (1) Marasmicin (1), (2) marasmin (2), allicin (3)—possesses antibacterial and antifungal activity, d-fructofuranosyl-β(2→6)-methyl-α-d-glucopyranoside (4), β-d-fructofuranosyl-(2→6)-α-d-glucopyranoside (5), methyl-α-d-glucopyranoside (6), bis(methylthiomethyl) disulfide (7)—found to constitute 48% of volatiles in aerial parts of T. violacea [55], methyl-2-thioethyl thiomethyl trisulfide (8)—found to constitute 16% of volatile compounds in aerial parts of T. violacea [55], methyl (methylthio)methyl disulfide (9)—found to constitute 10 % of volatile compounds in aerial parts of T. violacea [55], naphthalene (10)—interestingly observed to significantly increase in concentration in plants infected by the fungus Beauveria bassiana in comparison to untreated controls [59], nonanal (11)—also observed to significantly decrease in concentration in plants infected by the fungi Beauveria bassiana in comparison to untreated controls [59] and finally kaempferol (12)—which possesses multiple biological activities including antioxidant, anticancer and anti-inflammatory properties [60,61,62].

2.4. Pharmacological Studies of Tulbaghia Species

Because of its perceived medicinal value, Tulbaghia has received marked interest within the scientific community which has meticulously subjected it to various in vitro and in vivo studies experimentally evaluating its pharmacological activities. The volume of published studies generated from these investigations mirror the distribution of the genus with most articles on Tulbaghia having emerged from South Africa (Table 2), a country highly rich in this genus both in terms of species diversity and abundance.

Table 2

Published documents on the genus Tulbaghia per country.

Country	No. of Documents *
South Africa	99
United Kingdom	15
United States	12
Czech Republic	8
Italy	7
India	6
Germany	5
Australia	3
China	3
Belgium	2

* Data retrieved following query of the Scopus database (https://www.scopus.com/, accessed on 22 February 2022) using the keyword “Tulbaghia”. The search was carried out on 22 February 2022.

The greatest numbers of pharmacological screens have been on interrogating the antimicrobial properties of this genus. This is closely followed by cardiovascular, antioxidants and cancer investigations as shown in Table 3. T. violacea prominently features, being the most studied species, with T. alliacea and T. aticulata having received minimal attention.

Table 3

Number of published studies per specific disease or pharmacological area.

Disease	No. of Published Studies #
Antimicrobial	26
Cancer	11
Antioxidant	13
Diabetes	2
Cardiovascular	12
Antithrombogenic	2
Miscellaneous	17

# Studies considered are those published from 1997 to 2022. A number of these, published before 2013, have been succinctly discussed by Aremu and Van Staden [8].

2.4.1. Antimicrobial and Antiparasitic Activity

As antimicrobial resistance continues to be a global health threat, the need to find therapeutic alternatives has never been more urgent [63]. This has encouraged scientists to search for novel alternatives with natural products having drawn marked interest as a potential oasis of new antimicrobial agents [64,65,66]. Tulbaghia has received significant relevance in this regard, with multiple studies providing ample evidence substantiating its use as an antimicrobial agent. Extracts of T. violacea have potency against many microbial species including those designated as priority by the World Health Organization. These include Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus) and Klebsiella pneumoniae (K. pneumoniae) with MIC values ranging between 20 and 300 µg/mL [67]. This activity was confirmed in another study where the disc diffusion method was used [68]. In addition to bacteriostatic activity, extracts of T. violacea have shown noteworthy potency against yeasts including Candida albicans (C. albicans) and Candida parapsilosis (C. parapsilosis) with MIC and MMC values ranging between 20 and 40 µg/mL [68]. Beyond human pathogens, extracts of T. violacea have activity against microorganisms of agricultural significance, for example against the fungus Aspergillus flavus (A. flavus), which is responsible for significant agricultural produce loss at a global scale due to production of aflatoxins [69]. Extracts of T. violacea compromised cell wall synthesis by significantly reducing β-glucan and chitin synthesis in A. flavus corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively [70]. Further studies suggested an alternative mode of action (MoA) via reduction of ergosterol production in fungi [71]. Interestingly, related to value in agriculture, a patent has been filed on the use of extracts of T. violacea as a plant protecting remedy as a substitute for chemical agents [72]. Some thought-provoking studies have shown that growth conditions including light intensities, watering frequency and pH, substantially impact both growth and biological potency of T. violacea extracts against Fusarium oxysporum (F. oxysporum) [73,74]. Likewise, storage conditions of dried plant material also affect the antimicrobial potency of extracts [56]. In addition to antimicrobial activity, T. violacea has shown good antiparasitic activity against the parasitic worm Meloidogyne incognita (M. incognita) on tomato roots and in soil [75]. Antiparasitic activity has also been observed against Trypanosoma brucei (T. brucei) (IC50 = 2.83 µg/mL) and Leishmania tarentolae (L. tarentolae) (IC50 = 6.29 µg/mL) [67]. Table 4 highlights the antimicrobial activity of Tulbaghia species.

Table 4

Antimicrobial activity of Tulbaghia species.

Plant Species	Extraction Solvent	Plant Part Used	Biological Activity	References
T. violacea	Dichloromethane	Bulbs	MIC ranging from 20 to 300 µg/mL against Bacillus subtilis, methicillin-resistant S. aureus, S. epidermidis, E. coli, K. pneumoniae, P. aeruginosa, C. albicans and C. parapsilosis.	[67]
T. violacea	Hexane and ethanol	Flowers and callus cultures	Moderate to strong broad-antimicrobial (E. coli, P. aeruginosa, S. aureus, Aspergillus niger and C. albicans) activity observed by zone of inhibition in the agar well disc diffusion method.	[68]
T. violacea	Water	Bulbs	Significant reduction in A. flavus β-glucan and chitin synthesis corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively.This results in inhibition of ergosterol production in the fungus.	[70,71]
T. violacea	Acetone	Bulbs	Varied light intensities, pH and watering frequencies substantially impacted both growth and potency of plant extracts against the fungi F. oxysporum.	[73,74]
T. violacea	Water	Roots, bulbs, leaves and flowers	Significantly compromised population densities of the nematode M. incognita race 2 on tomato roots and in the soil.	[75]
T. violacea	Dichloromethane	Bulbs	Antiparasitic activity against T. brucei (IC50 = 2.83 µg/mL) and L. tarentolae (IC50 = 6.29 µg/mL).	[67]

2.4.2. Anticancer Activity

Owing to the need for novel anticancer agents [76] and motivated by the success of cancer drug discovery projects from natural products [77], Mthembu and Motadi in (2014), evaluated the in vitro anticancer properties of crude methanol extracts of T. violacea using an MTT assay [78]. Extracts displayed time- and concentration-dependent antiproliferative properties against cervical cancer cell lines with an IC50 of 150 µg/mL. The MoA was deciphered to be induction of apoptosis by a p53-independent pathway [78]. However, in contrast to this finding, continued work showed a proportional increase in the activity of caspase 3/7, and the expression of p53 genes strongly suggests apoptosis was triggered by a p53-dependent pathway [79]. This latter finding has been partly substantiated by data emerging from a study examining the antineoplastic properties of T. violacea against ovarian tumor cells. These extracts were shown to partially induce both apoptosis and necrosis with the most pronounced activity due to induction of autophagy [80].

Triple-negative breast cancer remains one of the most challenging cancers, being highly aggressive [81]. T. violacea extracts have demonstrated good cytotoxic activity against MDA-MB-231, with an IC50 of 300 µg/mL [82]. Additionally, extracts inhibited migration of the cancer cell lines (metastasis), an important physiological process in the progression of this cancer [83]. In addition to the gynecological cancers, antineoplastic properties of T. violacea were further observed against pancreatic cancer with 63% inhibition of cell proliferation at a concentration of 250 µg/mL [68]. Against a non-sex-specific cancer, T. violacea showed noticeable activity against oral cancer with an IC50 of 0.2 and 1 mg/mL for acetone and water-soluble extracts, respectively. Extracts activated caspase activity in a dose-dependent manner leading to induction of apoptosis in the human oral cancer cell line [84]. Using a bioassay guided approach, the active anticancer compounds in T. violacea have been identified to be glucopyranosides d-fructofuranosyl-β (2→6)-methyl-α-d-glucopyranoside and β-d-fructofuranosyl-(2→6)-α-d-glucopyranoside. Both compounds act by mediating induction of apoptosis in Chinese hamster cells by targeting the mitochondrial (intrinsic) pathway [85,86]. A summary of the anticancer activity of Tulbaghia species is shown in Table 5.

Table 5

Anticancer activity of Tulbaghia.

Plant Species	Extraction Solvent	Plant Part Used	Biological Activity	References
T. violacea	Methanol	Leaves and roots	Marked time- and dose-dependent cytotoxic effect on cancer cell lines. Induced apoptosis using p53-independent pathway.	[78]
T. violacea	Methanol, butanol, and hexane	Leaves	Methanol extract was prolific against multiple cell lines. Hela and ME-180 cell lines treated with methanol and hexane extracts showed an increase in caspase 3/7 activity. Both methanol and hexane extracts induced a 10-fold increase in expression of p53 gene in Hela cells.	[79]
T. violacea	Methanol:water:formic acid (80:20:0.1, v/v/v)	Flowers	Demonstrated activity against ovarian tumor cells.	[80]
T. violacea	Water and methanol	Leaves	Water-soluble extract emerged as the most cytotoxic (IC50 = 314 µg/mL), compared to the methanol extract (IC50 = 780 µg/mL), against the MDA-MB-231 triple-negative breast cancer cell line. Water-soluble extract prevented cell migration completely for 13 h at 300 µg/mL.	[82]
T. violacea	Hexane and ethanol	Flowers and callus cultures	Extracts showed marked cytotoxicity (60–74% growth inhibition at 250 µg/mL) against three different cell lines (Hep G2, PC-3 and MCF-7).	[68]
T. violacea	Acetone and water	Leaves	Anticancer activity against oral cancer with an IC50 (acetone extract) of 0.2 mg/mL; IC50 (water extract) of 1 mg/mL.	[84]
T. violacea	Methanol:water (1:1)	Whole plants	Two pro-apoptotic glucopyranosides d-fructofuranosyl-β (2→6)-methyl-α-d-glucopyranoside and β-d-fructofuranosyl-(2→6)-α-d-glucopyranoside isolated and identified as active anticancer agents in the plant.	[85]
T. violacea	Water	Whole plants	MoA of the three compounds, namely methyl-α-d-glucopyranoside, d-fructofuranosyl-β (2→6)-methyl-α-d-glucopyranoside and β-d-fructofuranosyl-(2→6)-α-d-glucopyranoside isolated from the water extract, deciphered to be through induction of apoptosis by targeting the mitochondrial (intrinsic) pathway	[86]

2.4.3. Antioxidant Activity

The imbalance of reactive oxygen species (ROS) and antioxidants in the body can lead to oxidative stress [87]. This physiological condition can result in cellular and tissue damage [88]. Oxidative stress is associated with pathologies including cancer, cardiovascular disease, diabetes, and neurodegenerative diseases amongst others [88,89]. To avert the development of oxidative stress, attenuation of ROS has been identified as a viable target, with natural products seen as a potential source capable of neutralizing it [88]. Tulbaghia has generated some interest on this front particularly as it is rich in compounds with proven antioxidant activity including phenols, tannins and flavonoids. Multiple studies have demonstrated that extracts of Tulbaghia have marked antioxidant activity as assessed using different assays in vitro including Trolox equivalent antioxidant capacity (TEAC; also commonly referred to as the ABTS assay), ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) (Table 6) [58,80,90,91]. Furthermore, using an in vivo model of Caenorhabditis elegans, T. violacea extracts attenuated oxidative stress produced by a free radical generator, (2,2′-azobis-2-amidinopropane dihydrochloride; AAPH), in the roundworm [80]. Data from these studies strongly suggested continued investigation of other species in the search for more potent antioxidant agents from Tulbaghia. The antioxidant activity of Tulbaghia species is highlighted in Table 6.

