Traditional uses and pharmacological properties of Clerodendrum phytochemicals.

Clerodendrum is a genus of ca. 500 species in the family Lamiaceae and widely distributed throughout the whole world. Up to now, many species of this genus have been described in various indigenous systems of medicine and are used in preparation of folklore medicines for the treatment of various life-threatening diseases, and more than eleven species of the Clerodendrum genus have been very well studied for their chemical constituents and biological activities, and 283 compounds, including monoterpene and its derivatives, sesquiterpene, diterpenoids, triterpenoids, flavonoid and flavonoid glycosides, phenylethanoid glycosides, steroids and steroid glycosides, cyclohexylethanoids, anthraquinones, cyanogenic glycosides, and others have been isolated and identified. Pharmacological studies have shown that these compounds and extracts from the Clerodendrum genus have extensive activities, such as anti-inflammatory and anti-nociceptive, anti-oxidant, anti-hypertensive, anticancer, antimicrobial, anti-diarrheal, hepatoprotective, hypoglycemic and hypolipidemic, memory enhancing and neuroprotective, and other activities. In this review, we attempt to highlight over phytochemical progress and list the phytoconstituents isolated from the genus Clerodendrum reported so far. The biological activities of this genus are also covered.

Introduction

Clerodendrum is a genus of flowering plants in the family Lamiaceae (Verbenaceae). Its common names include glorybower, bagflower, and bleeding-heart. Estimates of the number of species in Clerodendrum vary widely, from about 150 to about 500, and is native to tropical and warm temperate regions of the world, with most of the species occurring in tropical Africa and southern Asia, but with a few in the tropical Americas and northern Australasia, and a few extending north into the temperate zone in eastern Asia. Clerodendrum is a genus of small trees, shrubs, lianas, and sub herbaceousperennials. There are 40 species in mainland China, mainly spread in southern and southwest regions, including Clerodendrum serratum, Clerodendrum inerme, Clerodendrum bungei, Clerodendrum phlomidis, C. serratum var. amplexifolium, Clerodendron infortunatum, Clerodendrum trichotomum, Clerodendrum chinense, Clerodendrum petasites, Clerodendrum grayi, Clerodendrum indicum, and so on. C. trichotomum is a common ornamental in warmer parts of the world. Eight other species are also grown in the tropics for their abundant and attractive flowers. Both butterflies and hummingbirds are often attracted by blooming Clerodendrum.

Plants belonging to genus Clerodendrum are well known for their pesticidal properties, and various Clerodendrum species like C. indicum, C. phlomidis, C. serratum var. amplexifolium, C. trichotomum, C. chinense, C. petasites, etc. have been historically used as folk and traditional medicine to treat many kinds of diseases, such as cold, hyperpyrexia, asthma, furunculosis, hypertension, rheumatism, dysentery, mammitis, toothache, anorexia, leucoderma, leprosy, arthrophlogosis, and other inflammatory disease in various parts of the world such as India, China, Korea, Japan, Thailand, and Africa.6, 7, 8, 9 The traditional or ethnomedical claims of the species have also been evaluated. The biological activities of these species described in ancient literature have been reported to be associated with the chemical constituents present in the species.

A variety of constituents have been isolated and characterized from this genus, including: monoterpene and its derivatives, sesquiterpene, diterpenoids,12, 13 triterpenoids,14, 15 flavonoid and flavonoid glycosides, phenylethanoid glycosides,17, 18 steroids and steroid glycosides, cyclohexylethanoids, anthraquinones, cyanogenic glycosides, and others. Some of these constituents have been evaluated with a number of biological properties, mainly including anti-inflammatory and anti-nociceptive, anti-oxidant, anti-hypertensive, anticancer, antimicrobial, anti-diarrheal, hepatoprotective, hypoglycemic and hypolipidemic, memory enhancing and neuroprotective, and other activities.

In this review, we will summary all identified chemical constituents and biological activities from the genus Clerodendrum over the past few decades. It will provide a basis for the development of therapeutic agents and utilization of these plants in forthcoming studies.

Phytochemistry

To the best of our knowledge, over 280 chemical constituents have been isolated and identified from different species of the genus Clerodendrum, These compounds could be divided into: 27 monoterpene and its derivatives, 3 sesquiterpene, 58 diterpenoids, 31 triterpenoids, 43 flavonoid and flavonoid glycosides, 40 phenylethanoid glycosides, 43 steroids and steroid glycosides, 13 cyclohexylethanoids, 4 anthraquinones, 2 cyanogenic glycosides, and 19 others (Table 1). With respect to isolated phytochemicals of the genus, aerial parts, roots and leaves were the most common targets of investigation for bioactive principles and most of these compounds were reported from C. serratum, C. inerme, C. bungei, Clerodendrum incisum, C. infortunatum, and C. trichotomum. Diterpenoids, flavonoids, phenylethanoid glycosides, and steroids are abundant and major bioactive principles of this genus.

Table 1

The phytochemicals obtained from the Clerodendrum genus plants.

