Harnessing the Phytotherapeutic Treasure Troves of the Ancient Medicinal Plant Azadirachta indica (Neem) and Associated Endophytic Microorganisms

Abstract

Azadirachta indica, commonly known as neem, is an evergreen tree of the tropics and sub-tropics native to the Indian subcontinent with demonstrated ethnomedicinal value and importance in agriculture as well as in the pharmaceutical industry. This ancient medicinal tree, often called the “wonder tree”, is regarded as a chemical factory of diverse and complex compounds with a plethora of structural scaffolds that is very difficult to mimic by chemical synthesis. Such multifaceted chemical diversity leads to a fantastic repertoire of functional traits, encompassing a wide variety of biological activity and unique modes of action against specific and generalist pathogens and pests. Until now, more than 400 compounds have been isolated from different parts of neem including important bioactive secondary metabolites such as azadirachtin, nimbidin, nimbin, nimbolide, gedunin, and many more. In addition to its insecticidal property, the plant is also known for antimicrobial, antimalarial, antiviral, anti-inflammatory, analgesic, antipyretic, hypoglycaemic, antiulcer, antifertility, anticarcinogenic, hepatoprotective, antioxidant, anxiolytic, molluscicidal, acaricidal, and antifilarial properties. Notwithstanding the chemical and biological virtuosity of neem, it has also been extensively explored for associated microorganisms, especially a class of mutualists called endophytic microorganisms (or endophytes). More than 30 compounds, including neem “mimetic” compounds, have been reported from endophytes harbored in the neem trees in different ecological niches. In this review, we provide an informative and in-depth overview of the topic that can serve as a point of reference for an understanding of the functions and applications of a medicinal plant such as neem, including associated endophytes, within the overall theme of phytopathology. Our review further exemplifies the already-noted current surge of interest in plant and microbial natural products for implications both within the ecological and clinical settings, for a more secure and sustainable future.

Key words

neem - Azadirachta indica - Meliaceae - endophytic fungi - actinomycetes - bioactive compounds

Introduction

Neem (Azadirachta indica A. Juss.) is native to the Indian subcontinent and is often called a “wonder tree”. Considering the importance of neem in agriculture, medicine, industry, and environment, it is colloquially regarded as a tree for solving global problems [1]. India has a long history of using ethnomedicinal plants as traditional medicines (e.g., in Ayurveda, Unani, and Siddha). Neem is a preeminent natural resource containing a vast range of chemically diverse and structurally complex compounds possessing unique biological activities. It is interesting to note that over 400 secondary metabolites of different classes have already been reported from neem prospected from different ecological niches, which certainly justifies its historical use in the traditional medicinal sector ([1] and references therein).

Microbial associations are prevalent in plants; these multifaceted associations range from pathogenic, saprophytic, or opportunistic to more sustained mutualistic interactions such as mycorrhizal and endophytic (fungal, bacterial, and actinobacterial) [2]. Fungi are considered to be one of the most diverse life forms on earth. Although the magnitude of fungal diversity around the world is still open to debate, the estimate of hundreds to thousands of species to even millions has been put forth [2]. The most widely accepted estimate is that of Hawksworth [3] who estimated the size of 1.5 million species, out of which currently over 100 000 species have been discovered. Among the different niches that support the growth of microorganisms, particularly fungi, one unique and specialized habitat is inter- and intracellular spaces of higher plants. These microorganisms are called endophytes. The term “endophyte” was first used by De Bary [4], and the commonly accepted definition pertains to “fungi or bacteria which for all or part of their life cycle, invade the tissues of living plant and cause unapparent and asymptomatic infections entirely within plant tissues, without disease” [5]. Mostert and co-workers (2000) further postulated that “true endophytes are fungi whose colonization never results in visible disease symptoms” [6]. It is now well established that endophytes are capable of maintaining mutualistic associations with their host plants, which often lead to the co-evolution of certain functional traits such as the production of bioactive secondary metabolites. During their co-existence with host plants, endophytes encounter invasion by a plethora of specific and generalist pathogens. Therefore, in order to survive in their ecological niches, endophytes might evolve additional defense strategies such as production of chemical defense compounds, small-molecule chemical modulators for activating host plant defenses, and precursors to host plant secondary metabolites, among others. Thus far, endophytes have emerged as relevant sources of biologically active natural products, and they play an essential role in maintaining the ecological balance in plants. Endophytes harboring neem are, therefore, also an invaluable resource of both novel as well as well-known natural compounds having high and diverse biological functionality for significant medicinal, agricultural, and industrial exploitation [7]. In this review, we provide a detailed elaboration on the metabolites identified to date in the neem plant as well as their biological activities. Further, we discuss thoroughly endophytes reported from neem plants and the production of novel, biologically active metabolites.