Table 6

Antioxidant activity of Tulbaghia species.

Plant Species	Extraction Solvent	Plant Part Used	Biological Activity	References
T. violacea	Water	Leaves	Dose-dependent antioxidant activity measured using the DPPH (Log IC50 = 0.49 mg/mL) and ABTS (Log IC50 = 0.24 mg/mL) assays	[92]
T. violacea	Methanol/water/formic acid (80:20:0.1, v/v/v)	Flowers	Marked antioxidant activity was observed using 3 different types of assays, namely DPPH, FRAP and TREC	[80]
T. acutiloba	Hydro-methanolic extracts	Roots, rhizomes, leaves and flowers	Dose-dependent antioxidant activity observed with the rhizome extract emerging as the most active plant part (IC50 DPPH = 0.202 mg/mL and peak scavenging activity of 95)	[91]
T. violacea	Hexane and ethanol	Flowers and callus cultures	Dose-dependent antioxidant activity with IC50 ranging from 1.933 to 7.350 mg/mL in the DPPH assay	[68]
T. violacea	Acetone	Leaves	IC50 DPPH = 0.08 mg/mL; IC50 ABTS = 0.03 mg/mL	[84]
T. acutiloba	Acetone	Leaves	IC50 DPPH = 0.16 mg/mL; IC50 ABTS = 0.07 mg/mL	[84]
T. alliacea	Acetone	Leaves	IC50 DPPH = 0.06 mg/mL; IC50 ABTS = 0.06 mg/mL	[84]
T. cernua	Acetone	Leaves	IC50 DPPH = 0.21 mg/mL; IC50 ABTS = 2.34 mg/mL	[84]
T. leucantha	Acetone	Leaves	IC50 DPPH = 0.39 mg/mL; IC50 ABTS = 0.03 mg/mL	[84]
T. ludwigiana	Acetone	Leaves	IC50 DPPH = 0.26 mg/mL; IC50 ABTS = 0.09 mg/mL	[84]
T. natalensis	Acetone	Leaves	IC50 DPPH = 2.70 mg/mL; IC50 ABTS = 0.04 mg/mL	[84]

2.4.4. Antidiabetic, Anticardiovascular and Antithrombogenic Activity

The incidence of diabetes and cardiovascular diseases continues to grow substantially across the globe, with both conditions combined accounting for the highest global morbidity and mortality [93,94]. Both of these chronic conditions are closely linked with cardiovascular disease being responsible for high morbidity and mortality in diabetic patients [95]. Tulbaghia has been documented in ethnopharmacological studies for the treatment of these ailments with emerging scientific data strongly validating its use. In streptozotocin diabetes-induced rat models, T. violacea attenuated diabetes-associated physiological conditions resulting in improved body weights, reduced fasting blood glucose levels, enhanced glucose tolerance and significantly elevated plasma insulin and liver glycogen content [96]. These data were corroborated in another study in which T. violacea noticeably reduced blood glucose and serum lipid (triglyceride (TG), total cholesterol (TC), and very low-density lipoprotein (VLDL)) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model [97]. In an assessment for negating cardiovascular associated conditions, T. violacea in in vivo models markedly reduced systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP) and the heart rate in both age-induced and spontaneous hypertensive rats [98]. Furthermore, dosing rats with extracts of T. violacea led to improved kidney function [99]. This is an essential pharmacological property as kidney function is impaired in hypertension leading to high morbidity and mortality in people suffering from cardiovascular diseases [100].

One of the multiple factors strongly associated with cardiovascular disease is atherothrombotic vascular disease (AVD). Platelet aggregation plays a role in development of AVD and subsequent cardiovascular events [90,101]. Against this background, platelet aggregation has been identified as a key process to target to prevent AVD. Encouragingly, T. violacea demonstrated marked potency being able to significantly inhibit platelet adhesion 15 min post-exposure (Table 7) [90,92].

Table 7

Antidiabetic, anticardiovascular and antithrombogenic activity of Tulbaghia species.

Plant Species	Extraction Solvent	Plant Part Used	Biological Activity	References
Diabetes
T. violacea	Methanol	Rhizome	Attenuated diabetes associated physiological complications in streptozotocin-induced diabetic rats.	[96]
T. violacea	Methanol	Rhizome	Noticeably reduced blood glucose and serum lipid (TG, TC, and VLDL) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model.	[97]
Cardiovascular
T. violacea	Methanol	Leaves	Markedly reduced systolic BP, diastolic BP, mean arterial pressure and the heart rate in both age-induced and spontaneous hypertensive rats.	[98]
T. violacea	Methanol	Rhizome	50 mg/kg significantly improved kidney function in vivo.	[99]
T. acutiloba	Hydro-methanolic extracts	Roots, rhizomes, leaves and flowers	All extracts inhibited the Angiotensin-1-Converting Enzyme in vitro (> 50 % inhibition at a concentration range of 125–1000 μg/mL). Extracts of leaves demonstrated activity comparable to that of the control drug ramipril.	[91]
Antithrombogenic
T. violacea	Water	Leaves	Noticeable inhibition of platelet adhesion by a novel scaffold consisting of polycaprolactone incorporated with 10 % (w/w) plant extracts.	[90]
T. violacea	Water	Leaves	Marked inhibition of platelet adhesion (70% inhibition at 0.1 mg/mL within 15 min post-exposure).	[92]

2.4.5. Miscellaneous Pharmacological Activity

In addition to diabetes and cardiovascular diseases, T. violacea has shown activity against another chronic condition, Alzheimer’s disease. In an in vivo Alzheimer’s disease transgenic C. elegans strain model, T. violacea significantly reduced 1-42 β-amyloid peptide formation (Table 8) [80]. T. violacea exhibited in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA [102] and validating its traditional use for the treatment of epilepsy. T. violacea displayed marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5% w/v and 10% w/v) [59], further enhancing its credentials as a potential agricultural product. Somewhat concerning is that, extracts of T. violacea also induced genotoxic effects albeit at high test concentrations (250, 500 and 1000 µg/mL) in the Allium cepa assay [103]. Furthermore, broad murine macrophage antiproliferative and cytotoxicity activity, influenced by extract test concentrations, type of solvent and plant part used, have been observed (Table 8) [104]. There is consequently a need for rigorous assessment of safety of extracts of this and other species of the genus Tulbaghia.

Table 8

Miscellaneous biological properties of extracts of Tulbaghia species.

Plant Species	Extraction Solvent	Plant Part Used	Biological Activity	References
T. violacea	Methanol/water/formic acid (80:20:0.1, v/v/v)	Flowers	Reduced 1-42 β-amyloid peptide formation and arrested oxidative stress in vivo.	[80]
T. violacea	Methanol	Leaves	Demonstrated in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA.	[102]
T. violacea	Acetone	Mixture of leaves and bulbs	Marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5 % w/v and 10 % w/v).	[59]
T. violacea	Water	Leaves, stems, and roots	Induced conspicuous genotoxicity effects at high test concentrations (250, 500 and 1000 µg/mL) in the A. cepa assay.	[103]
T. violacea	Water and ethanol	Leaves, stems, and roots	Broad murine macrophage antiproliferative and cytotoxicity activity influenced by both extract test concentrations, type of solvent and plant part used.	[104]

3. The Genus Allium

3.1. Botanical Description

Species of the genus Allium are mostly found in warm–temperate and temperate zones of northern hemisphere as well as the boreal zone [105]. They are petaloid perennial herbs with parallel narrow leaves [33] and possess true bulbs, which are sometimes found on rhizomes [106]. Allium species are also characterized by onion or garlic odor and flavor similar to Tulbaghia [106]. Well known species include Allium cepa (A. cepa), Allium sativum (A. sativum), Allium ascalonicum (A. ascalonicum,), Allium porrum (A. porrum), and Allium schoenoprasum (A. schoenoprasum) (chive) [33]

Allium has over 500 species making it the largest genus of Amaryllidaceae [6,7]. There are plethora of species, notably A. cepa and A. sativum [107,108,109]. Other examples grown for their medicinal and nutraceutical value are Allium ducissae (A. ducissae), Allium strictum (A. strictum), Allium umbilicatum (A. umbilicatum), Allium victorialis (A. victorialis), A. ascalonicum, Allium chinense (A. chinense), Allium tuberosum (A. tuberosum), Allium griffithianum (A. griffithianum), Allium oreoprasum (A. oreoprasum), and Allium oschaninii (A. oschaninii). Species tolerate varying climatic conditions, hence are geographically distributed across several continents, including Asia, Africa, the Americas, and Europe [107,110]. Fernandes et al. identified A. cepa that colonizes four different geographical regions of the Madeira island, an archipelago near the North Atlantic ocean with a hot and/or warm-summer Mediterranean climate conditions [107]. As the world’s second-most relevant and cultivated horticulture vegetable crop, the onion (A. cepa), is distributed in over 175 countries and covers approximately six million hectares of the total land size of the world. Approximately two-thirds (66%) of global onion production emanates from the Asia, with China and India being the world’s largest producers [111]. The maximal diversification of A. cepa is found in Iran and Afghanistan’s Mediterranean basin. A. cepa thrives in areas with boreal, temperate, and tropical climates [108]. Similarly, A. sativum (garlic) bears close resemblance to onions and originates from Central Asia but has spread to include regions in Europe, America, and Africa [112]. The global garlic production estimates show that out of the 28.5 million tonnes (MT) of A. sativum cultivated, the majority (91.6%; 26.1 MT) were from Asia, followed by Europe (3.0%; 0.86 MT), America (2.9%; 0.83 MT), and with the least from Africa (2.7%; 0.73 MT) [112]. Bartolucci et al. identified A. ducissae, a new breed of Allium that grows in the mountainous regions of the Central Apennines in the Abruzzo and Lazio counties of Italy [113]. Furthermore, A. strictum, a Eurasian species, is distributed across China, Europe, Russia, Kazakhstan, Kyrgyzstan, and Mongolia [114,115]. A. umbilicatum, also called gladiolus or leek is usually localized in semi-arid regions and can tolerate sub-zero freezing winters [116]. It occurs as a weed in oases and span across Afghanistan, Iran, Pakistan, Turkmenistan, Tajikistan, and central and Eastern Asian regions [116]. As a representative circumboreal plant, A. victorialis has a wide altitudinal climatic tolerance [117]. It is predominantly located in lowland deciduous forest and subalpine birch forest, but seldom found in the subalpine meadows [117]. This species is scattered distribution on the island stretches of Japan, Russia, and Northern China [117,118]. Although practically grown throughout the world, A. ascalonicum, also called shallot, is native to the Middle East, and the name is derived from the Syrian city Ascalon. These shallots are distributed on the main islands of Indonesia, in Bangladesh, Japan, Korea, Malaysia, Taiwan, and Thailand [119]. A. chinense (locally referred to as Chinese/Japan onion or scallion, Kiangski scallion, oriental onion, Rakkyo) is an uncommon Allium species found mainly in the tropical and sub-tropical regions of China, Japan, Vietnam, and eastern areas of India [111,120]. A. tuberosum is an indigenous species native to southeastern Asia and regarded as a late-seasonal bloomer. During the initial growth phases, A. tuberosum is evergreen in hot climates but succumbs to cold climatic conditions. However, the Chinese chive becomes tolerant to all seasonal variations [121,122]. A. griffithianum and A. oreoprasum are geographically skewed towards the mountainous regions of Pakistan, Afghanistan, Kyrgyzstan, Uzbekistan, and Tajikistan [123], whereas A. oschaninii are located in the Darvaz mountains of Central Tajikistan [124].