No.	Phytochemicals	Plant parts	Source	Ref.
Monoterpene and its derivatives
1	Serratumin A	Aerial parts	C. serratum	23
2	Serratoside A	Aerial parts	C. serratum	24
3	Serratoside B	Aerial parts	C. serratum	24
4	7-O-p-couma-royloxyugandoside	Aerial parts	C. serratum	25
5	Monomelittoside	Aerial parts	C. inerme	26
6	Melittoside	Aerial parts	C. inerme	27
7	Sammangaoside C	Aerial parts	C. inerme	28
8	Inerminosides A	Leaves	C. inerme	10
9	Inerminosides C	Leaves	C. inerme	10
10	Inerminosides D	Leaves	C. inerme	10
11	Inerminoside C heptaacetate	Aerial parts	C. inerme	29
12	Inerminoside A	Aerial parts	C. inerme	29
13	Inerminoside A hexaacetate	Aerial parts	C. inerme	29
14	Inerminoside B	Aerial parts	C. inerme	29
15	Inerminoside B heptaacetate	Aerial parts	C. inerme	29
16	8-O-foliamenthoyleuphroside	Roots	C. incisum	30
17	2′-O,8-O-difoliamenthoyleuphroside	Roots	C. incisum	30
18	Euphroside	Roots	C. incisum	30
19	Plantarenaloside	Roots	C. incisum	30
20	Aucubin	Whole plants	C. thomsonae	27
21	8-O-acetylharpagide	Whole plants	C. thomsonae	27
22	Harpagide	Whole plants	C. thomsonae	27
23	Ajugoside	Leaves	C. thomsonae	27
24	8-O-acetylmioporoside	Whole plants	C. thomsonae	27
25	Reptoside	Whole plants	C. thomsonae	27
26	Ugandoside	Whole plants	C. ugandense	27
27	5-O-β-glucopyranosyl-harpagide	Aerial parts	C. chinense	31
Sesquiterpene
28	Sammangaoside A	Aerial parts	C. inerme	28
29	Sammangaoside B	Aerial parts	C. inerme	28
30	2-{(2S,5R)-5-[(1E)-4-hydroxy-4-methylhexa-1,5-dien-1-yl]-5-methyltetrahydrofuran-2-yl}propan-2-yl-β-d-glucopyranoside	Roots	C. bungei	32
Diterpenoids
31	Mandarone A	Stems	C. mandarinorum	33
32	Mandarone B	Stems	C. mandarinorum	33
33	Mandarone C	Stems	C. mandarinorum	33
34	Crolerodendrum A	Whole plants	C. philippinum	25
35	Bungone A	Stems	C. bungei	34
36	Bungone B	Stems	C. bungei	34
37	Inerme A	Leaves	C. inerme	35
38	Inerme B	Leaves	C. inerme	35
39	14,15-dihydro-15β-methoxy-3-epicaryoptin	Leaves	C. inerme	35
40	14,15-dihydro-15-hydroxy-3-epicaryoptin	Leaves	C. inerme	35
41	Clerodermic acid	Whole plants	C. inerme	36
42	Cleroinermin	Whole plants	C. inerme	37
43	3-epicaryoptin	Whole plants	C. paniculatum	38
44	Clerodin	Whole plants	C. paniculatum	38
45	Uncinatone	Stems	C. trichotomum	39
		Roots	C. bungei	40
		Roots	C. trichotomum	41
		Aerial parts	C. inerme	42
46	2-acetoxyclerodendrin B	Whole plants	C. infortunatum	25
47	Clerodendrin A	Whole plants	C. trichotomum	38
48	Clerodendrin B	Whole plants	C. trichotomum	38
49	Clerodendrin C	Whole plants	C. trichotomum	38
50	Clerodendrin D	Whole plants	C. trichotomum	38
51	Clerodendrin E	Whole plants	C. trichotomum	38
52	Clerodendrin F	Whole plants	C. trichotomum	38
53	Clerodendrin G	Whole plants	C. trichotomum	38
54	Clerodendrin H	Whole plants	C. trichotomum	38
55	Trichotomone	Roots	C. trichotomum	43
56	Sugiol	Stems	C. trichotomum	39
57	Teuvincenone A	Stems	C. trichotomum	39
58	Teuvincenone B	Stems	C. trichotomum	39
59	Teuvincenone F	Stems	C. trichotomum	39
		Roots	C. bungei	40
		Roots	C. trichotomum	41
60	Teuvincenone H	Stems	C. trichotomum	39
61	Cyrtophyllone B	Stems	C. trichotomum	39
62	Bungnate A	Roots	C. bungei	40
63	Bungnate B	Roots	C. bungei	40
64	15-dehydrocyrtophyllone A	Roots	C. bungei	40
65	15-dehydro-17-hydroxycyrtophyllone A	Roots	C. bungei	40
66	12,16-epoxy-11,14,17-trihydroxy-6-methoxy-17(15→16)-abeo-abieta-5,8,11,13-tetraene-7-one	Roots	C. bungei	40
67	Cyrtophyllone A	Roots	C. bungei	40
68	Villosin C	Roots	C. bungei	40
		Roots	C. trichotomum	41
69	19-hydroxyteuvincenone F	Roots	C. bungei	40
70	Mandarone E	Roots	C. bungei	40
		Roots	C. trichotomum	41
71	12,16-epoxy-11,14-dihydroxy-6-methoxy-17(15→16)-abeo-abieta-5,8,11,13,15-pentaene-3,7-dione	Roots	C. bungei	40
		Roots	C. trichotomum	41
72	12-O-β-d-glucopyranosyl-3,11,16-trihydroxyabieta-8,11,13-triene	Roots	C. bungei	40
73	6-methoxyvillosin C	Roots	C. trichotomum	41
74	18-hydroxy-6-methoxyvillosin C	Roots	C. trichotomum	41
75	(10R,16S)-12,16-epoxy-11,14-dihydroxy-6-methoxy-17(15→16)-abeo-abieta-5,8,11,13-tetraene-3,7-dione	Roots	C. trichotomum	41
76	(10R,16S)-12,16-epoxy-11,14-dihydroxy-18-oxo-17(15→16),18(4→3)-diabeo-abieta-3,5,8,11,13-pentaene-7-one	Roots	C. trichotomum	41
77	(10R,16R)-12,16-epoxy-11,14,17-trihydroxy-17(15→16),18(4→3)-diabeo-abieta-3,5,8,11,13-pentaene-2,7-dione	Roots	C. trichotomum	41
78	(3S,4R,10R,16S)-3,4:12,16-diepoxy-11,14-dihydroxy-17(15→16),18(4→3)-diabeo-abieta-5,8,11,13-tetraene-7-one	Roots	C. trichotomum	41
79	12,16-epoxy-11,14-dihydroxy-6-methoxy-17(15→16)-abeo-abieta-5,8,11,13,15-pentaene-3,7-dione	Roots	C. trichotomum	41
80	Formidiol	Roots	C. trichotomum	41
81	Teuvincenone E	Roots	C. trichotomum	41
82	12,16-epoxy-17(15→16),18(4→3)-diabeo-abieta-3,5,8,12,15-pentaene-7,11,14-trione	Roots	C. trichotomum	41
83	3β-(β-d-glucopyranosyl)isopimara-7,15-diene-11α,12α-diol	Roots	C. bungei	44
84	16-O-β-d-glucopyranosyl-3β-20-epoxy-3-hydroxyabieta-8,11,13-triene	Roots	C. bungei	44
85	Coleon U	Whole plants	C. canescens	45
86	Coleon U-12-methyl ether	Whole plants	C. canescens	45
87	Cleroserroside A	Aerial parts	C. serrartum	46
88	Cleroserroside B	Aerial parts	C. serrartum	46
Triterpenoids
89	3-O-acetyloleanolicacid	Aerial parts	C. inerme	42
90	3-O-acetyloleanolicaldehyde	Aerial parts	C. inerme	42
91	Glutinol	Aerial parts	C. inerme	42
92	Friedelin	Leaves	C. trichotomum	47
		Aerial parts	C. inerme	48
93	Taraxerol	Roots	C. indicum	49
		Whole plants	C. bungei	50
		Leaves	C. trichotomum	47
94	Clerodone	Whole plants	C. bungei	51
95	α-amyrin	Whole plants	C. bungei	51
96	Glochidone	Whole plants	C. bungei	50
97	Glochidonol	Whole plants	C. bungei	50
98	Glochidiol	Whole plants	C. bungei	50
99	Lupeol	Roots	C. indicum, C. villosum	49, 52
		Leaves	C. trichotomum	47
		Whole plants	C. canescens	51
		Aerial parts	C. inerme	42
100	α-amyrin 3-undecanotate	Whole plants	C. canescens	51
101	Lupeol acetate	Whole plants	C. canescens	51
102	Lupeol 3-palmitate	Whole plants	C. canescens	51, 52
103	Melastomic acid	Whole plants	C. canescens	51
104	β-amyrin acetate	Whole plants	C. canescens	51
105	Betulinic acid	Roots	C. villosum	49, 52
		Aerial parts	C. inerme	53
		Leaves	C. trichotomum	47
		Whole plants	C. canescens	51
106	Magnificol	Aerial parts	C. inerme	42
107	Glutinone	Aerial parts	C. inerme	42
108	Mi-saponin	Roots	C. wildii	54
109	Basic acid	Roots	C. wildii	54
110	Protobassic	Roots	C. wildii	54
111	Mi-glycoside I	Roots	C. wildii	54
112	Ursolic acid	Roots	C. japonicum	55
113	3β-hydroxy-D:B-friedo-olean-5-ene	Roots	C. indicum, C. villosum	49
114	Oleanolic acid	Whole plants	C. serratum	56
115	Oleanolic acid-3-acetate	Roots	C. indicum	49
116	Taraxerol-3β-yloctacosanoate	Roots, stems	C. philippinum	57
117	Se-saponin	Aerial parts	C. serratum	58
118	Lup-1,5,20(29)-trien-3-O-d-glucopyranoside	Leaves	C. inerme	59
119	Clerodendrumic acid	Leaves	C. glabrum	60
Flavonoid and flavonoid glycosides
120	5,7,8,4′-tetrahydroxy-6-methoxy-flavone	Aerial parts	C. serratum	23
121	5,6,7-trihydroxy-4′-methoxyflavone 7-glucopyranoside	Aerial parts	C. serratum	23
122	5, 7, 4′-trihydroxy-3′-methoxyflavone	Whole plants	C. serratum	25
123	Astragalin	Whole plants	C. philippinum	61
124	Apigenin	Aerial parts	C. inerme	48
125	Tricin	Whole plants	C. japonicum	25
126	Hispidulin	Roots	C. indicum	62
127	Hispidulin-glucuronide	Whole plants	C. infortunatum	63
128	Eupafolin	Whole plants	C. infortunatum	63
129	Scutellarin	Whole plants	C. infortunatum	63
130	Scutellarein	Whole plants	C. serratum	64
131	Pectolinarigenin	Aerial parts	C. inerme	65
132	7-hydroxyflavone	Flowers	C. phlomidis	66
133	7-hydroxyflavanone 7-O-glucoside	Flowers	C. phlomidis	66
134	Luteolin	Whole plants	C. serratum	64
135	Chalcone glycoside	Flowers	C. phlomidis	66
136	α-l-Rhamnopyranosyl-(1→2)-α-D-Glu-copyranosyl-7-O-naringin-4-d-glucopyranoside-5-methylether	Whole plants	C. phlomidis	25
137	4,2′,4′-trihydroxy-6′-methoxy ehalcone-4,4′-α-D-diglucoside	Whole plants	C. phlomidis	25
138	7-hydroxyflavonone	Flowers	C. phlomidis	66
139	Kaempferol	Whole plants	C. fragrans	67
140	5,4′-dihydroxy-kaempferol-7-O-β-rutinoside	Whole plants	C. fragrans	67
141	6-hydroxyflavone	Flowers	C. phlomidis	66
142	4′-methyl scutellarein	Aerial parts	C. inerme	65
143	Apigenin-7-O-glucuronide	Roots	C. serratum	68