Neem, the “Wonder Tree”

Neem (Azadirachta indica A. Juss.) is an indigenous medicinal plant of the Indian subcontinent [8]. The scientific name of this plant is derived from the Persian word “Azad dirakhat-I-Hind” meaning “noble or free tree of India” [9]. Neem had been described as early as 1830 by De Jussieu as an evergreen tree of the tropics and sub-tropics belonging to the family Meliaceae [10]. Medicinal properties of neem have been inscribed in the ancient testaments of Sanskrit literature as “Arishtha”, which translates to “reliever of sickness”. Dube (1996) described the ancient Indian names for the neem tree as prabhadra (very useful), paribhadrak (spreading its utility over vast distances), sarvobhadrak (useful in every way), and rajbhadrak (best among all the useful trees), all pointing towards its colossal worth in the Indian way of life [11]. Neem is widely used as a folk medicine for various therapeutic purposes as well as a source of agrochemicals for many centuries in the Indian agricultural system. The essential components of neem and their uses are summarized in [Fig. 1].

Fig. 1 Important Azdirachta indica (neem) plant parts and their uses.

Chemical Diversity of Compounds Reported from Neem

Around 406 compounds have been isolated from different tissues of neem, and several sporadic reviews have also been published on the chemistry and structural diversity of these compounds. The compounds have been divided into 2 major classes: isoprenoids and non-isoprenoids ([Fig. 2]). On the one hand, isoprenoids include diterpenoids and triterpenoids encompassing protomeliacins, limonoids, azadirone, and its derivatives; gedunin and its derivatives; vilasinin type of compounds; and C-seco-meliacins such as nimbin, salanin, and azadirachtin. On the other hand, non-isoprenoids are comprised of proteins (amino acids) and carbohydrates (polysaccharides), sulfur compounds, polyphenolics such as flavonoids and their glycosides, dihydrochalcone, coumarin, and tannins including aliphatic compounds, to name a few. The first isolated and characterized compound was nimbin, followed by nimbinin [12], [13]. A considerable assortment of compounds have been isolated from different tissues of neem including leaves, twigs, flowers, fruits, seeds, seeds oil, bark, and roots, which are summarized in [Table 1] along with their reported biological activities.

Fig. 2 Chemical classification of Azdirachta indica (neem) derived compounds.

Table 1 Biomolecules reported from different tissues of Azadirachta indica.