3.2. Traditional Uses of Genus Allium

Increasing scientific evidence asserts the traditional uses of plants in folklore medicine [124,125,126]. Researchers over the years have investigated various parts of local medicinal plants to identify phytoconstituents with potential bioactivity, and further develop them into new drug therapies [127,128]. Allium species contain the common phytocompounds (anthocyanins, flavonoids, organosulfur, sterols, saponins, phenolic acids, amino acids, vitamins and minerals) [129,130,131,132] with innumerable biological properties [130,131,132,133]. Owing to these biological advantages, Allium species are locally used in managing various diseases affecting human organs and organ systems such as inflammation, microbial pathologies and oxidative stress injuries [130,131,132,133]. In particular, A. cepa is used to treat alopecia, hearing impairment, menstrual disorders, erectile dysfunction and ocular and metabolic diseases [133,134,135]. Similarly, A. sativum is employed in the management of hematological disorders, carcinomas, muscle weakness and compromised airways [135,136,137,138,139]. Other varieties of Allium species also serve as appetizers, nerve soothers, and relieving agents against digestive, respiratory, and urinary system discomfort as seen in Table 9.

Table 9

Traditional medicinal uses of Allium species.

Plant Species	Mode of Preparation	Traditional Medicinal Uses	Reference
A. cepa	Raw, juice of bulb or rhizome, paste, decoctions, cataplasm, maceration, infusion	Alopecia, antilithic (stone disease), anti-obesity, blood purifying, bronchitis, constipation, cardiovascular disease, cough, diabetes, eye diseases, erectile dysfunction, fever, hearing loss, headaches, hemorrhoids, epilepsy, oligomenorrhea, jaundice, lower gastrointestinal bleeding, prostate cancer, rheumatism, rubefacient, sinusitis, stomach pains, snake bites, skin diseases, teeth disorders, reduce flatulence, wound healing	[133,134,135]
A. sativum	Extracts of leaves or bulb	Antiseptic, anthelmintic, antithrombotic, antilipidemic, aphrodisiac, anti-greying of hair, bronchitis, carminative, cough, colic, cancers (gastric, prostate, colorectal adenomatous polyps, squamous cell carcinoma), diabetes, diaphoretic, dysentery, eczema, facial paralysis, fever, flatulence, galactagogue, high blood pressure, intestinal worms, liver disorders, rheumatism, scabies, tetanus, stomach pains, tuberculosis	[135,136,137,138,139]
A. umbilicatum	Raw or cooked bulb, leaves, flowers	Non-specific reduction in blood cholesterol levels, tonify digestive and circulatory systems	[116]
A. victoralis	Fresh, pickled, boiled and salted flowers, leaves and roots	Appetizer, amenorrhea, pediatric otitis, bronchitis, diarrhea, dropsy, expectorant, hypofunction of stomach, inflammatory eye diseases, meteorism, gastroenteritis, heart diseases (atherosclerosis), rheumatism	[140]
A. ascalonicum/A. cepa var aggregatum	Bulb and leaves	Allergies, appetizer, cold, cancers, fever, obesity, rheumatoid arthritis, soothes nerves, diabetes, post-menopausal syndrome	[141,142,143,144,145]
A. chinense	Flower, leaves, roots, seedpods	Angina pectoris, astringent, bronchitis, carminative, chest pains, diarrhea, expectorant, pleurisy, tenesmus in cases of dysentery, reducing cholesterol, tonic to the digestive and circulatory systems	[146]
A. tuberosum	Raw or cooked leaves, roots, oils from seed	Asthma, abdominal pain, carminative, cuts and wounds, diabetes, diarrhea, kidney and bladder weakness, nocturnal emission, urinary incontinence, spermatorrhea, stomachic	[147]
A. griffithianum	Leaves and bulb	Carminative, colic indigestion, dyspepsia, diabetes control
A. oreoprasum	Leaves and bulb	Cough and cold, diabetes control, diarrhea, dysentery, fever, gastritis, oedema, headache, jaundice, stomachache, rheumatism, numbness of limbs	[124]

3.3. Phytochemistry of Allium

Owing to the numerous traditional uses of these species, it is not surprising that the genus contains several phytoconstituents which may be responsible for their observed activity. Table 10 outlines various phytochemicals isolated, their geographic location and their biological activity.

Table 10

Bioactive compounds isolated from Allium species.