144	5-hydroxy-4′, 7-dimethoxymethyl flavone	Whole plants	C. inerme	25
145	Salvigenin	Aerial parts	C. inerme	65
146	Acacetin	Leaves	C. inerme	69
		Aerial parts	C. inerme	48
147	Cynaroside	Aerial parts	C. inerme	13
148	2′,4,4′-trihydroxy-6′-methylchalcone	Flowers	C. phlomidis	66
149	Cirsimaritin	Aerial parts	C. petasites	70
150	Cirsimaritin-4′-glucoside	Aerial parts	C. mandarinorum	71
151	Quercetin-3′-methyl	Aerial parts	C. mandarinorum	71
152	Pectolinarigenin	Roots	C. indicum	49
153	5-hydroxy-6,7,4′-trimethoxyflavone	Aerial parts	C. inerme	53
154	5,7,4′-trihydroxy-flavone	Leaves	C. trichotomum	72
		Whole plants	C .serratum	56
155	5,7,4′-trihydroxy-3′-methoxyflavone	Whole plants	c. serratum	73
156	3,2′,3′-trihydroxy-4′-methoxychalcone	Seeds	C. phlomidis	74
157	3,2'-dihydroxy-4′,6′-dimethoxychalcone	Seeds	C. phlomidis	74
158	5-hydroxy-7-methoxyflavanone	Seeds	C. phlomidis	74
159	5-hydroxy-7-methoxyflavone	Seeds	C. phlomidis	74
160	Kaempferol-3-O-α-l-rhamnopyranoside	Seeds	C. phlomidis	74
161	Hispidulin7-O-glucuronide	Aerial parts	C. infortunatum	63
162	Naringin-4′- O-α- glucopyranoside	Flowers	C. phlomidis	66
Phenylethanoid glycosides
163	Decaffeoylverbascoside	Aerial parts	C. inerme	75
164	Darendoside B	Roots	C. bungei	40
165	Salidroside	Aerial parts	C. inerme	25
166	Verbascoside	Roots	C. bungei	40
		Roots	C. villosum	49
		Aerial parts	C. inerme	75
167	Isoverbascoside	Aerial parts	C. inerme	75
168	Campneoside I	Aerial parts	C. bungei	76
		Aerial parts	C. inerme	75
169	Cistanoside E	Aerial parts	C. inerme	75
170	Purpureaside B	Aerial parts	C. inerme	75
171	2-phenylethyl-3-O-(6-dexoy-α-l-mannopyranosyl)-β-d-glucopyranoside	Roots	C. bungei	32
172	Campneoside II	Aerial parts	C. bungei	76
173	Martynoside	Whole plants	C. japonicum	55
174	Jionoside D	Aerial parts	C. trichotomum	77
175	Clerodendronoside	Aerial parts	C. bungei	76
176	Cistanoside C	Aerial parts	C. bungei	76
177	Jionoside C	Aerial parts	C. bungei	76
178	Leucosceptoside A	Roots	C. bungei	40
		Aerial parts	C. bungei	76
179	Cistanoside D	Aerial parts	C. bungei	76
180	Cistanoside F	Aerial parts	C. bungei	76
181	Bungein A	Aerial parts	C. bungei	78
182	Monoacetylmartinoside	Whole plants	C. japonicum	55
183	Clerodenoside A	Whole plants	C. japonicum	55
184	3,4-dihydroxyphenylethanol	Whole plants	C. indicum	25
185	Isomartynoside	Roots	C. bungei	40
186	Serratumoside A	Aerial parts	C. serratum	79
187	Bunginoside A	Roots	C. bungei	40
188	3″,4″-di-O-acetylmartynoside	Roots	C. bungei	40
189	Acetylmartynoside A	Roots	C. bungei	40
190	Acetylmartynoside B	Roots	C. bungei	40
191	3″-O-acetylmartynoside	Roots	C. bungei	40
192	2″-O-acetylmartynoside	Roots	C. bungei	40
193	Martynoside	Roots	C. bungei	40
194	Trichotomoside	Roots	C. bungei	40
195	O-2-(3-hydroxy-4-methoxyphenyl)-ethyl O-2,3-di-O-acetyl-α-l-rhamnopyranosyl-(1→3)-(4-O-cis-feruloyl)-β-d-glucopyranoside	Roots	C. bungei	40
196	Isoacteoside	Roots	C. bungei	40
		Aerial parts	C. bungei	76
197	Darendoside A	Roots	C. bungei	40
198	Phlomisethanoside	Roots	C. bungei	40
199	Acteoside	Aerial parts	C. bungei	76
		Whole plants	C. serratum	56
200	Markhamioside F	Aerial parts	C. inerme	75
201	Benzylglucoside	Aerial parts	C. inerme	75
202	Myricoside	Aerial parts	C. serratum	79
Steroids and steroid glycosides
203	Stigmasterol	Roots	C. indicum	49
		Leaves	C. trichotomum	47
		Whole plants	C. serratum	56
204	α-spinasterol	Whole plants	C. serratum	64
205	Stigmasterol-3-O-β-d-glucopyranoside	Roots	C. indicum	49
		Whole plants	C. serratum	73
206	Serratin	Whole plants	C. serratum	80
207	Clerosterol	Roots	C. indicum, C. villosum	49
		Leaves	C. quadriloculare	81
		Leaves	C. trichotomum	47
208	Bungesterol	Whole plants	C. bungei	51
209	4α-methyl-24β-ethyl-5α-cholesta-14,25-dien-3β-ol	Aerial parts	C. inerme	36
210	4α,24,24-trimethyl-5α-cholesta-7,25-dien-3β-ol	Whole plants	C. inerme	62
211	4α-methyl-24β-ethyl-5α-cholesta-7,25-dien-3β-ol	Whole plants	C. inerme	62
212	Gramisterol	Whole plants	C. inerme	62
213	4α-methyl-24α-ethyl-5α-cholest-7-en-3β-ol	Whole plants	C. inerme	62
214	Obtusifoliol	Whole plants	C. inerme	62
215	24,24-dimethyl-5α-cholesta-7,25-dien-3β-ol	Whole plants	C. inerme	62
216	22,23-dihydrostigmasterol	Whole plants	C. japonicum	55
217	25,26-dehydrostigmasterol	Whole plants	C. japonicum	55
218	22-dehydroclerosterol 3β-O-β-D-(6′-O-margaroyl)-glucopyranoside	Leaves	C. trichotomum	82
		Whole plants	C. quadriloculare	81
219	Sitosterol	Leaves	C. trichotomum	47
220	Stigmasterol	Aerial parts	C. inerme	48
221	24β-methylcholesta-5,22E,25-trien-3β-ol	Whole plants	C. fragrans	83
222	24α-ethyl-5α-cholest-22E-en-3β-ol	Whole plants	C. fragrans	83
223	Colebrin A	Aerial parts	C. colebrookianum	84
224	Colebrin B	Aerial parts	C. colebrookianum	84
225	Colebrin C	Aerial parts	C. colebrookianum	84
226	Colebrin D	Aerial parts	C. colebrookianum	84
227	Colebrin E	Aerial parts	C. colebrookianum	84
228	Dehydropo-riferasterol	Aerial parts	C. splendens	25
229	Campesterol	Stems	C. phlomidis	85
230	Cholestanol	Stems	C. phlomidis	85
231	(22E)-stigmasta-4,22,25-trien-3-one	Roots	C. indicum	49
232	Stigmasta-4,25-dien-3-one	Roots	C. indicum	49
233	Stigmasta-4,22-dien-3-one	Roots	C. indicum	49
234	22-dehydroclerosterol	Roots	C. indicum, C. villosum,	49
		Leaves	C. quadriloculare	81
		Leaves	C. trichotomum	47
235	β-sitosterol	Roots	C. villosum	49
		Aerial parts	C. inerme	53
		Whole plants	C. bungei	50
236	22-dehydroclerosterol-3-O-β-d-glucopyranoside	Roots	C. indicum, C. villosum	49
237	Clerosterol-3-O-β-d-glucopyranoside	Roots	C. indicum, C. villosum	49
238	β-sitosterol-3-O-β-d-glucopyranoside	Roots	C. villosum	49
239	(22E,24R)-stigmasta-4,22,25-trien-3-one	Leaves	C. trichotomum	82
240	(20R,22E,24R)-3β-hydroxy-Stigmasta-5,22,25-trien-7-one	Leaves	C. trichotomum	82
241	(20R,22E,24R)-stigmasta-22,25-dien-3,6-dione	Leaves	C. trichotomum	82
242	(20R,22E,24R)-6β-hydroxy-Stigmasta-4,22,25-trien-3-one	Leaves	C. trichotomum	82
243	(20R,22E,24R)-stigmasta-5,22,25-trien-3β,7β-diol	Leaves	C. trichotomum	82
244	(20R,22E,24R)-stigmasta-22,25-dien-3β,6β,9α-triol	Leaves	C. trichotomum	82
245	Bis(2-ethylhexyl)phthalate	Whole plants	C. serratum	56
Cyclohexylethanoids
246	1-hydroxy-1-(8-palmitoyloxyethyl)cyclohexanone	Leaves	C. trichotomum	20
247	5-O-butyl cleroindin D	Leaves	C. trichotomum	20
248	Rengyolone	Leaves	C. trichotomum	20
		Aerial parts	C. bungei	86
249	Cleroindin C	Leaves	C. trichotomum	20
250	Cleroindin B	Leaves	C. trichotomum	20
251	Rengyol	Leaves	C. trichotomum	20
252	Clerobungin A(1a)	Aerial parts	C. bungei	86
253	Clerobungin A(1b)	Aerial parts	C. bungei	86
254	(+)-rengyolone	Aerial parts	C. bungei	86
255	Cleroindicin	Aerial parts	C. bungei	86
256	5-O-ethylcleroindicin D	Aerial parts	C. bungei	78
257	6″-O-[(E)-caffeoyl] rengyoside B	Roots	C. bungei	32
258	Clerodenone A	Roots	C. bungei	32
Anthraquinones
259	Aloe-emodin	Stems	C. trichotomum	39
260	Emodin	Stems	C. trichotomum	39
261	Chrysophanol	Stems	C. trichotomum	39
262	2,5-dimethoxybenzoquinone	Whole plants	C. serratum	73
Cyanogenic glycosides
263	(R)-lucumin	Leaves	C. grayi	87
264	(R)-prunasin	Leaves	C. grayi	87
Others
265	B-friedoolean-5-ene-3-β-ol	Aerial parts	C. inerme	53
266	Stigmasta-5,22,25-trien-3-β-ol (3)	Aerial parts	C. inerme	53
267	Spicatolignan B	Stems	C. trichotomum	39
268	Trans-phytol	Leaves	C. trichotomum	47
269	1H-indole-3-carboxylic acid	Leaves	C. trichotomum	47
270	Palmitic acid	Leaves	C. trichotomum	72
271	Octadecanoic acid	Leaves	C. trichotomum	72
272	Cis-cinnamic acid	Aerial parts	C. serratum	23
273	Trans-cinnamic acid	Aerial parts	C. serratum	23
274	P-coumaric acid	Aerial parts	C. serratum	23
275	Syringic acid	Aerial parts	C. inerme	48
276	P-methoxybenzoic acid	Aerial parts	C. inerme	48
277	Daucosterol	Aerial parts	C. inerme	48
278	2-({6-O-[(4-hydroxy-3-methoxyphenyl)carbonyl]-β-d-glucopyranosyl}oxy)-2-methylbutanoic acid	Roots	C. bungei	32
279	24β-ethylcholesta-5,22E,25-triene-3β-ol	Aerial parts	C. phlomidis	88
280	Pentadecanoic acid β-D-glucoside	Aerial parts	C. inerme	66
281	Cryptojaponol	Aerial parts	C. kiangsiense	89
282	Fortuning E	Aerial parts	C. kiangsiense	89
283	12-methoxy-6,11,14,16-tetrahydroxy-17(15→16)-abeo-5,8,11,13-abietatetraen-3,7-dione	Aerial parts	C. kiangsiense	89