Sl. No.	Plant tissue	Compounds	Compound class	Biological activity	References
n. a.: not available
1	Leaves	Quercetin-3-o-β -d-glucopyranoside (isoquercitrin)	Flavonoids	n. a.	[14]
2	Leaves	3-hydroxystigmasta-5-en-7-one	Steroids	Antiplatelet aggregation	[15], [16]
3	Leaves	n-Hexacosanol	Miscellaneous compounds	Potent feeding stimulants for larvae of the silkworm	[17], [18]
4	Leaves	Tetratriacontane	Hydrocarbons	n. a.	[19]
5	Leaves	Hexacosene	Hydrocarbons	n. a.	[19], [20]
6	Leaves	β-carotene	Hydrocarbons	n. a.	[21]
7	Leaves	Nimbandiol	Pentanortriterpenoids	Antimalarial activity	[22]
8	Leaves	α-Linolenic acid	Fatty acids and their derivatives	Reduces cardiovascular disease	[23], [24]
9	Leaves	Xanthophylls	Miscellaneous compounds	Antioxidant activities	[20], [21], [25]
10	Leaves	Kaempferol-3-O-rutinoside (or nicotiflorin)	Flavonoids	n. a.	[26]
11	Leaves	Myricetin-3-O-rutinoside	Flavonoids	n. a.	[26]
12	Leaves	Quercetin-3-O-α-L-rhamnoside	Flavonoids	n. a.	[26]
13	Leaves	Quercetin-3-O-rutinoside	Flavonoids	n. a.	[26]
14	Leaves	Quercetrin	Flavonoids	Inhibitors of azoxymethanol-induced colonic neoplasia	[27], [28], [29], [30], [31]
15	Leaves	Rutin	Flavonoids	Inhibitors of azoxymethanol-induced colonic neoplasia	[27], [28], [29]
16	Leaves	Oxalic acid	Acids and their derivatives	n. a.	[32]
17	Leaves	Ascorbic acid	Acids and their derivatives	n. a.	[32]
18	Leaves	Melianol	Mononotriterpenoids	n. a.	[32]
19	Leaves	2′,3′-dehydrosalannol	Ring-C-seco-tetranotriterpenoids	n. a.	[33]
20	Leaves	1,3-diacetyl-11,19-deoxo-19-oxomelia-carpin	Ring-C-seco-tetranotriterpenoids	n. a.	[34]
21	Leaves	Isoazadirolide	Ring-C-seco-tetranotriterpenoids	n. a.	[35]
22	Leaves	Desfurano-6-α-hydroxyazadiradione	Octanortriterpenoids	Insecticidal activity against fourth instar larvae of mosquito (Anopheles stephensi)	[36]
23	Leaves	22, 23-dihydronimocinol	Tetranortriterpenoids	Insecticidal activity fourth instar larvae of the mosquito (Anopheles stephensi)	[36]
24	Leaves	Nimbocinolide	γ-Hydroxybutenolides	n. a.	[37]
25	Leaves	Isonimbocinolide	γ-Hydroxybutenolides	n. a.	[38]
26	Leaves	23-O-methylnimocinolide	γ-Hydroxybutenolides	Insect growth regulating effect on mosquitoes (Aedes aegypti)	[39]
27	Leaves	1, 7-O-deacetyl-23-O-methyl-7α-O-senecioylnimocinolide	γ-Hydroxybutenolides	Insect growth regulating effect on mosquitoes (Aedes aegypti)	[39]
28	Leaves	Meldenin	Tetranortriterpenoids	Antimalarial activity	[40], [41], [42]
29	Leaves	Isomeldenin	Tetranortriterpenoids	Antimalarial activity	[41], [42], [43]
30	Leaves	Meldenindiol	Tetranortriterpenoids	n. a.	[41], [43]
31	Leaves	β-sitosterol	Steroids	Insecticidal activity	[20], [44]
32	Leaves	Zafaral	Tetranortriterpenoids	Insect growth regulating against houseflies and toxic on larvae of mosquitoes	[45]