Plant Species	Plant Part	Country	Isolated Compounds	Bioactivity	References
A. ursinum L.	Leaves,underground parts,fresh flowers	PolandBulgaria	1,2-di-O-α-linolenoyl-3-O-β-d-galactopyranosyl-sn-glycerol; β-sitosterol3-O-β-d-glucopyranoside;kaempferol 3-O-β-glucopyranoside and kaempferol 3-O-β-neohesperidoside.(-S-)-spirost-5-en-3β-ol tetrasaccharide, (25R)-spirost-5,25(27)-dien-3 β-ol tetrasaccharide, 3-hydroxypregna-5,16-dien-20-one glycoside.Thymidine, adenosine, astragalin (kaempferol-3-O-β-d-glucopyranoside, kaempferol-3-O-β-d-glucopyranosyl-7-O-β-d-glucopyranoside, kaempferol-3-O-β-d-neohesperoside, and kaempferol-3-O-β-d-neohesperoside-7-O-β-d glucopyranoside.	Anti-ADP-aggregation activity in human blood platelets.Inhibition of human platelet aggregation.Cytotoxic activity against murine melanoma B16 and sarcoma XC.	[148,149,150,151]
A. mongolicum	Aerial parts	China	Mongoflavonoids A1, A2, A3, A4, B1, B2 and monogophenosides A1, A2, A3, B.	Increase in the height of mouse small intestine.	[152]
A. cepa. A. cepa L.	Pigmented scales of red onion,bulbs,red onion skin waste	Naples	Quercetin.3-O-(3″-O-β-glucopyranosyl-6″-O-malonyl-β-glucopyranoside)-4-O-β-glucopyranoside, cyanidin 3,4′-di-O-β-glucopyranoside, cyanidin-4′-O-β-glucoside, peonidin 3-O-(6 ″-O-malonyl-β-glucopyranoside).5-hydroxy-3-methyl-4-propylsulfanyl-5H-furan-2-one, (hydroxymethyl) furfural, acetovanillone, methyl 4-hydroxyl cinnamate and ferulic acid methyl ester.3-O-β-glucopyranoside and 3-O-(6″-O-malonyl-β-glucopyranoside) of 5-carboxypyranocyanidin.Ceposide A, ceposide B and ceposide C.Spiraeoside (4′-O-glucoside of quercetin).Onionin A1, onionin A2, onionin A3, onionin B1 and B2.Onionin A1 (3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophen-2-sulfoxide-S-oxide).Cyanidin 3-glucoside (Cy 3-Glc), 3-malonylglucoside (Cy3-MaGlc), cyanidin 3-laminaribioside (Cy 3-Lam) and 3-malonyllaminaribioside (Cy 3-MaLam).	Anti-inflammatory and immunomodulatory effect.Induction of quinone reductase.Antifungal activity. Radical scavenging, anti-inflammatory, inhibition of the expression of B-cell lymphoma 2.Suppression of tumor progression in mouse ovarian cancer (Onionin A1).Suppression of tumor-cell proliferation through the inhibition of polarization of M2 activated macrophages.	[153,154,155,156,157,158,159,160,161]
A. sativum. A. sativum L. var. voghiera. A. sativum L.	Root, protobulb, leaf sheath and blade, bulbs,tuber	Italy	Nerolidol, α-pinene, terpinolene.Voghieroside A1/A2, voghieroside B1/B2, voghieroside C1/C2, voghieroside D1/D2 and voghieroside E1/E2.Adenosine and guanosine.	Antifungal activity against Sclerotium cepivorum.Antimicrobial activity.Strong inhibitory effect on human platelet aggregation generated by 2 μM ADP in both primary and secondary waves (adenosine).	[162,163,164]
A. schoenoprasum	Whole plant,pale-purple flowers		(20S, 25S)-spirost-5-en-3β, 12β,21-triol 3-O-α-L-rhamnopyranosyl-(1→2)-β-d-glucopyranoside, (20S, 25S)-spirost-5-en-3β, 11α,21-triol 3-O-α-L-rhamnopyranosyl-(1→2)-β-d-glucopyranoside, laxogenin 3-O-α-L-rhamnopyranosyl--(1→2)-[β-d-glucopyranosyl-(1→4)]-[β-d-glucopyranoside, (25R)-5α-spirostan-3β, 11α-diol 3-O-β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside.(cyanidin 3-O-β-glucosideAII) (kaempferol 3-O-(2-O-β-glucosylFIII-β-glucosideFII)-7-O-β-glucosiduronic acid FIV) malonate AIII (AII-6→AIII-1, FIV-2→AIII-3), 1, (cyanidin 3-O-(3-O-acetyl-β-glucosideAII) (kaempferol 3-O-(2-O-β-glucosylFIII-β-glucosideFII)-7-O-β-glucosiduronic acid FIV) malonate AIII (AII-6→AIII-1, FIV-2→AIII-3), 2, and 7-O-(methyl-O-β-glucosiduronateFIV).	Cytotoxicity against HCT 116 and HT-29 human colon cancer lines.	[165,166]
A. minutiflorum Regel	Bulbs		Minutoside A, minutoside B, Minutoside C, alliogenin, neoagigenin	Antifungal activity.	[167]
A. neapolitanum	Extracts		3-O-{[2-O-α-1-rhamnopyrnosyl-4-O-β-d-glucopyranosyl]-β-d-glucopyranoside}, isorhamnetin; 3-O-{[2-O-α-1-rhamnopyrnosyl-6-O-β-d-glucopyranosyl]-β-d-glucopyranoside}, isorhamnetin; 3-O-{[2-O-α-1-rhamnopyranosyl-4-O-β-d-glucopyranosyl]-β-d-glucopyranoside}-7-O-β-d-glucopyranoside and isorhamnetin; 3-O-{[2-O-α-1-rhamnopyranosyl-6-O-β-d-gentiobiosyl]-β-d-glucopyranoside}.	Antiplatelet aggregation activity.	[168]
A. tripedale	Bulbs,leaves	Iran	6,7-dimethoxy-N-trans-caffeoyltyramine; N-trans-feruloyltyramine. (+)-S-(1-butenyl)-L-cysteine sulfoxide (homoisoalliin), S-(1-butenyl)-L-cysteine (desoxyhomoisoalliin).	NR.	[167,168]
A. porrum L.	Bulbs		Kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-β-d-galactopyranosyl]-(1→4)-O-β-d-glucopyranoside; Kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-β-d-glucopyranosyl]-(1→6)-O-β-d-glucopyranoside.(25R)-5 α-spirostan-3 β, 6 β-diol 3-O-[O-β-d-glucopyranosyl-(1→2)-O-[β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside}; (25R)-5 α-spirostan-3 β, 6 β-diol 3-O-{O-β-d-glucopyranosyl-(1→3)-O-β-d-glucopyranosyl-(1→2)-O-[β-d-xylopyranosyl-(1→3)]-O-β-d-galactopyranosyl-(1→4)-β-d-galactopyranoside}	Antiplatelet aggregation activity.Antifungal activity.	[169,170,171]
A. chinense.A. chinense G. Don	Bulbs		Chinenoside II and chinenoside III.(25 R,S)-5 α-Spirostan-3β-ol tetrasaccharide, (25R)-3 β-hydroxy-5 α-spirostan-6-one di- and tri-saccharides.Xiebai-saponin I (laxogenin 3-O-β-xylopyranosyl (1→4)-[α-arabinopyranosyl (1→6)-β-glucopyranoside), laxogenin 3-O-α-arabinopyranosyl (1→6)-β-glucopyranoside, laxogenin, isoliquiritigenin, isoliquiritigenin-4-O-glucoside, and β-sitosterol glucoside.	Inhibition of cAMP phosphodiesterase.Antitumor-promoting activity (laxogenin).	[172,173,174,175]
A. macrostemon.A. macrostemon Bunge	Bulbs,leaves	Japan	Macrostemonoside G (26-O-β-d-glucopyranosyl-22-hydroxy-5-β-furost-25(27)-ene-3 β,12 β,26 triol 3-O-β-d-glucopyranosyl(1-->2)-β-d-galactopyranoside) and I (26-O-β-d-glucopyranosyl-22-hydroxy-5 β-furost-25(27)-ene-12-one-3 β,26-diol 3-O-β-d-glucopyranosyl(1→2)-β-d-galactopyranoside).tigogenin-3-O-β-d-glucopyranosyl(1-->2) [β-d-glucopyranosyl(1→3)1]-β-d-glucopyranosyl(1→4)-β-d-galactopyranoside (1) and tigogenin-3-O-β-d-glucopyranosyl(1→2)[β-d-glucopyranosyl (1→3)(6-O-acetyl-β-d-glucopyranosyl)] (1→4)-β-d-galactopyranoside (2). Macrostemonoside E-(25R)-26-O-β-d-glucopyranosyl-5 α-furost-20(22)-ene-3 β,26-diol-3-O-β-d-glucopyranosyl (1→2) [β-d-glucopyranosyl (1→3)]-β-d-glucopyranosyl (1→4)-β-d-galactopyranoside; Macrostemonoside F(II)-(25R)-26-O-β-d-glucopyranosyl-5 β-furost-20(22)-ene-3 β,26-diol-3-O-β-d-glucopyranosyl (1→2)-β-d-galactoside. Allimacronoid A (1-O-(E)-feruloyl-β-d-glucopyranosyl (1-2)-[β-d-glucopyranosyl (1-6)]-β-d-glucopyranose), Allimacronoid B (1-O-(E)-feruloyl-{β-d-glucopyranosyl (1-4)-[β-d-glucopyranosyl (1-2)]}-[β-d-glucopyranosyl (1-6)]-β-d-glucopyranose) and Allimacronoid Cn1-O-(E)-feruloyl-{β-d-glucopyranosyl (1-6)-[β-d-glucopyranosyl (1-2)]}-[β-d-glucopyranosyl (1-6)]-β-d-glucopyranose.	In vitro inhibition of ADP-induced human platelet aggregation (macrostemonoside G).Inhibitory activity against rabbit platelet aggregation induced by ADP (1).	[176,177,178,179]
A. schubertii	Bulbs		(25R and S)-5 α-spirostan-2 α,3 β,6 β-triol 3-O-β-d-glucopyranosyl-(1→2)-O-[4-O-benzoyl-β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside, (25R and S)-5 α-spirostan-2α,3β,6 β-triol 3-O-β-d-glucopyranosyl-(1→2)-O-[3-O-benzoyl-β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside, (25R and S)-5 α-spirostan-2α,3β,6 β-triol 3-O-β-d-glucopyranosyl-(1→2)-O-[4-O-(3S)-3-hydroxy-3-methylglutaroyl-β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside and 26-O-β-d-glucopyranosyl-(25R and S)-5 α-furostan-2α,3β,6β,22 zeta,26-pentol 3-O-β-d-glucopyranosyl-(1→2)-O-[β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside.	NR.	[180]
A. tuberosum	Seeds	Shanghai	(2α, 3β, 5α, 25S)-2,3,27-trihydroxyspirostane 3-O-α-L-rhamnopyranoyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-β-d-glucopyranoside.Tuberoside J-(25R)-5 α-spirostan-2α,3β,27-triol 3-O-α-L-rhamnopyranosyl-(1-->2)-β-d-glucopyranoside; Tuberoside K-(25R)-5α-spirostan-2α,3β 27-triol 3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-d-glucopyranoside; and Tuberoside L-27-O-β-d-glucopyranosyl-(25R)-5α-spirostan-2α,3β,27-triol 3-O-α-d-rhamnopyranosyl-(1-->2)-[α-L-rhamnopyranosyl-(1→4)]-β-d-glucopyranoside.Tuberoside M-(25S)-5β-spirostane-β,3 β-diol 3-O-α-L-rhamnopyranosyl-(1→4)-β-d-glucopyranoside.Tuber-ceramide (N-(2′,3′-dihydroxy-tetracosenoyl)-2-amino-1,3,4-trihydroxy octadecane), and Cerebroside (N-(2′,3′-dihydrox-tetra-cosenoyl)-2-amino-1,3,4-trihydroxy octadecane).	Tuberoside M inhibits the proliferation of the human promyelocytic leukemia cell line (HL-60)	[181,182,183]
A.albopilosum and A. ostrowskianum	Bulbs		(25 R and S)-5 α-spirostane-2α, 3 β,6 β-triol 3-O-(O-β-d-glucopyranosyl-(1→2)-O-[3-O-acetyl-β-d-xylopyranosyl-(1→3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside), (25R)-2-O-[(S)-3-hydroxy-3-methylglutaroyl]-5 α-spirostane-2α, 3β, 6β-triol 3-O-(O-β-d-glucopyranosyl-(1→2)-O-[β-d-xylopyranosyl-(1—>3)]-O-β-d-glucopyranosyl-(1→4)-β-d-galactopyranoside), (22S)-cholest-5-ene-1β, β,16 β,22-tetraol 1-O-α-L-rhamnopyranoside 16-O-(O-α-L-rhamnopyranosyl-(1→3)-β-d-glucopyranoside), 1β, 3β, 16β-trihydroxycholest-5-en-22-one 1-O-aα-L-rhamnopyranoside 16-O-(O-α-L-rhamnopyranosyl-(1→3)-β-d-glucopyranoside), 1β,3β,16 bβ-trihydroxy-5 α-cholestan-22-one 1-O-α-L-rhamnopyranoside 16-O-(O-α-L-rhamnopyranosyl-(1→3)-β-d-glucopyranoside) and (22S)-cholest-5-ene-1β,3β, 16β,22-tetraol 16-O-(O-β-d-glucopyranosyl-(1→3)-β-d-glucopyranoside).	NR.	[184]
A.fistulosum.A.fistulosum L.	Whole plant,leaves,seeds	Iran	Fistulomidate A ((1Z,2E)-Methyl3-(3,4-dimethoxyphenyl)-N-(4-hydroxyphenethyl) acrilimidate) and Fistulomidate B ((1Z,2E)-Methyl3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrilimidat).Onionin A1, onionin A2, and onionin A3.Glycerol mono-(E)-8,11,12-trihydroxy-9-octadecenoate, tianshic acid, 4-(2-formyl-5-hydroxymethylpyrrol-1-yl) butyric acid, p-hydroxybenzoic acid, vanillic acid, and daucosterol.	Antibacterial and cytotoxic activity. Suppression of tumor progression in mouse ovarian cancer (onionin A1).Inhibition of the growth of Phytophtohora capsici on V8 media (glycerol mono-(E)-8,11,12-trihydroxy-9-octadecenoate and V).	[159,185,186]
A.carolinianum DC	Bulb	Mongolia	Cinnamoylphenethylamine derivative	Weak cytotoxic activity	[187]
A.ampeloprasum var. porrum (Leek)	Plant parts		A-β- d -glucopyranoside	Anticancer activity against MCF-7 human breast cancer cell.	[187]
A.ascalonicum L.		China	Ascalonicoside C-(25R)-26-O-β-d-glucopyranosyl-22-hydroxy-5α-furost-2-one-3β,5,6β, 26-tetraol-3-O-α-L-rhamnopyranosyl-(1→2)-β-d-glucopyranoside. Ascalonicoside d-(25R)-26-O-β-d-glucopyranosyl-22-methoxy-5α-furost-2-one-3β,5,6β, 26-tetraol-3-O-α-L-rhamnopyranosyl-(1→2)-β-d-glucopyranoside. (25R)-26-O-β-d-glucopyranosyl-22-hydroxy-5-ene-furostan-3β,26-diol-3-O-α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[ α-L-rhamnopyranosyl-(1→2)]-β-d-glucopyranoside. 25R)-26-O-β-d-glucopyranosyl-22-hydroxy-5-ene-furostan-3β, 26-diol-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-arabinofuranosyl-(1→4)]-β-d-glucopyranoside.	NR.	[188,189]
A. siculum	Bulbs	Zwanenburg, The Netherlands	(Z)-Butanethial S-oxide, (R(S),R(C),E)-S-(1-butenyl)cysteine S-oxide (homoisoalliin).	NR.	[190]
A. chrysanthum	Barks	Guangzhou, China	Chrysanthumones A (6″,6″-dimethyl-4″,5″-dihydropyrano [2″,3″: 8,7]-6″′,6″′-dimethyl-prenyl-4″′,5″′-dihydropyrano [2″′,3″′:2′,3′]apigenin) and B((E)-5,7-dihydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-1-enyl)-4H-chromen-4-one).	NR.	[191]
A. L. melanocrommyum section Megaloprason.	Bulbs	Central Asia	L-(+)-S-(2-pyridyl)-cysteine sulfoxide.	NR.	[192]
A.ampeloprasum L.	Bulbs	United States of America	Ampeloside Bs1 (apigenin 3-O-β-glucopyranosyl (1 → 3)-β-glucopyranosyl (1 → 4)-β-galactopyranoside), ampelosides Bf1 ((25R)-26-O-β-glucopyranosyl-22-hydroxy-5α-furostane-2α,3β,6β,26-tetraol-3-O-β-glucopyranosyl(1 → 3)-β-glucopyranosyl-(1 → 4)-β-galactopyranoside) and Bf2 ((25R)-26-O-β-glucopyranosyl-22-hydroxy-5α-furostane-2α,3β,6β,26-tetraol-3-O-β-glucopyranosyl(1 → 4)-β-galactopyranoside).	Weak antifungal activity by ampeloside Bs1.	[193]
A.bakeri Reg.	Tuber		Adenosine, guanosine, and tryptophan, β-sitosterol β-d-glucoside.	Strong inhibitory effect on human platelet aggregation generated by 2 μM ADP in both primary and secondary waves (adenosine).	[162]
A. victorialis var. platyphyllum	Aerial parts, bulbs	Korea	Gitogenin 3-O-lycotetroside, astragalin and kaempferol 3, 4′-di-O-β-d-glucoside.	Cytotoxic activity.	[194]
A.nutans L.	Underground plant parts		Deltoside, nolinofuroside D, 25R Δ(5)-spirostan 3β-ol-3-O-α-L-rhamnopyranosyl(1-->2)-[β-d-glucopyranosyl(1→4)]-O-β-d-galactopyranoside and 25R Δ(5)-spirostan 1 β, 3β-diol 1-O-β-d-galactopyranoside.	NR.	[195]
A. giganteum	Bulbs	Japan	3-O-acetyl-(24S,25S)-5α-spirostane-2α,3β,5α,6β,24-pentol 2-O-β-d-glucopyranoside.	Inhibition of cAMP phosphodiesterase activity.	[196]
A.hookeri Thwaites	Rhizomes	China	Di-2-propenyl trisulfide, diallyl disulfide, and dipropyl trisulfide.	Antimicrobial activity against Aspergillus fumigatus and C. albicans.	[197]