Monoterpene and its derivatives

Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings. Most monoterpenes are fragrant and the main composition of essential oil. Twenty-seven monoterpenes and derivatives (1–27) were isolated from the roots, leaves, aerial parts of C. serratum, C. inerme, C. incisum, C. trichotomum, Clerodendrum ugandense, and C. chinense.

Sesquiterpenes

Sesquiterpenes are bitter substances and a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. They often contain α, β-unsaturated-γ-lactone as a major structural feature. In recent studies, sesquiterpenes have been associated with anti-tumor, cytotoxic, and anti-microbial activities. But, only three sesquiterpenes (28–30) were obtained from the aerial parts and roots of C. inerme and C. bungei, respectively.

Diterpenoids

To date, fifty-eight diterpene compounds (31–88) have been isolated and identified from this genus, and all of them are labdane diterpenoids. These compounds can be sorted to five types based on the pentacyclic ring on C12: a furan ring, dihydrofuran ring, lactone ring, α,β-undersaturated lactone ring, and tetrahydrofuran ring. Many of these chemical compounds have shown remarkable bioactivities in vivo or in vitro study.

Triterpenoids

So far, a total of thirty-one triterpenoids (89–119), including 3-O-acetyloleanolicacid (89), 3-O-acetyloleanolicaldehyde (90), glutinol (91), friedelin (92), taraxerol (93), clerodone (94), α-amyrin (95), glochidone (96), glochidonol (97), glochidiol (98), lupeol (99), α-amyrin 3-undecanotate (100), lupeol acetate (101), lupeol 3-palmitate (102), melastomic acid (103), β-amyrin acetate (104), betulinic acid (105), magnificol (106), glutinone (107), etc. have been purified and characterized from the whole plants, roots, leaves, or aerial parts of C. inerme, C. trichotomum, C. indicum, C. bungei, Clerodendrum canescens, Clerodendrum villosum, Clerodendrum wildii, Clerodendrum japonicum, C. serratum, Clerodendrum philippinum, or Clerodendrum glabrum.

Flavonoid and flavonoid glycosides

Flavonoids, important secondary metabolites, are widespread throughout the plant kingdom. Flavonoids and their derivatives are the main bioactive components of this genus, and receiving extreme attention. Up to now, forty-three flavonoid and flavonoid glycosides (120–162), including astragalin (123), apigenin (124), and tricin (125), hispidulin (126), hispidulin-glucuronide (127), eupafolin (128), scutellarin (129), scutellarein (130), pectolinarigenin (131), 7-hydroxyflavone (132), 7-hydroxyflavanone 7-O-glucoside (133), luteolin (134), chalcone glycoside (135), etc. have been isolated and identified from the roots, leaves, aerial parts of different Clerodendrum species.

Phenylethanoid glycosides

Phenylethanoid glycosides are another kind of characteristic compounds of the Clerodendrum species with antioxidant activity. To date, forty phenylethanoid glycosides (163–202) have been obtained from this genus and the structure contains three parts: sugar chain, phenylacetyl, and coffee-acyl or ferulic-acyl. The sugar chain is often composed of glucose, rhamnose, xylose or arabinose. The phenylacetyl is linked to C1-glucopyranose, and coffee-acyl or ferulic-acyl is often connected with the C4 or C6 of glucose.

Steroids and steroid glycosides

Steroids are terpenes based on the cyclopentane perhydroxy phenanthrene ring, but they are considered separately because of their chemical, biological and medicinal importance. Steroids are found in nature in free as well as in glycosidic form. There are many steroids reported from plants and they are termed phytosteroids. Total forty-three steroids and steroid glycosides (203–245) have been obtained and identified from Clerodendrum species, mainly from C. trichotomum, Clerodendrum colebrookianum, and C. bungei.

Cyclohexylethanoids

A series of cyclohexylethanoids (246–258), including two new compounds 1-hydroxy-1-(8-palmitoyloxyethyl) cyclohexanone (246) and 5-O-butyl cleroindin D (247), together with four known ones, rengyolone (248), cleroindin C (249), cleroindin B (250), rengyol (251), were isolated from the leaves of C. trichotomum, and the others (252–258) were obtained and identified from the aerial parts and roots of C. bungei.

Anthraquinones

Only four anthraquinones (259–262), aloe-emodin (259), emodin (260), chrysophanol (261) and 2,5-dimethoxybenzoquinone (262), have been isolated and identified from the stem of C. trichotomum and C. serratum.

Cyanogenic glycosides

Two cyanogenic glycosides (263–264), including (R)-lucumin (263) and (R)-prunasin (264) have been obtained and identified from the leaves of C. grayi.

Others

A range of other compounds (265–283) were isolated and identified from the aerial parts, stems, leaves and roots of C. inerme, C. trichotomum, C. serratum, C. bungei, C. phlomidis, and Clerodendrum kiangsiense.

Pharmacological properties

Wide clinical uses of traditional Chinese medicine of the genus Clerodendrum have inspired researchers to investigate its pharmacological properties and to validate the uses of different species as therapeutic remedy. More and more studies showed that extracts or active compounds isolated from Clerodendrum species exhibited a wide range of pharmacological activities (Table 2).

Table 2

The pharmacological activities of extracts and compounds from the genus Clerodendrum.