33	Fresh leaves	Zeeshanol	Trinortriterpenoids	n. a.	[46]
34	Dried leaves	4α, 6α-dihydroxy-A-homozadirone	Tetranortriterpenoids	n. a.	[47]
35	Air dried leaves	Azadirachtolide	Tetranortriterpenoids	n. a.	[48]
36	Air dried leaves	Deoxyazadirachtolide	Tetranortriterpenoids	n. a.	[48]
37	Air dried leaves	Sulfonoquinovosyldiacylglyceride	Glyceride	Antileukemic activity	[49]
38	Fresh leaves	Azadirachtanin	Tetranortriterpenoids	Hyperglycemic activity	[50], [51]
39	Fresh leaves	Nimocinolide	γ-Hydroxybutenolides	Insect growth-regulating properties	[44]
40	Fresh leaves	Isonimocinolide	γ-Hydroxybutenolides	Insect growth- regulating properties	[44]
41	Undried leaves	Nimbocinone	Protolimonoids	n. a.	[51]
42	Leaves extract	Meliacinanhydride	Tetranortriterpenoids	n. a.	[45]
43	Undried winter leaves	Nimocinol (nimonol or 6-hydroxyazadirone)	Tetranortriterpenoids	Antimalarial activity	[42], [52]
44	Fresh green whole leaves	14, 15-epoxynimonol	Tetranortriterpenoids	n. a.	[53]
45	Fresh leaves	Desfurano-desacetylnimbin-17-one	Octanortriterpenoids (ring-C seco-octanortriterpenoids)	n. a.	[54]
46	Chloroform extract of dried leaves	Meliacinolin	Tetranortriterpenoid	Antidiabetic	[55]
47	Methanolic extract of fresh leaves	Odoratone	Protolimonoids	Mortality on fourth instar larvae of mosquitoes (Anopheles stephensi)	[56]
48	Methanolic extract of fresh leaves	Meliatetraolenone	Tetranortriterpenoids	Insecticidal activity	[56]
49	Methanolic extract of the fresh leaves	6α-O-acetyl-7-deacetylnimocinol	Tetranortriterpenoids	Toxicity on fourth instar larvae of mosquitoes (Aedes aegypti)	[57]
50	Methanolic extract of the fresh leaves	Meliacinol	Tetranortriterpenoids	Protection against Tacaribe virus to mice brain	[57]
51	Powdered neem leaves	3-deacetyl-3-cinnamoyl azadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[58]
52	Flower	Neeflone	Tetranortriterpenoid	n. a.	[59]
53	Flower	Flowerone	Flavonoids	n. a.	[60]
54	Flower	Flowerin	Flavonoids	n. a.	[60]
55	Flower	Azharone	Flavonoids	n. a.	[61]
56	Flower	3′-prenylnaringenin	Flavonoids	n. a.	[60]
57	Flower	Trichilenone acetate	Triterpenoid	n. a.	[60]
58	Flower	Prenylated flavanones, 5,7,4′-trihydroxy-8-prenylflavanone	Flavanones	Antimutagenic	[62]
59	Flower	5,4′-dihydroxy-7-methoxy-8-prenylflavanone	Flavanones	Antimutagenic	[62]
60	Flower	5,7,4′-trihydroxy-3′,8-diprenylflavanone	Flavanones	Antimutagenic	[62]
61	Flower	5,7,4′-trihydroxy-3′,5′-diprenylflavanone	Flavanones	Antimutagenic	[62]
62	Flowers	Melicitrin (a glycoside of myricetin)	Flavonoids	n. a.	[63]
63	Flowers	Kaempferol-3-glucoside (also called astragalin)	Flavonoids	n. a.	[63]
64	Flowers	Quercetin-3-galactoside (or hyperin)	Flavonoids	n. a.	[63]
65	Flowers	Myricetin-3-arabinoside	Flavonoids	n. a.	[63]