NR: not reported.

The chemical structures of compounds from the genus Allium are shown in Figure 4.

Figure 4

Chemical structures of compounds isolated from the genus Allium. Quercetin (13), vanillic acid (14) and adenosine (15).

3.4. Pharmacological Effects of Allium

There are several species within Allium whose biological activities have been well established [198]. This section focuses on the pharmacological activities associated with these species.

3.4.1. Antimicrobial Activities

Garlic has shown antimicrobial effects against Gram-positive, Gram-negative and acid fast stain organisms [199,200,201]. Allicin from garlic showed effectiveness toward methicillin-resistant S. aureus (MRSA) [200]. Extracts from garlic also showed broad-spectrum fungicidal effect against several fungi including Candida, Trichophyton, Cryptococcus, Aspergillus, Trichosporon and Rhodotorula species. Garlic extract was recently found to inhibit Meyerozyma guilliermondii and Rhodotorula mucilaginosa germination and growth [202]. A study by Fufa reported the antifungal activity of various A. sativum extracts, namely aqueous, ethanol, methanol, and petroleum ether against human pathogenic fungi such are Trichophyton verrucosum, T. mentagrophytes, T. rubrum, Botrytis cinereal (B. cinerea), Candida species, Epidermophyton floccosum, A. niger, A. flavus, Rhizopus stolonifera, Microsporum gypseum, M. audouinii, Alternaria alternate, Neofabraea alba, and Penicillium expansum [203]. Essential oil from garlic showed antifungal activity against a number of fungi such as (C. albicans, C. tropicalis and Blastoschizomyces capitatus). Saponins extracted from A. sativum had antifungal activity against B. cinerea and Trichoderma harzianum [204]. Allium species from Ghana were reported by Danquah et al. to possess anti-infective and resistance modulatory effects on selected microbial strains [205]. Allium hirtifolium was found to exhibit antimicrobial activities against E. faecalis [206].

Previous studies have shown that garlic extract inhibit the growth of Blastocystis species in vivo and this effect was attributed to the several phytochemicals contained in garlic extracts. Examples of these phytochemicals are thiosulfinates and allicin which have been investigated to possess antibacterial and antiprotozoal effects [204,207]. Garlic extracts have been evaluated for antiviral effects against influenza B, human rhinovirus type 2, human cytomegalovirus (HCMV), parainfluenza virus type 3, Herpes simplex type 1 and -2, vaccinia virus, and vesicular stomatitis virus [208]. Danquah et al. again reported the antitubercular effects of analogues of disulfides from A. stipitatum as well as their anti-biofilm and anti-efflux effects [209].

3.4.2. Antioxidant Properties

It has been reported that frequent garlic intake promotes internal antioxidant activities and reduces oxidative adverse effects either by increasing the endogenous antioxidant synthesis or reducing the production of oxidizing agents such as oxygen-free radical species (ORS) [210]. It has also been demonstrated that garlic possesses protective properties against gentamycin as well as acetaminophen-induced hepatotoxicity by improving antioxidant status, and regulating oxidative stress [200]. Garlic extract was found to elevate the activities of selected antioxidant enzymes (e.g., superoxide dismutase (SOD)) and decrease glutathione peroxidase (GSH-Px) in rats’ hepatic tissues [13,118,211]. Saponins extracted from garlic were reported to scavenge intracellular ROS and protect mouse-derived C2C12 myoblasts towards growth inhibition and H2O2-induced DNA damage [13,212]. A. ursinum aqueous extract also demonstrated antioxidant effect which lasted approximately 16 h [213]. A. hirtifolium was reported to possess antioxidant capacity by neutralizing the free radical species in a system [214].

3.4.3. Anti-Inflammatory Properties

It has been reported widely that garlic extracts and its related phytochemicals possess anti-inflammatory activity. A study by Ahmad et al. revealed that garlic extracts significantly impaired liver inflammation and damage caused by Eimeria papillata infections [215]. The mechanism underlying the anti-inflammatory effects of garlic was attributed to the inhibition of emigration of neutrophilic granulocytes into epithelia as described by Hobauer et al. [216] and Gu et al. [217]. The chloroform extract of aged black garlic acts by reducing NF-κB activation in human umbilical vein endothelial cells caused by tumor necrosis factor-α (TNF-α) and the methanolic extract also reported to prevent the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) production by NF-κB inactivation [218]. A report by Jin et al. confirmed that thiacremonone (a sulfur compound isolated from garlic) prevents neuroinflammation and amyloidogenesis by blocking the NF-κB activity, and therefore makes it an ideal remedy to manage neurodegenerative disorders (e.g., Alzheimer’s disease) related to inflammation [219].

Krejčová et al. reported that pyrithione and related sulfur-containing pyridine N-oxides from Persian shallot possessed anti-inflammatory and neurological activity [220]. The extracts of A. stipitatum were reported to exhibit antibacterial effect in vivo against methicillin-resistant S. aureus [221]. Anti-inflammatory effect of A. hookeri on carrageenan-induced air pouch mouse model was also established by Kim et al. [222].

3.4.4. Anticancer Activity

Comparison of the anticancer effect of raw garlic extracts against other extracts from different plants found garlic to be the most effective and highly specific anticancer agent [223]. The anticancer mechanisms of garlic extracts were reported to be mediated via inhibition of cell growth and proliferation, regulation of carcinogen metabolism, stimulation of apoptosis, prevention of angiogenesis, invasion, and migration; and thus affording the anticancer agent with minimal negative effects [13]. Chabria et al. reported that allicin isolated from garlic suppresses colorectal cancer metastasis through enhancing immune function and preventing the formation of tumor vessels as well as surviving gene expression to enhance the cancer cell’s apoptosis [224]. Fleischauer and Arab [225] reported that continuous garlic intake could decrease different kinds of cancer propagation such as cancer of the lung, colon, stomach, breast, and prostate. Piscitelli et al. reported that garlic reduced the plasma concentrations of saquinavir by approximately 50% in healthy participants after a 3-week garlic supplement intake. In addition to this, many researchers evaluated the antitumor and cytotoxic actions of garlic and its related constituents in vitro and in vivo [226].

3.4.5. Other Pharmacological Effects of Allium Species

Investigations on extracts of A. sativum (garlic) revealed anticholinesterase effects, which could be further developed and utilized in the management of Alzheimer’s disease [227,228,229]. Garlic is known to possess hypolipidemic effects by reducing the total glycosaminoglycans concentration in heart and aorta [230]. Garlic is also known to reduce the level of cholesterol either by acid stimulation and excretion of neutral steroids or by reducing the cholesterogenic and lipogenic effects of fatty acid synthase, 3-hydroxy-3-methyl-glutaryl-CoA reductase, malic acid, and glucose-6 phosphate dehydrogenase in hepatocytes [231]. Garlic tablets formulated by Ashraf et al. and administered at a dose of 600 mg/day for 12 weeks in diabetic patients with dyslipidemia resulted in high HDL, low LDL and TC levels [232].

Allicin, a constituent in garlic, was found to reduce diabetes mellitus in rats, which was similar to that demonstrated by glibenclamide and insulin [233]. Garlic extracts reduce body weight, adipose tissue mass and improved plasma lipid profiles in mice with high-fat diet-induced obesity [234]. The mechanism of these activities is downregulation of multiple gene expression such as adipogenesis along with upregulation of the mitochondrial inner membrane proteins expression [234]. Garlic extract is widely known to significantly control blood pressure by reducing both systolic and diastolic pressures [235]. Moreover, several reports have confirmed the antihypertensive effects of garlic [236]. Extracts of A. stipitatum were also assessed and established to possess significant wound healing properties [237].

4. The Genus Crinum

4.1. Geographical Distribution of Crinum

Crinum, which also belongs to the Amaryllidaceae family, comprises approximately 160 beautiful lilies that grow naturally in coastal areas of the tropics and subtropics. They are widely distributed in Africa, Asia, Australia and America [238,239,240,241]

4.2. Traditional Uses of Crinum

Plants of the genus Crinum have been used to treat various diseases across the world [242]. In China and Vietnam, Crinum plants in traditional medicine are believed to possess antiviral and immune-stimulatory properties. A hot aqueous extract of Crinum latifolium (C. latifolium) is used as an antitumor agent. Crinum asiaticum (C. asiaticum) is used in Malaysia to treat rheumatism and to relieve local pain [239]. Crinum amabile Donn. (C. amabile) is used in Vietnam to induce emesis, as well as for rheumatism and earache [241].

The bulbs of C. asiaticum L. are used as a tonic, laxative and expectorant in Indian traditional medicine, as well as for treating urinary tract diseases [241]. The seeds are used as purgatives, diuretics, and tonics, while the raw roots are used as an emetic. The leaves are also very useful in the management of skin problems, inflammation and cough [241]. C. latifolium L. is also used to treat rheumatism, abscesses, earaches, and as a tonic. Crinum pratense (C. pratense) and Crinum longifolium (C. longifolium) are also used as bitter tonics, laxatives and in the management of chest illnesses [243].