Pharmacological activities	Extract/Compound	Types	Testing subjects	Dose	Effects	Ref.
Anti-inflammatory and anti-nociceptive activity	3-Hydroxy, 2-methoxy-sodium butanoate	In vivo	Carrageenan-induced inflammation and freund complete adjuvant (FCA)-induced arthritic rat models	25, 50, 100 mg/kg, i.g.	Reduced the paw edema response, decrease lysosomal enzymes, protein-bound carbohydrates, and acute phase protein levels	90
	Methanol extract from C. petasites	In vivo	Ethyl phenylpropiolate-induced ear edema and carrageenan-induced paw edema in rats	1, 2, 4 mg/ear, i.g.	Inhibited prostaglandin synthesis	91
	Ethanol extract from C. laevifolium	in vitro	lipoxygenase	10–1000 μg/ml	Displayed the greatest inhibition capacity with the IC50 value of 14.12 μg/ml	92
	Methanolic extract from C. inerme	In vivo	Formalin induced hind paw edema animals	50, 100, 200 mg/kg, i.g.	Inhibited main inflammatory mediators	53
	Petroleum ether and chloroform extracts from C. paniculatum	In vitro	Human red blood cell membrane stabilization method	1000 μg/ml	Showed 57.15% protection and 48.98% protection of HRBC in hypotonic solution, respectively	93
	Petroleum ether and chloroform extracts from C. paniculatum	in vivo	Carrageenan-induced rat paw edema model	200 400 mg/kg, i.g.	Inhibited of the cyclooxygenase leading to inhibition of prostaglandin synthesis	93
	Hispidulin	In vitro	RAW 264.7 macrophage stimulated with LPS	12.5, 25, 50, 100, and 200 μM	inhibited PGE2 production as well as iNOS and cyclooxygenase-2 expressions	94
	Methanolic extract from C. serratum	In vivo	Carrageenan and arachidonic acid induced hind paw edema in rats	50, 100, 200 mg/kg, i.g.	Inhibition of synthesis and inflammatory mediators release	97
	n-Butyl extract from C. bungei	In vivo	acetic acid-induced writhing model	1.0 g/kg, i.p.	prolonged the latency reaction, suppressed the prostaglandin production	102
	Aqueous extracts from C. bungei	In vivo	DNFB-induced hypersensitivity	10 and 20 g/kg, i.p.	Restrained the phlogistic infiltration, improved the ear edema, reduced the writhes of abdominal cavity and the ear edema	103
	Methanolic extract of C. indicum	In vivo	Carrageenan and arachidonic acid induced hind paw edema in rats	200 and 400 mg/kg, i.g.	Reduced the number of writhes with 62.57%, inhibited the acetic acid-induced writhing test with 70.76%, respectively	104
	Aqueous extract from C. inerme	In vivo	Milk-induced hyperpyrexia in rabbits	100 and 200 mg/kg, p.o.	Raising the pain threshold at different time of observation	105
Anti-oxidant activity	Ethanol extract from C. infortunatum	In vitro	DPPH-radicals	250 μg/ml	Inhibited DPPH	106
	Phenolic extracts from C. volubile	In vitro	DPPH-radicals, OH radicals	0–100 μg/ml	Inhibited DPPH free radicals and OH radicals	107
	Monoacetylmartinoside	In vitro	DPPH-radicals	25 μmol/l	Inhibited DPPH	108
	3″,4″-O-acetylmartynoside	In vitro	DPPH-radicals	37 μmol/l	Inhibited DPPH	108
	Acteoside	In vitro	DPPH-radicals	60 μmol/l	Inhibited DPPH	108
	Methanolic extract from C. inerme	In vitro	DPPH-radicals	100 μg/ml	Inhibited DPPH	53
	5-Hydroxy-6,7,4′-trimethoxyflavone	In vitro	DPPH-radicals	20 μM	Inhibited DPPH	53
	Ethanolic extract from C. serratum	In vitro	DPPH-radicals, FRAP, hydrogen peroxide radical	50–250 μg/ml	Inhibited DPPH, FRAP, hydrogen peroxide radical	109
	Methanolic extract from C. serratum	In vitro	DPPH-radicals, ABTS-radicals	0.125–1.0 mg/ml	Inhibited DPPH	110
	Methanolic extract from C. serratum	In vitro	DPPH-radicals	200–1000 μg/ml	Inhibited DPPH	111
	Phenolic extracts from C. volubile	In vitro, in vivo	DPPH-radicals, lipid peroxidation assay	0–312.60 μg/ml	Reduced the MDA content	107
	Methanolic extract from C. umbellatum	In vivo	Schistosoma mansoni-infected mice	100, 200, and 400 mg/kg, i.g.	Decreased MDA level, increase CAT activity and GSH level	113
	Methanolic extracts from C. siphonanthus	In vitro	Thiocyanate method, DPPH-radicals	0–120 mg/ml	Scavenging lipid peroxide (IC50 = 8 mg/ml) and DPPH radicals (IC50 = 7 mg/ml)	114
Anti-cancer activity	Methanolic extract from C. serratum	In vivo	DMBA-induced skin tumorigenesis in male mice	300, 600 and 900 mg/kg, i.g.	Curtailed tumor development	115, 116
	Methanolic extract from C. serratum	In vivo	DLA cell model	100 and 200 mg/kg	Reduced skin papilloma incidence and multiplicity	117
	Cryptojaponol, fortunin E, 12-methoxy-6,11,14,16-tetrahydroxy-17(15→16)-abeo-5,8,11,13-abietatetraen-3,7-dione	In vitro	HL-60, SMMC-7721, lA-549, MCF-7 cell lines	1.8–5.0 μM	Exhibited cytotoxicity	89
	Compounds 45, 70, 76, 78, 81, and 82	In vitro	BGC-823, Huh-7, KB, KE-97, and Jurkat	0.83–50.99 μM	Exhibited cytotoxicity	41
	Total flavonoids from C. Bungei	In vitro	HepG2	0.025–250 μg/ml	Inhibited HepG2 cells proliferation	119
	Trichotomone	In vitro	A549, Jurkat, BGC-823 and 293T WT	7.51–19.38 μM	Exhibited cytotoxicity	43
	Compounds 240 and 243	In vitro	Hela cell	28.92–35.67 μg/ml	Exhibited moderate cytotoxicity	82
Anti-bacterial activity	Methanolic extract from C. siphonanthus	In vitro	Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhi, Staphylococcus aureus, Escherichia coli, and Bacillus subtilis	5 mg/disc	The inhibition zones were 30, 16, 16, 12, 11.5 and 10 mm, respectively	114
	n-Butyl extract from C. bungei	In vitro	Staphylococcus aureus and Micrococcus pyogenes	50 mg/ml	The MIC values were 50 mg/ml and 25 mg/ml, respectively	120
	Aqueous extract from C. bungei	In vitro	Rhizoctonia cerealis, Fusarium graminearum, Rhizoctonia solani, and Setosphaeria turrum	50–400 mg/ml	Displayed the strong antibacterial action on Fusarium graminearum, and the MIC values 10 mg/ml	121
Anti-fungal activity	Ethyl acetate extract from C. inerme	In vitro	Alternaria, Lasiodiplodia, Pestalotiopsis, Nigrospora, Diaporthe, and Phomopsis	50 μg/disc	Inhibited the growth of most fungi	122
	Ethyl acetate and chloroform extracts from C. infortunatum	In vitro	B. megaterium, S. typhi, K. pneumoniae and to fungi against A. niger and C. albicans	1–512 μg/ml	Inhibited B. subtilis, K. pneumonia, S. aureus and E. coli growth	123
Anti-plasmodial activity	Ethyl acetate, methanol and aqueous extracts from C. rotundifolium	In vitro	NF54 chloroquine sensitive and FCR3 chloroquine-resistant strains of Plasmodium falciparum	5 μg/ml	Inhibited the growth of NF54 and FCR3 strains of Plasmodium falciparum	124
Insecticidal activity	Aqueous extract from C. chinense	In vitro	A. subpictus, A. albopictus, and C. tritaeniorhynchus	647.05–6877.28 μg/ml	Reduced populations of vector mosquitoes without detrimental effects on predation rates of non-target aquatic organisms, such as D. indicus, A. bouvieri and G. affinis	125
Anti-hypertensive activity	Aqueous extract from C. colebrookianum	In vivo, in vitro	Fructose-induced hypertension model in rats and in isolated frog heart.	50–100 mg/ml	The 100 mg/ml test samples were showed calcium antagonism in rat ileum and at 50 mg/ml and 75 mg/ml doses exhibited ROCK-II and PDE-5 inhibition respectively	126
	Compounds 64, 166, 178, 196	In vitro	ACE and a-glucosidase inhibitory activity assay	0.1–0.7 mM	Inhibited ACE and a-glucosidase.	123
Anti-obesity activity	Methanolic extract from C. phlomidis	In vivo	High fat diet induced obesity in female mice	200–400 mg/kg, i.g.	Decreased food consumption, body weight, adiposity index, pancreatic lipase activity, adiposity diameter, glucose, insulin, SGOT, SGPT, TG, TC and LDL-c levels	40
	Aqueous extract from C. glandulosum	In vivo	High fat diet induced obesity in C57BL/6J mice	0–200 μg/ml	Decreased adipogenesis, TG accumulation, leptin release and G3PDH activity	130
Anti-diarrheal activity	Methanolic extract and chloroform fraction from the C. indicum	In vitro	Castor oil-induced diarrhea testing	400 mg/kg	Inhibited defecation	104
	Methanolic extract from C. phlomidis	In vivo	castor oil induced diarrhea and PGE2 induced enteropooling in rats	600–800 mg/kg, p.o.	Exhibited significant inhibitory activity	131
Hepatoprotective activity	Ethanolic extract of C. inerme	In vivo	CCl4-induced liver damage in rats	200 mg/kg, i.g.	Decreased the serum ALT, AST, ALP, TGL, TC, and increased the GSH level	132
	Alcoholic extract from C. serratum	In vivo	CCl4-induced wistar rats	20 mg/kg, i.g.	Reduced the level of serum bilirubin and liver function marker enzymes	133
	Alcoholic and aqueous extract from C. serratum	In vivo	CCl4-induced liver damage in rats	200 mg/kg, i.g.	Restored AST, ALT, and ALP level	134
	Methanolic extract from C. umbellatum	In vivo	Schistosoma mansoni-infected mice	100, 200 and 400 mg/kg, i.g.	Reduced ALT activity and increase total protein level	113
Hypoglycemic and hypolipidemic activities	Aqueous extract from C. capitatum	In vivo	High fat diet fed rats	100, 400 and 800 mg/kg, i.g.	Reduced the mean fasting plasma glucose concentration, TC, VLDL-c and LDL-c	136
	Aqueous extract from C. glandulosum	In vivo	High fat diet fed rats	200, 400 and 800 mg/kg, i.g.	Suppressed the HMG CoA reductase and cholesterol ester synthase activity, increased the plasma lecithin cholesterol acyl transferase and lipoprotein lipase levels	137
Memory enhancing effects	Methanolic extract from C. infortunatum	In vivo	Rectangular maze and Y maze (interoceptive behavioral models)	100 and 200 mg/kg, i.g.		138
Neuroprotective effects	Compound 46	In vivo	Rat hippocampal nerve terminals (synaptosomes)	10 and 50 mg/kg, i.p.	Inhibited depolarization-evoked glutamate release and cytosolic free Ca2+ concentration in the hippocampal nerve terminals, inhibited glutamate release	69
Other activities	Ethanolic extract from C. petasites	In vitro	Isolated guinea-pig	2.25–9 mg/ml	Exhibited significantly tracheal smooth muscle relaxant activity	9
	Methanolic extract from C. phlomidis	In vivo	Phenobarbitone sodium-induced sleeping time	200, 400 and 600 mg/kg, i.g.	Reduced spontaneous activity, decreased exploratory behavioral profiles	139
	Ethanol extract from C. inerme	In vivo	Spontaneous locomotor activity or performance in the rotarod test	100 mg/kg, i.p.	Reduced methamphetamine-induced hyperlocomotion in mice	62