66	Fresh flowers	Diepoxyazadirol	Apo-protolimonoids	n. a.	[60]
67	Fresh flowers	Trichilinone	Tetranortriterpenoids	n. a.	[60]
68	Fresh flowers	O-methylazadironolide	γ-Hydroxybutenolides	n. a.	[60]
69	Fresh flowers	1S,2S,5R-1,4,4-Trimethyl-tricyclo[6.3.1.0 (2,5)]dodec-8-ene	Sesquiterpenoids	n. a.	[64]
70	Fresh flowers	2-Methoxy-5,4′-dimethyl-benzenebutanal	n. a.	n. a.	[64]
71	Fresh flowers	1,4-Dimethoxy-2-(methylthio)-benzene	n. a.	n. a.	[64]
72	Fresh flowers	n-Hexadecanoic acid or palmitic acid	n. a.	n. a.	[64]
73	Fresh flowers	Methyl n-hexadecanoate or methyl palmitate	n. a.	n. a.	[64]
74	Fresh flowers	Methyl octadecanoate acid or methyl stearate	n. a.	n. a.	[64]
75	Fresh flowers	Methyl 17-hydroxymethyloctadecanoate	n. a.	n. a.	[64]
76	Fresh flowers	Decahydro-1,1,3a-trimethyl-7-methylene-[1aS-(1aa′, 3aa′, 7aa′, 7ba′]-1H-cyclopropa[a] naphthalene	Sesquiterpenoids	n. a.	[64]
77	Fresh flowers	1,1,4,8-Tetramethyl-cis,cis,cis-4,7,10-cycloundecatriene	Sesquiterpenoids	n. a.	[64]
78	Fresh flowers	Methyl docosanoate or methyl beheniate	n. a.	n. a.	[64]
79	Fresh flowers	Methyl dodecanoate or methyl laurate	n. a.	n. a.	[64]
80	Fresh flowers	Methyl tetradecanoate or methyl myristate	n. a.	n. a.	[64]
81	Fresh flowers	Methyl eicosanoate	Hydrocarbons	n. a.	[64]
82	Fresh flowers	Methyl heptadecanoate	Hydrocarbons	n. a.	[64]
83	Fresh flowers	Methyl hexacosanoate	Hydrocarbons	n. a.	[64]
84	Fresh flowers	Methyl 15-methylheptadecanoate	Hydrocarbons	n. a.	[64]
85	Fresh flowers	Methyl 14-methylpentadecanoate	Hydrocarbons	n. a.	[64]
86	Fresh flowers	Methyl 12-methyltridecanoate	Hydrocarbons	n. a.	[64]
87	Fresh flowers	Nonanedioic acid monomethylester	Hydrocarbons	n. a.	[64]
88	Fresh flowers	Methyl octacosanoate	Hydrocarbons	n. a.	[64]
89	Fresh flowers	Methyl 9-oxononaoate	Hydrocarbons	n. a.	[64]
90	Fresh flowers	Methyl 4-oxooctanoate	Hydrocarbons	n. a.	[64]
91	Fresh flowers	Methyl pentacosanoate	Hydrocarbons	n. a.	[64]
92	Fresh flowers	Methyl tetracosanoate	Hydrocarbons	n. a.	[64]
93	Fresh flowers	Methyl 9-methyltetradecanoate	Hydrocarbons	n. a.	[64]
94	Fresh flowers	Methyl 8-(2-furyl)-octanoate	Hydrocarbons	n. a.	[64]
95	Fresh flowers	Germacrene B	Sesquiterpenoids	n. a.	[64]
96	Fresh flowers	a-himachalene	Sesquiterpenoids	n. a.	[64]
97	Fresh flowers	α-Sitosterol	Steroids	n. a.	[64]
98	Fresh flowers	α-Sitosterol acetate	Steroids	n. a.	[64]
99	Fresh flowers	Lanosterol	Steroids	n. a.	[64]
100	Fresh flowers	Tyrosol	Phenolic constituents	n. a.	[60]
101	Fresh flowers	Dodecasanoic acid	Fatty acids and their derivatives	n. a.	[15]
102	Fresh flowers	Heptadecanoic acid or margarnoic acid	Fatty acids and their derivatives	n. a.	[15]
103	Fresh flowers	Hexacosanoic acid or cerotic acid	Fatty acids and their derivatives	n. a.	[15]