Crinum zeylanicum (C. zeylanicum) L. is used in Sri Lanka to treat abscesses and fevers; the bulbs are also used as rubefacient in rheumatism and against snake bites; and the juice from the leaves used to treat earaches [244].

The roots of Crinum species have been used in African traditional medicine to cure urinary infections, coughs and colds, renal and hepatic disorders, ulcers, sexually transmitted infections, and backache, as well as enhance breastfeeding in both animal and human mothers [241]. Crinum kirkii Bak. (C. kirkii), a widespread East African grassland plant, is used to heal wounds in Kenya. In Tanzania, the fruit and inner part of the bulbs are used as purgatives, and the outer scales employed as rat poison [245,246]. Extracts of Crinum delagoense (C. delagoense) Verdoorn is utilized in Zulu and Xhosa traditional medicine in South Africa to treat urinary tract infections and body oedema [247,248,249]. Rheumatism, aching joints, septic sores, varicose veins, and kidney and bladder infections have all been treated using the South African Crinum bulbispermum (C. bulbispermum) [250]. In Cameroon, Crinum pupurascens (C. pupurascens) Herb is used to treat sexual asthenia and spleen disorders. Crinum species (C. defixum Keraudren et Gawl., C. firmifolium Baker, C. modestum Baker) are as well used in Madagascar to treat abscesses, anthrax, and otitis. It is also employed as an emetic, diaphoretic, and emollient. Externally, Crinum firmifolium (C. firmifolium) is used to treat a variety of parasite skin afflictions [40,243].

4.3. Phytochemistry of Crinum

Several phytochemical and pharmacological studies have been conducted on the genus Crinum. The compounds isolated from various species of Crinum as well as their biological activities have been outlined in Table 11.

Table 11

Bioactive compounds isolated from Crinum species.

Plant Species	Plant Part	Country	Isolated Compounds	Bioactivity	References
C. x amabileC. x amabile Donn ex Ker Gawl	Bulbs Stems, roots	EcuadorBrazilThailand	Haemanthamine/crimine-type alkaloid.Lycorine-type alkaloidGalanthamine-type alkaloid.Augustine N-oxide, buphanisine N-oxide.Amabiloid A.	Anticholinesterase(anti-AChE) and antibutyrylcholinesterase (anti-BuChE) activity.	[249,250,251]
C. defixum Ker-Gawl	Bulbs	India	Hydrazide derivative. (E)-N-[(E)-2-butenoyl]-2-butenoylhydrazide.	Anti-genotoxic activity.	[252]
C. moorei	Bulblets		Cherylline, crinamidine, crinine, epibuphanisine, lycorine, powelline, undulatine, 1-epideacetylbowdensine, 3-O-acetylhamayne.3-[4′-(8′-aminoethyl) phenoxy] bulbispermine, mooreine.	NR.	[253]
C. biflorum	Bulbs	Senegal	5,6,7-trimethoxy-3-(4 hydroxybenzyl) chroman-4-one, 3-hydroxy-5,6,7-trimethoxy-3-(4-hydroxybenzyl) chroman-4-one, 3-hydroxy-5,6,7-trimethoxy-3-(4-methoxybenzyl) chroman-4-one, 5,6,7-trimethoxy-3-(4-methoxybenzyl) chroman-4-one, (E)-N-(4-hydroxyphenethyl)-3-(4-hydroxyphenyl) acrylamide.	Anticancer, anti-AChE, anti-glucosidase activity.	[254,255]
C. asiaticumC. asiaticum var. sinicumC. asiaticum L.C. asiaticum var. japonicum.C. asiaticum L. var. sinicum.	Seeds, rhizome, fruitsBulbs, stems, leaves	Beijing, China,Hainan Province,Japan,Island of Jeju in Korea	Flavonoids Isopowellaminone.(2R,3S)-7-methoxyflavan-3-ol (1:), (2R,3S)-7-hydroxy-flavan-3-ol (2:), (2R,3S)-2 ′-hydroxy-7-methoxy-flavan-3-ol (3:).Norgalanthamine.CrinamineCAL-n. Crijaponine A, crijaponine B, ungeremine, lycorine, 2-O-acetyllycorine, 1,2-O-diacetyllycorine, (-)-crinine, 11-hydroxyvittatine, hamayne,(+)-epibuphanisine, crinamine, yemenine A, epinorgalanthamine.Criasiaticidine A, pratorimine, Lycorine, 4′-hyd’oxy-7-methoxyflavan.Crinamine, lycorine, norgalanthamine, epinorgalanthamine.Asiaticumines A, asiaticumines B.	Inhibitory activity against LPS-induced nitric oxide production.Anticancer activity (against cervical cancer SiHa cells).Inhibition of platelet aggregation.Promotion of hair growth through dermal papilla proliferation. Inhibition of the growth of HepG2 tumor cells.Anti-AChE activity, cytotoxic activity.Cytotoxic against Meth-A (mouse sarcoma) and Lewis lung carcinoma (mouse lung carcinoma).Inhibition of the activity of hypoxia inducible factor-1 (crinamine).Cytotoxicity.	[256,257,258,259,260,261,262,263,264,265,266]
C. kirkii Baker	Bulbs		Noraugustamine, 4aN-dedihydronoraugustamine, 3-O-acetylsanguinine, 1,2-diacetyllycorine.	Antiparasitic activity against Trypanosoma brucei (T. brucei) rhodesiense, Trypanosoma cruzi (T. cruzi).	[267,268]
C. macowanii	Bulbs		Macowine, lycorine, cherylline, crinine, krepowine, powelline, buphanidrine, crinamidine, undulatine, 1-epideacetylbowdensine, 4a-dehydroxycrinamabine.	NR.	[249]
C. firmifolium	Leaves	Madagascar	2-alkylquinolin-4(1H), 2-alkylquinolin-4(1H).	Antiplasmodial activity.	[269]
C. latifolium	BulbsLeaves	China.Hanoi, Vietnam	4,8-dimethoxy-cripowellin C. 4,8-dimethoxy-cripowellin D, 9-methoxy-cripowellin B, 4-methoxy-8-hydroxy-cripowellin B, cripowellin C.C. latines A, C. latines B and C. latines C.4-senecioyloxymethyl-3,4-dimethoxycoumarin, 5,6,3 ′-trihydroxy-7,8,4 ′-trimethoxyflavone.4-methyloxysenecioyl-6,7-dimethoxycoumarin, 5,6,3′-trihydroxy-7,8,4′trimethoxyflavone.	Cytotoxic against tumor cell lines, antimicrobial activity, antioxidant activity.Inhibitory activity against human umbilical venous endothelial cells.	[270,271,272]
C. scillifolium	Bulbs		Scillitazettine, scilli-N-desmethylpretazettine.	Mild antiplasmodial activity	[273]
C. zeylanicum (L)	Bulbs, leaves, flowers, fruits	CubaSri Lanka	Crinine, Lycorine, 11-O-acetoxyambelline, ambelline, 6-hydroxybuphanidrine, 6-ethoxybuphanidrine, 3-acetylhamayne, 6-hydroxycrinamine, hamayne, 6-methoxycrinamine.	Antiproliferative effect.	[246,274]
C. jagus (J. Thomps) Dandy	Bulbs, leaves	SenegalGhana	Gigantelline, gigantellinine, gigancrinine, sanguinine, cherylline, lycorine, crinine, flexinine, hippadine.Galanthamine, galanthamine N-oxide, powelline.	Anti-AChE activity,inhibitors of TcAchE, hAChE and hBChE	[275,276]
C. abyscinicum Hochst. ExA. Rich	Bulbs	Ethiopia	6-hydroxycrinamine, lycorine.	Antiproliferative activity against A2780 epithelial ovarian cancer and MV4-11 acute myeloid leukemia cell lines.	[277]
C. erubescens	Above ground plant parts	Puntarenas, Costa Rica	Cripowellin A, cripowellin B, cripowellin C, cripowellin D, hippadine.	Antiplasmodial activity.	[278]
C. yemense	Bulbs	Yemen	6-hydroxy-2H-pyran-3-carbaldehyde.Yemenines A, B and C, 1, (+)-bulbispermine, (+)-crinamine, (+)-6-hydroxycrinamine, (-)-lycorine.	Tyrosinase inhibitor.Inhibit nitric oxide production, induce nitric oxide synthase.	[277,278,279,280]
C. bulbispermumC. bulbispermum III	Bulbs	Egypt	8-hydroxylycorin-7-one, 2-deoxylycorine, vittatine, 11-hydroxyvittatine, hippamine.4-hydroxy-2′,4′-dimethoxydihydrochalcone, 4,5-methylenedioxy-4′-hydroxy-2-aldehyde [1,1′-biphenyl], hippacine, 4′-hydroxy-7-methoxyflavan-3-ol, 2(S),3′,4′-dihydroxy-7-methoxy flavan, isolarrien, isoliquiritigenin, liquiritigenin.Bulbispermine.	NR.	[281,282,283]
C. powellii	Bulbs	SwitzerlandColombia	Linoleic acid ethyl ester, alkaloid hippadine, calleryanin, 4′-hydroxy-7-methoxyflavan. Lycorine, 1-O-acetyllycorine, ismine.	AChE inhibitor (linoleic acid ethyl ester).Inhibition of topoisomerase 1 activity.	[284,285]
C. glaucum	Bulbs	Nigeria	Hamayne, lycorine, haemanthamane, crinamine.	Choline esterase inhibitory activity.	[286]
C. purpurascens	Leaves	Cameroon	4,5-ethano-9,10-methlenedioxy-7-phenanthridone, 4,5-ethano-9-hydroxy-10-methoxy-7-phenanthridone, α-d-glucopyranoside.	Antibacterial activity	[287]

NR: not reported.

Chemical structures of common compounds from Crinum are shown in Figure 5.

Figure 5

Chemical structures of compounds isolated from the genus Crinum. Lycorine (16), crinamine (17), galantamine (18) and crinine (19).

4.4. Pharmacological Activities of Crinum

4.4.1. Anti-Inflammatory and Analgesic Effects

The anti-inflammatory and the analgesic properties of various Crinum species have been investigated by several authors. The anti-inflammatory effect of C. asiaticum as well as its effect on bradykinin-induced contractions on isolated uterus has been reported [288,289,290,291]. The ethanolic extract of C. asiaticum demonstrated significant analgesic effect in an acetic-acid-induced writhing test [292]. Antipyretic and anti-inflammatory properties of C. jagus were recently reported by Minkah and Danquah [291]. Leaf extract of C. bulbispermum has also been established to possess antinociceptive effects [293,294].