Anti-inflammatory and anti-nociceptive activities

Many studies have provided data on anti-inflammatory effects of C. phlomidis, C. petasites, Clerodendrum laevifolium, C. inerme, C. bungei, and C. serratum extracts of aerial parts, roots, leaves and stems. Of these, lots of studies have provided data on anti-inflammatory effects of C. serratum (Bharangi) extracts of aerial parts, roots and stems. An aqueous extract of roots reported significant anti-inflammatory effects at high dose (180 mg/kg, p.o.) in granuloma pouch model in rats. Roots in low dose (90 mg/kg, p.o.) and stems in high dose (180 mg/kg, p.o.) showed significant preventive effects in comparison with dexamethasone (a standard anti-inflammatory agent). Thus, it can be postulated that roots are more effective than stems and it would be useful as antiallergic and antiinflammatory drug for disease like asthma.95, 96 The methanolic extract of the aerial parts of C. serratum was demonstrated dual inhibitory effects on arachidonic acid metabolism or an inhibitor of phospholipase A2 when studied in ethyl phenylpropiolate-induced ear edema and in carrageenan and arachidonic acid induced hind paw edema in rats, and the extract exerted an inhibitory activity on the acute phase of inflammation due to an inhibition of synthesis and inflammatory mediators release through cyclooxygenase and lipoxygenase pathways. In contrast, the alcoholic root extract of C. serratum showed a potent antiinflammatory effect by reducing paw edema (acute) and cotton-pellet granuloma (chronic) in inflammation models. Apigenin-7-glucoside isolated from C. serratum roots has been demonstrated for anti-inflammatory effects in rats. The hydro-alcoholic extract (50, 200 and 500 mg/kg dose) of Bharangyadi preparation showed inhibition of carrageenan induced inflammation due to the inhibition of the enzyme cyclooxygenase and subsequent inhibition of prostaglandin synthesis which rationalizes traditional use of this plant in bronchial asthma and related inflammatory conditions. This anti-inflammatory effect of C. serratum might be observed due to flavonoids and saponins, but other active substances might also be responsible leading to synergistic effects.

Prakash et al reported that the monomer compound 3-hydroxy, 2-methoxy-sodium butanoate (HMSB, at doses of 25, 50, 100 mg/kg, i.g.) isolated from the leaves of C. phlomidis displayed anti-inflammatory and anti-arthritic effects on carrageenan-induced inflammation and freund complete adjuvant (FCA)-induced arthritic rat models. The results showed that HMSB could significantly reduce the paw edema response, decrease lysosomal enzymes, protein-bound carbohydrates, and acute phase protein levels. In addition, HMSB could significantly down-regulate pro-inflammatory cytokines TNF, IL-1 and IL-6 protein levels and mRNA expression in the joints with a dose-dependent manner. These results indicated that the HMSB possess considerable potency in anti-inflammatory action and has a prominent anti-arthritic effect. Panthong et al evaluated the anti-inflammatory and antipyretic activities of the methanol extract (at doses of 1.0, 2.0, 4.0 mg/ear, i.g.) from C. petasites. The results proved that the extract possessed moderate inhibitory activity on acute phase of inflammation in a dose-related manner on ethyl phenylpropiolate-induced ear edema (ED50 = 2.34 mg/ear) as well as carrageenan-induced paw edema (ED30 = 420.41 mg/kg) in rats, and also reduced the alkaline phosphatase activity in serum. Moreover, the extract exhibited an excellent antipyretic effect in yeast-induced hyperthermic rats. The anti-inflammatory and antipyretic effects of the methanol extract may be caused by the inhibition of the prostaglandin synthesis. The ethanol extract from the leaves of C. laevifolium exhibited the greatest anti-inflammatory activity against lipoxygenase with the IC50 of 14.12 μg/ml in vitro study. In addition, the methanolic extract from the aerial parts of C. inerme exhibited anti-inflammatory activity at doses of 50, 100 and 200 mg/kg in formalin induced hind paw edema animals. The anti-inflammatory activity of petroleum ether, chloroform, ethyl acetate, alcohol, and aqueous extracts of fresh leaves from Clerodendrum paniculatum Linn was evaluated by in vitro (human red blood cell membrane stabilization method) and in vivo methods (0.1 ml of 1% w/v carrageenan-induced rat paw edema model). Petroleum ether and chloroform extracts which showed, best in vitro anti-inflammatory activity also showed a dose dependent (200 and 400 mg/kg) significant reduction in paw edema when compared to the control (indomethacin, 10 mg/kg).

Srisook et al found that two flavones, hispidulin (126) and acacetin (146) isolated from the ethyl acetate (EA) extracts from the leaves of C. inerme exhibit the most potent inhibitory activity on nitric oxide (NO) production in RAW 264.7 macrophage stimulated with lipopolysaccharide (LPS). Furthermore, IC50 values of hispidulin and acacetin were 43.7 ± 4.0 and 43.5 ± 6.4 μM, respectively. Hispidulin also inhibited prostaglandin E2 (PGE2) production as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 expressions via the blockade of nuclear factor kappa B (NF-κB) DNA binding activity and the c-Jun NH2-terminal protein kinase (JNK) way.

Narayanan et al (1999) studied anti-nociceptive effects of an alcoholic extract of C. serratum roots (50, 100 and 200 mg/kg) in acetic acid induced writhing (200 mg/kg) and hot plate method (100 and 200 mg/kg). A reduction in the number of abdominal constrictions in acetic acid induced writhing in mice indicated the anti-nociceptive effect of C. serratum which has further been supported by the findings of hot plate method where a significant increase in area under curve was observed. However, the response was much less when compared to morphine and exact mechanism remains to be investigated in detail. The authors have also indicated significant antipyretic activity of alcoholic extract (100 and 200 mg/kg) of C. serratum roots in rabbit model through a dose dependent reduction in pyrexia after administration of C. serratum. The ethanolic extract of C. serratum leaves has been found to produce considerable centrally acting analgesic activity in tail flick test at 250 mg/kg dose and peripherally acting analgesic activity in acetic acid induced writhing test at 500 mg/kg dose which was found comparable with diclofenac sodium. Blockade of capillary permeability or release of endogenous substances like prostaglandins might be a postulated mechanism. In another study, the author has established a potent analgesic effect of methanolic extract of the aerial parts of C. serratum when injected subcutaneously into the right dorsal hind paw of the mice via an inhibition of peripherally and centrally mediated nociception in early as well as in late phase.

The n-butyl extract (at dose of 1.0 g/kg, i.p.) from the roots of the C. bungei displayed a significant anti-nociceptive effect in an acetic acid-induced writhing model, prolonged the latency reaction in the hot-plate test in 15, 30, 60 and 90 min in mice. Moreover, the extracts administered in combination with naloxone significantly prolonged the latency reaction, and indicating that naloxone did not revert the action of the extract effect. Also, the extracts notably suppressed the production of prostaglandin (PG) in a dose-dependent manner. The extracts from the roots of C. bungei significantly restrained the phlogistic infiltration, improved the ear edema and reduced the writhes of abdominal cavity and the ear edema induced by 2,4-dinitro-1-fluorobenzene (DNFB)-induced hypersensitivity. The methanolic extract of C. indicum at doses of 200 and 400 mg/kg showed a significant (P < 0.001) and dose-dependent reduction in the number of writhes with 62.57% and 70.76% of inhibition in the acetic acid-induced writhing test, respectively. Thirumal et al reported that the aqueous extract obtained from C. inerme leaves (at doses of 100 and 200 mg/kg, p.o.) displayed significant analgesic effect by raising the pain threshold at different time of observation (0–120 min).

The combination of antiinflammatory, anti-nociceptive and antipyretic effects of the Clerodendrum genus indicated a prospect of intervention with prostaglandin synthesis, as prostaglandins have been established as a common mediator in all these responses. However, this possibility remains to be investigated thoroughly. Advanced studies can be undertaken in the direction of purification of the chemical constituents of the leaves and investigation of the biochemical pathways for the development of a potent analgesic agent with a low toxicity and better therapeutic index.

Antioxidant activity

Gouthamchandra et al have demonstrated the antioxidant activity of the ethanol extract of leaves of C. infortunatum with the highest scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay (IC50 values 250 μg/ml). Moreover, the ethanol extract at 250 μg/ml concentration displayed significantly radical scavenging activity in hydroxyl, superoxide anion, and nitric oxide radical in vitro, and the scavenging ratio were 68.58%, 62.06%, and 52.65%, respectively. Adefegha et al reported that the phenolic (free and bound) extracts from the leaves of Clerodendrum volubile scavenging DPPH free radicals and OH radicals in a concentration dependent manner. Interestingly, the IC50 values revealed that the free soluble phenolic extract (IC50 = 89.18 μg/ml and 924.90 μg/ml) have a significantly higher scavenging ability against DPPH free radicals and OH radicals than the bound phenolic extracts (IC50 = 133.40 μg/ml and 1224.0 μg/ml), respectively. Three phenylethanoid glycosides monoacetylmartinoside (182), 3″,4″-O-acetylmartynoside (188) and acteoside (199) isolated from the roots of Clerodendrum lindleyi exhibited significant in vitro antioxidant activity in DPPH assay, and the radical scavenging rate were 25, 37, 60 μmol/l, respectively. The methanolic extract and 5-hydroxy-6,7,4′-trimethoxyflavone (153) isolated from the aerial parts of C. inerme showed notably scavenging activity with maximum inhibition of 61.84% for the methanolic extract (100 μg/ml) and 37.19% for 5-hydroxy-6,7,4′-trimethoxyflavone (20 μM), respectively, using DPPH assay.