104	Fresh flowers	15-methylheptadecanoic acid	Fatty acids and their derivatives	n. a.	[15]
105	Fresh flowers	12-methyltridecanoic acid or isomyristic acid	Fatty acids and their derivatives	n. a.	[15]
106	Fresh flowers	Nonanedioic acid	Fatty acids and their derivatives	n. a.	[64]
107	Fresh flowers	Octacosanoic acid	Fatty acids and their derivatives	n. a.	[15]
108	Fresh flowers	Octadecanoic acid or stearic acid	Fatty acids and their derivatives	n. a.	[64]
109	Fresh flowers	9-oxononaoic acid or azelaldehydic acid	Fatty acids and their derivatives	n. a.	[15]
110	Fresh flowers	4-oxooctanoic acid	Fatty acids and their derivatives	n. a.	[15]
111	Fresh flowers	Pentacosanoic acid	Fatty acids and their derivatives	n. a.	[15]
112	Fresh flowers	9-methyltetradecanoic acid	Fatty acids and their derivatives	n. a.	[15]
	Fresh flowers	17-hydroxysteric acid	Fatty acids and their derivatives	n. a.	[15]
113	Fresh fruits	Melianone	Protolimonoids	Antifeeding activity	[65], [66]
114	Fresh fruits	Nimolinone	Protolimonoids	n. a.	[65], [67]
115	Fresh fruits	Nimocin	Tetranortriterpenoids	n. a.	[44]
116	Fresh fruits	Nimbocinol	Tetranortriterpenoids	Insect growth inhibitory activity	[44], [67]
117	Fresh ripe fruits	Azadirachtol	Apo-protolimonoids	Potent antifeedant	[68], [69], [70]
118	Fresh ripe fruits	Azadirachnol (naheedin)	Apo-protolimonoids	n. a.	[71]
119	Fresh ripe fruits	Azadirol	Apo-protolimonoids	n. a.	[72]
120	Fruits	17-epi-Azadiradione	Tetranortriterpenoids	n. a.	[73]
121	Fruits	17-β -hydroxyazadiradione	Tetranortriterpenoids	Antifeedant activities and growth inhibitor activity against larvae of rice leaf folder	[73], [74]
122	Fruits	Nimbocetin	Acids and their derivatives	n. a.	[31]
123	Fruits	5-hydroxymethylfurfural	Miscellaneous compounds	n. a.	[31]
124	Fruits	Ochinolide B	Ring-C-seco-tetranotriterpenoids	n. a.	[75], [76]
125	Fruits	Nimbochalcin	Coumarin and chalcones	n. a.	[31]
126	Fresh fruit coats	Azadironic acid	Tetranortriterpenoids	Toxic against mosquito (Anopheles stephensi)	[77], [78]
127	Fresh fruit coats	Limocinin	Tetranortriterpenoids	n. a.	[79]
128	Fresh fruit coats	Limocin-A	Tetranortriterpenoids	Insecticidal activity	[77], [79]
129	Fresh fruit coats	Limocin-B	Tetranortriterpenoids	Insecticidal activity	[77], [79]
130	Fresh fruit coats	Limocin-C	Tetranortriterpenoids	n. a.	[80]
131	Fresh fruit coats	Limocin-D	Tetranortriterpenoids	n. a.	[80]
132	Fresh fruit coats	Meliacinolactol	Trinortriterpene	n. a.	[80]
133	Fresh undried ripe fruits	Nimolicinolic acid	Hexanortriterpenoids	n. a.	[81]
134	Fresh fruit coats	Desfuranoazadiradione	Octanortriterpenoids	Insect growth regulating activity	[77], [82]
135	Fresh fruit coatings	Galoxolide or 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran	n. a.	n. a.	[17], [83]