4.4.2. Anticancer and Cytotoxicity Effects

The cytotoxic effects of C. asiaticum extract was investigated and was shown to exert toxic effect on brine shrimps and murine P388 D1 cells [294,295,296,297,298]. Yui et al. demonstrated that hot water extracts of C. asiaticum exhibited potent inhibition of calprotectin-induced cytotoxicity in MM46 mouse mammary carcinoma cells. This activity whi1ch was later attributed to lycorine, an active compound in C. asiaticum [297]. Some alkaloids isolated from the bulbs of C. asiaticum have been reported to show remarkable inhibition against tumor cell lines A549, LOVO, HL-60, and 6T-CEM [261].

The extract of C. asiaticum exhibited antiproliferative and chemosensitizing effects against multi-drug-resistant cancer cells [298,299]. The antiangiogenic activity of the methanolic leaf extract of C. asiaticum was evaluated and established by Yusoff [300]. The cytotoxic effect of the essential oil extracted from C. asiaticum was as well established in MCF-7 cells [301]. A recent work done by Yu et al. reported the inhibition of the growth of HepG 2 cells in a dose-dependent manner by polysaccharide CAL-n, an isolate from C. asiaticum [262]. Also, the neuroprotection and anti-neuroinflammatory effects in Neuronal Cell Lines were reported by Lim et al. [279,302]. Alkaloids from C. bulbispermum have also been reported to possess cytotoxic activities [284]. Evaluation of the cytoprotective potential of C. bulbispermum, after induction of toxicity using rotenone, in SH-SY5Y neuroblastoma cells proved that, the plant has such effect as reported [303]. Aboul-Ela et al. [279] tested the cytotoxic effect of C. bulbispermum bulbs using the brine shrimp bioassay.

4.4.3. Antimicrobial Properties

The in vitro antitubercular effects of C. asiaticum on Mycobacterium tuberculosis (M. tuberculosis) surrogate, Mycobacterium smegmatis (M. smegmatis), were reported [291,304]. C. asiaticum was shown to possess a broad-spectrum antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal pathogens [291,299]. Antifungal activities of the essential oil and extracts of C. asiaticum against pathogenic fungi have also been established [305,306]. It is reported that the methanolic root extract of C. asiaticum exerts significant anti-HIV-1 activity [307]. The ethanolic extract of C. asiaticum significantly inhibited selected bacteria as evaluated by Naira et al. [308]. Dichloromethane extract of C. asiaticum was found to be the most effective against selected oral and vaginal Candida species [309]. Minkah and Danquah again demonstrated the antimicrobial activity of extracts of C. jagus against clinically significant microorganisms in the High-throughput spot culture growth inhibition (HT-SPOTi) assay [291]. Water/Ethanol extract of C. jagus was observed to be active on Shigella flexneri-induced diarrhea in rats [310]. The antimicrobial and antioxidant properties of C. jagus make it suitable as a wound healing agent [311]. The crude methanolic extract of C. jagus was investigated to have effect on Mycobacterium tuberculosis [312,313]. The crude alkaloid of C. jagus inhibited Dengue virus infection [314]. C. macowanii has also been shown to possess biological effects such as antifungal, antiviral and antiplasmodial activities [315].

4.4.4. Antioxidant Properties

There antioxidant effects of C. asiaticum have been studied extensively. The ethanolic extract exhibited protective effects on human erythrocyte [316]. C. asiaticum bulbs also exerted remarkable free radical scavenging ability [317]. The antioxidant activity of the ethanolic extract of C. asiaticum leaves in alloxan-induced diabetic rats was well demonstrated [318]. More recent work on the methanolic extract of C. asiaticum showed antioxidant effects [319]. Potent DPPH radical scavenging activity was also observed for the aqueous C. asiaticum leaf extract [304]. Both the leaves and bulbs of C. jagus are important sources of antioxidant compounds [320]. A methanolic bulb extract of C. bulbispermum showed mild radical scavenging activity [321]. The leaf extracts of C. bulbispermum also showed modest antioxidant activity in a thiobarbituric acid reactive substances assay [297].

4.4.5. Other Pharmacological Properties

Kumar reported the wound healing activities of the ethanolic C. asiaticum extract. The extract was found to possess pro-healing effects when topically applied on animal models by influencing various stages of healing process [322]. C asiaticum extract and norgalanthamine potentially influenced hair growth via inhibition of 5α-reductase activity and TGF-β1-induced canonical pathway [39,314]. There is a report on the inhibitory effects of three C. asiaticum genotypes against key enzymes implicated in the pathogenesis of Alzheimer’s disease and diabetes [319].

The anti-obesity effect of the C. asiaticum extract on a high-fat diet-induced obesity in monogenic mice has been reported [323,324]. An active fraction of C. jagus was shown to possess anticonvulsant activities in experimental rats [325].

Ethyl acetate and methanol extracts of C. bulbispermum have also been shown to exhibit acetylcholinesterase inhibitory properties [321]. The alkaloid galanthamine isolated from C. bulbispermum and other genera of Amaryllidaceae, has been approved for the treatment of Alzheimer’s disease [326]. Cognitive enhancing effect of a hydroethanolic extract of C. macowanii against memory impairment induced by aluminum chloride in balb/c mice has as well been reported [327].

5. The Genus Cyrtanthus

5.1. Botanical Description

Another large genus of the family Amaryllidaceae is Cyrtanthus. Cyrtanthus is derived from a Greek word for curved flower [6]. Species of this genus have numerous, black, winged seeds and give off a strong onion smell [6]. They possess a rhizome or bulb, flowers and a loculicidal capsule fruit [6]. They have leaves that are linear to lorate [6]. Flowers are funnel shaped with their stamens fixed in the corolla tube [6]. Species that belong to this genus include Cyrtanthus elatus (C. elatus) (Jacq.) Traub, Cyrtanthus obliquus (C. obliquus) (L.f.) Aiton, and Cyrtanthus mackenii (C. mackenii) Hook [44].

5.2. Geographical Distribution

Cyrtanthus is diverse and is a large sub-Saharan Africa genus consisting of approximately 55 species found mostly in South Africa. Cyrtanthus extends from the summer-dry southwest to the summer rainfall northeast [328]. The genus displays diverse floral morphology. The three major lineages show varying biogeographic affinities.

Clade A comprises taxa located in Southern African Grassland Biome with a few outliers in the Savanna Biome to the east and north, the Indian Ocean Coastal Belt Biome to the extreme east and the Fynbos Biome to the south [328]. Hence, it falls in the Afrotemperate Phytogeographical Region [329] that encompasses Afromontane phytochorion in the north and the Cape Floristic Region in the south [328]. Most existing species in the Afrotemperate lineage (Cyrtanthus attenuatus (C. attenuatus), Cyrtanthus macowanii (C. macowanii), Cyrtanthus epiphyticus (C. epiphyticus), C. mackenii subsp. cooperi, Cyrtanthus huttonii (C. huttonii), Cyrtanthus macmasteri (C. macmasteri), Cyrtanthus suaveolens (C. suaveolens), Cyrtanthus stenanthus (C. stenanthus var. stenanthus) and Cyrtanthus flanaganii (C. flanaganii) occur currently in the south-eastern African temperate grasslands. Cyrtanthus tuckii var. transvaalensis (C. tuckii) is the only species found in the grassland of the Highveld in the northern parts of South Africa. Few species are found outside this grassland area and includes Cyrtanthus angustifolius (C. angustifolius), Cyrtanthus fergusoniae (C. fergusoniae) and Cyrtanthus aureolinus (C. aureolinus) in the Cape Region together with C. mackenii subsp. Mackenii and Cyrtanthus brachyscyphus (C. brachyscyphus) that occupies drainage lines on the subtropical Indian Ocean Coastal Belt [330]. Southern Africa is the area where Cyrtanthus breviflorus (C. breviflorus) is found extending northwards in a series of disjunct populations along mountain corridors to East Africa and Angola.

Clade B is limited to the Fynbos and Succulent Karoo Biomes which constitute the Greater Cape Region, referred to hereafter as ‘the Cape’ [331]. Cyrtanthus labiatus (C. labiatus) and Cyrtanthus montanus (C. montanus) from the Baviaansklo of Mountains and Eastern Cape are found at the interface of the Fynbos and Albany Thicket Biomes. The Richtersveld species, Cyrtanthus herrei (C. herrei) is found in the semi-arid Succulent Karoo [328]. Most species found in ‘the Cape’ lineage are located on the summer-dry, southeast coast forelands with half the number in the Fynbos of the nonseasonal rainfall Eastern Cape. Cyrtanthus carneus (C. carneus, C. elatus, Cyrtanthus guthrieae (C. guthrieae, C. labiatus, Cyrtanthus leptosiphon (C. leptosiphon), Cyrtanthus leucanthus (C. leucanthus, Cyrtanthus montanus (C. montanus), and Cyrtanthus odorus (C. odorus) are found in specific vegetation types and soils.

Only two species of this taxon, namely Cyrtanthus collinus (C. collinus) and Cyrtanthus ventricosus (C. ventricosus) are well known, inhabiting the same soils and aspect in habitats on the continuous Cape Fold mountain ranges [328]. Cyrtanthus collinus is found on the coastal and inland mountains of the southern Cape and C. ventricosus extends from the Cape Peninsula into the Eastern Cape [328].

Most species of Clade C are found in the eastern lowlands and midlands of southern Africa, where they are concentrated in the subtropical biomes, Albany Thicket and Savanna [330,332]. This lineage constitutes Cyrtanthus flammosus (C. flammosus) and Cyrtanthus spiralis (C. spiralis), which are narrowly widespread to the Albany Thicket Biome. Confined to the Savanna Biome are Cyrtanthus eucallus (C. eucallus) and Cyrtanthus galpinii (C. galpinii) in the Lowveld. Other species span the Albany Thicket and Savanna Biomes: the Eastern Cape Cyrtanthus helictus (C. helictus) and, extending northwards from the Albany region through South Africa, Zimbabwe, western Mozambique and East Africa into Sudan, is Cyrtanthus sanguineus (C. sanguineus) [328]. Cyrtanthus obliquus, adapted to nutrient-poor soils, occupies rocky habitats in east–west tending valleys. A summary of their geographic distribution is presented in Table 12.

Table 12

Geographical distribution of the Genus Cyrtanthus.