Bhujbal et al have demonstrated in-vitro antioxidant effects of ethanolic root extract of C. serratum (50–250 μg/ml) at various concentrations in the DPPH radical scavenging assay (IC50 value 175 μg/ml); FRAP (ferric reducing antioxidant power) assay and hydrogen peroxide radical scavenging assay (IC50 value 85 μg/ml) and suggested the role of polyphenols and flavonoids for the observed antioxidant effects in the extract. The antioxidant potential of methanolic extract of leaves of C. serratum was found more potent (EC50 value 0.51 μg/ml) due to higher polyphenolic content than other extracts (petroleum ether, chloroform and water) when evaluated in trolox equivalent antioxidant capacity (TEAC) in DPPH and 2,20-azinobis-(3-ethylbenzothiazoneline-6-sulfonic acid) diammonium salt (ABTS) assays. Antioxidant potential of methanolic extract (200–1000 μg/ml) from the leaves of C. serratum was further supported by additional reports on DPPH assay, reducing power assay and total antioxidant activity assay.

Feng et al reported that the flavonoid compound from C. bungei exhibited strong scavenging capability on nitrite, superoxide anion free radicals and hydroxyl free radicals, and also showed stronger antioxidant effect on pork fat than vitamin C. Also, the phenolic extracts (free and bound) from the C. volubile leaf were able to significantly reduce the MDA content in a dose dependent manner (0–312.60 μg/ml). The free soluble phenolic extracts (192.30–77.90%) had a significantly higher concentration dependent inhibition of MDA compared with that of the bound phenolic extract (192.30–91.30%). Jatsa et al reported that the methanolic extract (at doses of 100, 200, and 400 mg/kg, i.g.) of Clerodendrum umbellatum significantly decrease malondialdehyde (MDA) level, increase catalase (CAT) activity and glutathione level. The methanolic extracts of leaves of Clerodendrum siphonanthus displayed extremely effective in scavenging lipid peroxide (IC50 = 8 mg/ml) and DPPH radicals (IC50 = 7 mg/ml).

Anticancer activity

Chinchali et al reported that administration of methanolic extract of C. serratum leaves significantly reduced tumor development in 7,12-dimethylbenz[α] anthracene (DMBA) induced skin carcinogenicity in testis, liver and kidney of mice.115, 116 The researchers have further demonstrated that flavonoids and phenolics can effectively reduce the incidence and multiplicity of skin papilloma, many investigators have confirmed anti-cancer property of C. serratum by various in vivo and in-vitro studies.117, 118 The methanolic extract of roots of C. serratum exhibited notably in vivo anticancer activity using DLA cell model at the dose 100 and 200 mg/kg body weight.

Xu et al reported that diterpenoids cryptojaponol (281), fortunin E (282), 12-methoxy-6,11,14,16-tetrahydroxy-17(15→16)-abeo-5,8,11,13-abietatetraen-3,7-dione (283) isolated from the hydroalcoholic extract of the herb of C. kiangsiense exhibited significant cytotoxicity against human myeloid leukemia (HL-60), hepatocellular carcinoma (SMMC-7721), lung cancer (A-549) and breast cancer (MCF-7) cell lines, and the range of IC50 values was 1.8–5.0 μM. The results suggested that these compounds might have promising potential to be anticancer agents.

Compounds 45, 70, 76, 78, 81, and 82 isolated and identified from the roots of C. trichotomum displayed remarkable in vitro cytotoxicity activity against five human cancer cell lines (BGC-823, Huh-7, KB, KE-97, and Jurkat) by using the CellTiter Glo™ Luminescent cell viability assay method with the IC50 values ranging from 0.83 to 50.99 μM. Among of them, teuvincenone E (81) exhibited the most potent activity against these five cell lines with the IC50 values of 3.95, 5.37, 1.18, 1.27, and 0.83 μM, respectively. The total flavonoids isolated from the C. Bungei significantly inhibited the human hepatoma HepG2 cells proliferation at concentrations of 0.025, 0.25, 2.5, 25, 250 μg/ml in vitro, and the inhibition rates were 5.55%, 12.73%, 14.84%, 62.44%, and 76.81%, respectively. A dimeric diterpene trichotomone (55) isolated from the roots of the C. trichotomum exhibited strong in vitro cytotoxicities against several human cancer cell lines (A549, Jurkat, BGC-823 and 293T WT) with IC50 values ranged from 7.51 to 19.38 μM. Two steroids, (20R,22E,24R)-3β-hydroxy-stigmasta-5,22,25-trien-7-one (240), and (20R,22E,24R)-stigmasta-5,22,25-trien-3β,7β-diol (243) isolated from the leaves of C. trichotomum exhibited moderate cytotoxicity against Hela cell with IC50 values at 35.67 and 28.92 μg/ml, respectively.

Antimicrobial activity

Antibacterial activity

Arokiyaraj et al reported that the methanolic extract of leaves of C. siphonanthus exhibited significant antibacterial effect against Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhi, Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, and the inhibition zones were 30, 16, 16, 12, 11.5 and 10 mm, respectively. Liu et al reported that the n-butyl extract from the roots of C. bungei displayed prominent antibacterial effect against Staphylococcus aureus and Micrococcus pyogenes, and the minimal inhibitory concentration (MIC) values were 50 mg/ml and 25 mg/ml, respectively. Moreover, the aqueous extracts from the roots of C. bungei have notably antibacterial action on Rhizoctonia cerealis, Fusarium graminearum, Rhizoctonia solani, and Setosphaeria turrum, especially the aqueous extract exhibited strongest antibacterial action on Fusarium graminearum, and the MIC values 10 mg/ml. The methanolic extract, and chloroform fraction of C. indicum showed moderate activity against the tested microorganisms in terms of both zones of inhibition (ranged from 9 to 13 mm, 10 to 13 mm and 10 to 13 mm, respectively, at a concentration of 400 μg/disc) and spectrum of activity.

Antifungal activity

Gong et al firstly found that the crude ethyl acetate extract of endophytes from the stems of C. inerme exhibit broad in vitro antifungal activity against a number of fungal pathogens, including Alternaria, Lasiodiplodia, Pestalotiopsis, Nigrospora, Diaporthe, and Phomopsis, and inhibit the growth of most fungi. The ethyl acetate and chloroform extracts of root, leaf, and stem of the C. infortunatum showed significant inhibitory activity over the bacteria and fungus comparable to the standard drug tetracycline and fluconazole. The maximum average diameter zone of inhibition was recorded to bacterial strains against Bacillus megaterium, S. typhi, K. pneumoniae and to fungi against Anisops niger and Clerodendrum albicans. The MIC values of ethyl acetate and chloroform root extract were determined as 64 μg/ml to B. subtilis and K. pneumoniae; to S.-β-haemolyticus and S. typhi for ethyl acetate extracts, 128 μg/ml to S. aureus, and E. coli for both ethyl acetate and chloroform root extracts but only S. typhi and S.-β-haemolyticus for chloroform extract.

Antiplasmodial activity

Adia et al revealed that the ethyl acetate, methanol and aqueous extracts from the leaves of Clerodendrum rotundifolium exhibit significantly in vitro antiplasmodial activity against the chloroquine-sensitive and chloroquine resistant Plasmodium falciparum strains with the IC50 < 5 μg/ml for the first time.

Insecticidal activity

Lots of pharmacological tests and clinical observations have shown that different extract and/or compound prescriptions derived from C. chinense have significant insecticidal effects against diseases and organisms including schistosomiasis and trichomoniasis. Govindarajan et al reported that C. chinense-fabricated silver nanoparticles (Ag NPs) display higher toxicity against Anisops subpictus, Anisops albopictus, and Clerodendrum tritaeniorhynchus with the LC50 values of 10.23, 11.10, and 12.38 μg/ml, respectively. Also, C. chinense-fabricated Ag NPs were found safer to non-target organisms Diplonychus indicus, Anisops bouvieri and Gambusia affinis, with respectively LC50 values ranging from 647.05 to 6877.28 μg/ml. These results indicated that C. chinense-fabricated Ag NPs are a promising and eco-friendly tool against larval populations of mosquito vectors of medical and veterinary importance, with negligible toxicity against non-target aquatic organisms.

Antihypertensive activity

Lokesh et al evaluated the anti-hypertensive potential of the aqueous extract, and its aqueous, n-butanol, ethyl-acetate and chloroform fractions of C. colebrookianum leaves using fructose-induced hypertension model in rats and isolated frog heart. The results showed that the each fraction display negative inotropic and chronotropic effect on isolated frog heart and significant reduction in systolic blood pressure and heart rate in hypertensive rats. Moreover, each fraction at 100 mg/ml showed calcium antagonism in rat ileum and at 50 mg/ml and 75 mg/ml doses exhibited Rho-kinase (ROCK-II) and phosphodiesterase-5 (PDE-5) inhibition, respectively. The antihypertensive activity of C. colebrookianum may mediate mainly by cholinergic action and following ROCK-II and PDE-5 inhibition. Liu et al demonstrated that four compounds 15-dehydrocyrtophyllone A (64), verbascoside (166), leucosceptoside A (178), and isoacteoside (196), isolated from dried roots of C. bungei showed inhibitory effects against angiotensin converting enzyme (ACE) and a-glucosidase. Among of them, 5-dehydrocyrtophyllone A exhibited an inhibitory effect against ACE with an IC50 value of 42.7 μM, while the three phenylethanoid glycosides, verbascoside, leucosceptoside A, and isoacteoside, exhibited stronger inhibitory effects against a-glucosidase, with IC50 values of 0.5 mM, 0.7 mM, and 0.1 mM, respectively.

Anti-diabetic activity

Bachhawat et al reported that the methanolic extract (100 mg/ml) of C. serratum roots was evaluated for alpha-glucosidase inhibitory activity using enzyme assay. The extract was not found significantly effective (32.3% inhibition rate with IC50 value 265 μg/ml) and may require higher dose to produce the effect.

Anti-obesity activity

Obesity, initially thought as a problem of the developed world, has now become a worldwide malady because of increasing prevalence in the developing countries as well as developed countries. The impact of methanolic extract of C. phlomidis on weight reduction in feeding high fat diet induced obesity in female mice had been investigated. The studies showed that the methanolic extract of C. phlomidis at 200 and 400 mg/kg significantly decrease food consumption, body weight, adiposity index, pancreatic lipase activity, adiposity diameter, glucose, insulin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), triglycerides (TG), total cholesterol (TC) and low-density lipoprotein (LDL-c) levels induced by feeding high fat diet induced obesity in female mice, and the LD50 value was found to be more than 2000 mg/kg. Jadeja et al reported that the aqueous extract from the leaves of Clerodendron glandulosum exhibited significant anti-adipogenic effect by decreasing adipogenesis, TG accumulation, leptin release and glyceraldehyde 3-phosphate dehydrogenase (G3PDH) activity along with higher glycerol release without significantly altering viability of 3T3L1 pre-adipocytes in vitro. This study was a profound scrutiny of C. glandulosum extract and its role in preventing adipocyte differentiation and visceral adiposity by down regulation of PPARγ-2 related genes and leptin expression. This study validates the traditional therapeutic claim of use of CG extract in controlling obesity.

Anti-diarrheal activity

Pal. et al reported that the methanolic extract and chloroform fraction from the C. indicum at a dose of 400 mg/kg produced 21.74% and 26.96% inhibition of defecation in castor oil-induced diarrhea testing, respectively, which were found to be comparable to that of standard drug loperamide (37.39% inhibition at 50 mg/kg) with regard to the severity of diarrhea. The methanolic extract (at doses of 600 and 800 mg/kg, p.o.) from the leaves of the C. phlomidis showed significant inhibitory activity against castor oil induced diarrhea and PGE2 induced enteropooling in rats. Also, the extract also showed a significant reduction in gastrointestinal motility in charcoal meal test in rats. Anti-diarrheal activity of the plant supported its traditional use in diarrhea by the people of Australia and India.

Hepatoprotective activity

Gopal et al reported that the ethanolic extract of C. inerme leaves exhibit hepatoprotective activity on CCl4-induced (0.5 ml/kg, i.p.) liver damage in rats at a dose of 200 mg/kg. The extract significantly decreases the serum enzyme alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), triglycerides (TGL), total cholesterol (TC), and significantly increased the glutathione level. Vidya et al reported that administration of an alcoholic extract from the roots of C. serratum (20 mg/kg) for two weeks significantly reduced the level of serum bilirubin and liver function marker enzymes in carbon tetrachloride (CCl4) induced wistar rats indicating its potential as a hepatoprotective agent possibly due to the radical scavenging activity of the flavonoids present in the drug.

Also, Agrawal et al found that the alcoholic (200 mg/kg. p.o.) and aqueous extract (200 mg/kg, p.o.) from the leaves of C. serratum possess significant hepatoprotective effects by restoring the normal level of AST, ALT, and ALP with significant reduction in liver weight. Reports on the biomarker ursolic acid, isolated from alcoholic root extract suggested restorative effects on the levels of AST, ALT and ALP towards respective normal value, to stabilize the plasma membranes as well as to repair hepatic tissue damage caused by CCl4. Ursolic acid was found to normalize the disturbed antioxidant status by maintaining the levels of glutathione and by inhibiting the production of malondialdehyde or may be due to the inhibition of toxicant activation and the enhancement of body defense system.

The ethanol extract of the polyherbal composition from the roots of C. serratum showed significant protection against acetaminophen-induced hepatotoxicity in rats, and the function may be through DPPH free radical scavenging activity. The methanolic extract (at doses of 100, 200 and 400 mg/kg, i.g.) of C. umbellatum significantly reduced ALT activity and increase total protein level. These findings provided scientific evidence to the ethnomedicinal reports of C. serratum in treating acute jaundice; however investigations are still required to fully explicate the exact mechanisms behind the protection.

Hypoglycemic and hypolipidemic activities

Adeneye et al reported that the fresh leaves aqueous extract of Clerodendrum capitatum possess obvious hypoglycemic and hypolipidemic activities, the extracts (at doses of 100, 400 and 800 mg/kg, i.g.) could significantly reduce the mean fasting plasma glucose concentration in a dose-dependent lowering effects. Furthermore, the extracts also could notably decrease the total cholesterol, VLDL-c and LDL-c with a dose-related, but significant elevate the triglycerides and HDL-c with a dose-related in plasma. Jadeja et al reported that the aqueous extract (200, 400 and 800 mg/kg, i.g.) of C. glandulosum leaves significantly prevented increment in plasma and tissue lipid profiles in high fat diet (HFD) fed rats, suppressed activity levels of HMG CoA reductase (Hepatic) and cholesterol ester synthase (Hepatic and intestinal), and increased the activity levels of plasma lecithin cholesterol acyl transferase and lipoprotein lipase (plasma, hepatic and adipose), and increased excretion of triglycerides, cholesterol and bile acids through faeces.

Memory enhancing effects

Gupta et al reported that the methanolic extract of C. infortunatum leaves exhibited promising memory enhancing effects at dose of 200 mg/kg (i.g.), and the effects was closely approximated the results for the standard drug Brahmi, the higher dose evoking pronounced alteration behavior and better learning assessments. The presence of steroids, terpenoids, fats and flavonoids were confirmed in this extract by TLC. The extract is likely to develop a promising nootropic to prevent dementia senilis disease.

Neuroprotective effects

One flavonoid acacetin (146) isolated from the C. inerme was investigated for neuroprotective activity. It was observed that acacetin inhibited depolarization-evoked glutamate release and cytosolic free Ca2+ concentration in the hippocampal nerve terminals. Moreover, acacetin (at doses of 10 and 50 mg/kg, i.p.) inhibited glutamate release from hippocampal synaptosomes by attenuating voltage-dependent Ca2+ entry and effectively prevents kainic acid (KA)-induced in vivo excitotoxicity.

Other activities

Hazekamp et al found that the ethanolic extract of C. petasites leaves exhibited a dose-dependently tracheal smooth muscle relaxant activity on isolated guinea-pig at concentrations from 2.25 to 9 mg/ml, and the active principle was isolated and identified as the flavonoid hispidulin. The results indicated that hispidulin may be beneficial in the treatment of asthma related diseases. In additional, the methanolic extract (at doses of 200,400 and 600 mg/kg, i.g.) of C. phlomidis leaves was found to cause significant reduction in spontaneous activity, and decreases in exploratory behavioral profiles by the Y-maze and head dip test. Also, the extract exhibit significantly reduction in muscle relaxant activity by rotarod, 30° inclined screen and traction tests, as well as significantly potentiated the phenobarbitone sodium-induced sleeping time. Huang et al demonstrated for the very first time that hispidulin isolated from the dichloromethane and the n-hexane fractions of ethanol extract of C. inerme significantly reduced methamphetamine-induced hyperlocomotion (MIH) in mice at dose of 100 mg/kg (i.p.) that did not affect their spontaneous locomotor activity or performance in the rotarod test, a measure for motor coordination. This study suggested that hispidulin may be a good therapeutic potential in hyper-dopaminergic disorders.

Conclusions

In present review, more than 300 chemical constituents have been isolated and identified from the genus of Clerodendrum, and pharmacological studies indicated that the crude extracts and some special monomer compounds of the genus Clerodendrum exert various biological activities, such as anti-inflammatory and anti-nociceptive, antioxidant, anticancer, antimicrobial, anti-hypertensive, anti-obesity, anti-diarrheal, hepatoprotective, memory enhancing, and neuroprotective activities. Terpenes, including monoterpene and its derivatives, sesquiterpene, diterpenoids, triterpenoids, as the major characteristic constituents with significant biological activities, have great potential to be developed into new drugs, especially for anti-inflammatory, antioxidant, anticancer, and antimicrobial agents. In addition, important activities, such as anti-hypertensive, anti-obesity, and hepatoprotective activities indicated that Clerodendrum genus can be a promising source of biologically active compounds for these diseases.

The genus Clerodendrum has gained a wide acceptance for its pharmacological activities against various ailments. Although above 400 species of the genus Clerodendrum were distributed all over the world, only a few of them have been investigated and studied so far. From this review, it can be concluded that phytochemical and pharmacology investigations were mainly focused on C. serratum, C. bungei, C. inerme, C. trichotomum, Clerodendrum chinense, C. colebrookianum, C. phlomidis, C. petasites, C. grayi, and C. indicum. For some species, such as C. grayi was only studied phytochemically, no biological activity was reported up till now. Many other species are totally unknown phytochemically and biologically. Following these species may be of a great importance in discovering new bio-active compounds. On the other hand, few reports have been published concerning the toxic effects of isolated components, and quantitative informations of the genus Clerodendrum were also relatively sparse.

All in all, the omnibearing study on this genus Clerodendrum should be performed as soon as possible, which will provide reliable theory evidence for better exploit and utilize the resources of the species in this genus.

Conflict of interest statement

The authors declare no conflict of interest.