Lineage	Location	Species	References
Clade A	Southern Africa Grassland Southeastern African temperate grasslandsGrassland of the Highveld in the northern partsSubtropical Indian Ocean Coastal BeltEast Africa and Angola	C. attenuatus, C. macowanii, C. epiphyticus, C. mackenii subsp. cooperi, C. huttonii, C. macmasteri, C. suaveolens, C. stenanthus var. stenanthus,C. flanaganiiC. tuckii var. transvaalensisC. angustifolius, C. fergusoniaeC. aureolinus, C. mackenii subsp. Mackenii, C. brachyscyphusC. breviflorus	[328]
Clade B	Baviaanskloof Mountains and Eastern Cape (Fynbos and Albany Thicket Biomes)Semi-arid Succulent KarooGreater Cape Region (“the Cape”)Coastal and inland mountains of the southern CapeCape Peninsula into the Eastern Cape	C. labiatus, C. montanusC. herreiC. carneus, C. elatus, C. guthrieae, C. labiatus, C. leptosiphon, C. leucanthus,C. montanus, C. odorusC. collinusC. ventricosus	[328]
Clade C	Albany Thicket BiomeSavanna BiomeNorthwards from the Albany region through South Africa, Zimbabwe, Western Mozambique and East Africa into SudanAlbany Thicket and Savanna BiomesExtends beyond the Savanna Biome into the Sub-Escarpmentand Highveld grasslandsFynbos BiomeSouthern parts of the Nama Karoo	C. flammosus, C. spiralisC. eucallus, C. galpiniiC. sanguineusC. helictusC. contractusC. wellandiiC. smithiae	[328]

5.3. Traditional Uses

Cyrtanthus obliquus, locally known as umathunga in South Africa, is used traditionally in the management of chronic coughs, headaches and scrofula [43,44]. C. obliquus root infusions are also employed in the management of stomach aches [333] while the crushed roots have been reported to find use in the management of leprosy [334]. Cyrtanthus species are also employed in the management of ailments associated with pregnancy, as well as cystitis, age-related dementia and leprosy [43,44]. Bulbs of C. contractus extracted in May and September is widely used locally in the management of mental illness, infections, inflammation, and cancer [335]. Infusions from species such as C. breviflorus, C. contractus, C. mackenii, C. sanguineus, C. stenanthus and C. tuckii are used by the Zulu in South Africa as protective sprinkling charms against storms and evil spirits [336]. Extracts of C. breviflorus Harv. are used as an anti-emetic agent and in the management of worm infestations such as tapeworm and roundworm. Extracts of C. elatus also finds use in the management of cough, headache and in labour induction [337].

5.4. Phytochemistry of Cyrtanthus

Species of Cyrtanthus have been identified as reservoirs for a host of chemical compounds. In a study performed by Mahlangeni et al., four homoisoflavanones, namely 5,7-dihydroxy-6-methoxy-3-(4′-methoxybenzyl)chroman-4-one, 5,7-dihydroxy-6-methoxy-3-(4′hydroxybenzyl)chroman-4-one and two 5,7-dihydroxy-6-methoxy-3-(4′-methoxybenzylidene)chroman-4-one, 5,7-dihydroxy-3-(4′hydroxybenzylidene)-chroman-4-one were isolated from the hexane, methanol and dichloromethane extracts of Cyrtanthus obliquus [338]. The bulbs of C. obliquus extracted with ethanol also revealed the presence of novel alkaloid obliquine, as well as 1α-hydroxygalanthamine, 3-epimacronine, narcissidine, tazettine and trisphaeridine [339].

The presence of lycorine, tazettine and 11-hydroxyvittatine in dried bulb ethanol extract of Cyrtanthus mackenii (Hook f.) has been demonstrated by Masi et al. [340]. Fresh bulb methanol extracts of C. contractus also contains a phenanthridone alkaloid called narciclasine [335]. Furthermore, two crinine alkaloids; haemanthamine and haemanthidine have been isolated from fresh bulb ethanol extracts of C. elatus. Further studies on the alcoholic extracts of the fresh bulbs also yielded the alkaloids zephyranthine, galanthamine and 1,2-O-diacetylzephyranthine [43,44]. Tazettine, maritidine, O-methylmaritidine, and papyramine are all phytochemicals that have been identified in fresh bulb methanol extracts of C. falcatus [337].

Chemical structure of compounds isolated from Cyrtanthus have been shown in Figure 6.

Figure 6

Chemical structures of selected compounds from Crytanthus. Zephyranthine (20), 1,2-O-diacetylzephyranthine (21), haemanthamine (22), haemanthadine (23), galanthamine (18), 5,7-dihydroxy-6-methoxy-3-(4ꞌ-methoxybenzyl)chroman-4-one (24), 5,7-dihydroxy-6-methoxy-3-(4ꞌ-methoxybenzylidene)chroman-4-one (25), 5,7-dihydroxy-6-methoxy-3-(4ꞌhydroxybenzyl)chroman-4-one (26), 5,7-dihydroxy-3-(4ꞌhydroxybenzylidene)-chroman-4-one (27) and naciprimine (28).

5.5. Pharmacological Activities

5.5.1. Antioxidant Activity

5,7-dihydroxy-6-methoxy-3-(4′-methoxybenzyl)chroman-4-one and 5,7-dihydroxy-6-methoxy-3-(4′-hydroxybenzyl)chroman-4-one isolated from the fresh bulbs of C. obliquus have been shown to possess significant antioxidant activity with an IC50 of 371.54 and 288.40 µg/mL, respectively [338].

5.5.2. Anti-Inflammatory Activity

The methanol extract of the bulbs of C. contractus has been investigated and shown to possess significant anti-inflammatory activity. The extract exhibited dose-dependent inhibition of E-selectin, a proinflammatory agent, when tested on endothelial cells. Further studies of the methanol extract on human umbilical vein endothelial cells revealed a concentration-dependent reduction in THP-1 adhesion via blockade of the expression of endothelial adhesion molecule ICAM-1. Narciclasine was identified as the main anti-inflammatory compound in the methanol extract of the bulbs of C. contractus [335].

The dichloromethane (DCM) extracts of C. falcatus (roots) and C. mackenii (leaves) were shown to interfere with the activity of cyclooxygenase 2 (COX-2) by at least 90%. DCM extract of C. suaveolens also blocked prostaglandin synthesis via antagonizing COX-2 activity by 81.6 %. Moderate inhibition (approximately 70%) of COX-2 activity was also observed with the methanol extracts of the roots and leaves of C. falcatus [341,342]. Selective inhibition of COX-2 by these extracts makes them suitable candidates for development for clinical use.

5.5.3. Inhibition of Acetylcholinesterase

The phenanthridone alkaloid nacriprimine, isolated from the ethanolic bulb extract of C. contractus has been shown to possess mild acetylcholinesterase inhibition property with an IC50 of 78.9 µg/mL compared to the 40-fold more potent standard galanthamine with an IC50 of 1.9 µg/mL [11].

5.5.4. Antimicrobial Activity

Cyrtanthus species and their isolated compounds have demonstrated noteworthy antimicrobial activity against a panel of microorganisms. C. suaveolens bulbs/roots and leaves isolated with DCM demonstrated broad-spectrum antimicrobial activity against B. subtilis, E. coli, K. pneumoniae, M. luteus and S. aureus with zones of inhibition ranging between 0.13–0.91 mm. DCM extracts of C. falcatus also inhibited the growth of B. subtilis S. aureus and E. coli. C. mackenii bulb/root extracts also inhibited the growth M. luteus and S. aureus [337].

Haemanthamine and haemanthidine isolated from the bulbs of C. elatus have been investigated for their activity against parasitic protozoans [43]. Haemanthamine showed activity against trophozoite stage of Entamoeba histolytica (E. histolytica) HK9 with an IC50 of 0.75 μg/mL and mild activity against Plasmodium falciparum (P. falciparum) NF54 with an IC50 of 0.67 μg/mL. The activity against E. histolytica was compared to ornidazole with an IC50 0.28 μg/mL whiles the activity against P. falciparum was compared to chloroquine with an IC50 of 0.004 μg/mL and artemisinin with an IC50 of 0.002 μg/mL [43].

Haemanthidine also showed weak activity against P. falciparum, T. brucei rhodesiense STIB 900, and T. cruzi Tulahuen C4 with an IC50 of 0.70, 1.1 and 1.38 μg/mL, respectively. Melarsoprol with an IC50 of 0.002 μg/mL and benznidazole with an IC50 of 0.56 μg/mL were used as standards for Trypanosoma brucei rhodesiense STIB 900, and Trypanosoma cruzi Tulahuen C4, respectively [43].

5.5.5. Cytotoxic Activity

Haemanthamine isolated from C. elatus was shown to possess cytotoxic activity which was mediated via the apoptotic pathway as depicted in rat hepatoma cell (5123tc). The ED50 was determined at 15 μM and this result was of particular interest due to its selectivity; haemanthamine demonstrated insignificant activity in normal human embryo kidney (293t) cells [337].

Alkaloids isolated from C. obliquus tested for cytotoxic activity against Chinese Hamster ovarian and human hepatoma (hepG2) cells showed no cytotoxic activity up to a concentration of 100 μg/mL [339].

Tazettine isolated from C. falcatus and other members of Amaryllidaceae has been reported to possess cytotoxic activity on colon cell line murine alveolar non-tumoral fibroblast [343,344]. Papyramine, also extracted from C. falcatus showed cytotoxic activity against murine alveolar non-tumoral fibroblast and human lymphoid neoplasm as well [343,344].

5.5.6. Miscellaneous Pharmacological Activities

Roots of C. falcatus and C. surveolens extracted with DCM exhibited mutagenicity in Salmonella strain TA98 which was higher than that observed in the leaves of these plants. Mutagenicity was, however, not observed in the methanol extracts of these plants [337]. The mutagenicity of C. suaveolens has been attributed to the compound captan isolated from the bulbs/roots using DCM [344].

A summary of the traditional uses, phytochemicals and pharmacological activities of Cyrtanthus species have been highlighted in Table 13.

Table 13

A summary of the traditional uses, phytochemicals and pharmacological activities of Cyrtanthus species.

Plant Species	Traditional Uses	Compounds	Pharmacological Activities	References
C. obliquus	Chronic cough, headache and scrofula	5,7-dihydroxy-6-methoxy-3-(4′-methoxybenzyl)chroman-4-one, 5,7-dihydroxy-6-methoxy-3-(4′-hydroxybenzyl)chroman-4-one	Antioxidant activity	[338]
C. contractus	Mental illness, protective charm against evil spirits	NarciclasineNarciprimine	Anti-inflammatory activity (via inhibition of E-selectin, blockade of the expression of endothelial adhesion molecule ICAM-1)Acetylcholinesterase inhibitor	[337]
C. breviflorus	Emesis, worm infestations, protective charm against evil spirits	haemanthamine, lycorine, crinamine hydrochloride and tazettine	Antihelminthic	[337,342]
C. elatus	Cough, headache, labor induction	Haemanthamine, zephyranthine, galanthamine and 1,2-O-diacetylzephyranthine	Antiprotozoan activity, selective cytotoxic activity	[43,44,337]
C. falcatus	Not known to be used by the traditional South African people	Papyramine, epipapyramine, maritidine, O-methylmaritidine and tazettine	Antibacterial activity against B. subtilis S. aureus and E. coli, mutagenicity, cytotoxic activity	[342,343,344]
C. suaveolens	No traditional use has been reported	Captan	Mutagenicity, anti-inflammatory activity via inhibition of COX-2, fungicide	[342,344]

6. Conclusions

The discovery of new drugs in response to the growing burden of infectious and non-communicable diseases is of utmost necessity in this era. The genera Tulbaghia, Allium, Crinum, and Cyrtanthus of the Amaryllidaceae family have been well presented and shown to be a source of promising medicinal compounds with varying biological properties. Further research is therefore necessary to propel these compounds through clinical trials for possible usage in therapeutics. Although natural products have been attributed with high safety profiles, the presence of mutagenic compounds in crude extracts of these plants underscores the importance of pharmacological studies prior to their use in traditional medicine. These findings are relevant in light of augmenting the lean pipeline of drug discovery.