136	Fresh fruit coatings	Methyl 14-methyl-pentadecanoate	n. a.	n. a.	[83]
137	Fresh fruit coatings	2,6-bis(1,1-dimethylethyl)-4-methyl phenol	n. a.	n. a.	[83]
138	Fresh fruit coatings	2-(phenylmethylene)-octanal or α-hexylcinnamaldehyde	n. a.	n. a.	[83]
139	Fresh fruit coatings	Ethyl hexadecanoate or ethyl palmitate	n. a.	n. a.	[83]
140	Fresh fruit coatings	Ethyl 9Z-octadecenoate or ethyl oleate	n. a.	n. a.	[83]
141	Fresh fruit coatings	Methyl 14-methyl pentadecanoate	n. a.	n. a.	[83]
142	Fresh fruit coatings	3,7-dimethyl-1-octen-7-ol or dihydromyrcenol	n. a.	n. a.	[83]
143	Fresh fruit	Azadironol	Octanortriterpenoids	n. a.	[77], [84]
144	Fruit coat extract	Meliacinin	Dinortriterpenoids	Toxic against mosquito (Anopheles stephensi)	[77], [78]
145	Fresh fruit coats	Salimuzzalin	Tetranortriterpenoids	n. a.	[40], [84]
146	Fruit coatings	Limocinol	Protolimonoids	n. a.	[79]
147	Fruit coatings	Limocinone	Protolimonoids	n. a.	[79]
148	Fruit coatings	Kulactone	Protolimonoids	n. a.	[72]
149	Fruit coats	Methyl (2E, 6E)-farnesoate or Methyl-3,7,11-trimethyl-2E,6E,10-dodecatrienoate	Sesquiterpenoids	n. a.	[17], [83]
150	Fruit coats	Dihydromyreenol	Monoterpenoids	n. a.	[17]
151	Fruit coats	T-butylated hydroxytoluene	Phenolic constituents	n. a.	[17]
152	Fruit coats	α-hexyl cinnamaldehyde	Phenolic constituents	n. a.	[17]
153	Fruit coats	β -asarone	Phenolic constituents	Antifungal activity	[17], [83], [85]
154	Fruit coats	Azadirolic acid	Dinortriterpenoids	n. a.	[84]
155	Fruit coats	Azadiradionol	Dinortriterpenoids	n. a.	[84]
156	Fruit coats	Azadironolide	γ-Hydroxybutenolides	n. a.	[86]
157	Fruit coats	Isoazadirodionolide	γ-Hydroxybutenolides	n. a.	[86]
158	Fruit coats	Azadiradionolide	γ-Hydroxybutenolides	n. a.	[86]
159	Fruit coats	Icosane	Hydrocarbons	n. a.	[71]
160	Fruit coats	Docosane	Hydrocarbons	n. a.	[71]
161	Fruit coats	2-methyltricosane	Hydrocarbons	n. a.	[71]
162	Fruit coats	Docosene	Hydrocarbons	n. a.	[71]
163	Fruit coats	n-pentadecane	Hydrocarbons	n. a.	[83]
164	Fruit coats	n-hexadecane	Hydrocarbons	n. a.	[83]
165	Fruit coats	n-heptadecane	Hydrocarbons	n. a.	[83]
166	Fruit coats	n-tetracosane	Hydrocarbons	n. a.	[83]
167	Fruit coats	n-hexacosane	Hydrocarbons	n. a.	[83]
168	Fresh, undried, and unruptured ripe fruits	Isonimolicinolide	Tetranortriterpenoids	n. a.	[81]
169	Seeds	Vepaol	Ring-C-seco-tetranotriterpenoids	n. a.	[58], [87], [88]
170	Seeds	Isovepaol	Ring-C-seco-tetranotriterpenoids	n. a.	[88], [89]
171	Seeds	Indole acetic acid	Acids and their derivatives	Plant growth hormone	[90]
172	Seeds	Indole pyruvic acid	Acids and their derivatives	n. a.	[90]
173	Seeds	Tiglic acid	Acids and their derivatives	n. a.	[90]
174	Seeds	7-deacetylazadiradione	Tetranortriterpenoids	n. a.	[91]
175	Seeds	Epoxyazadiradione	Tetranortriterpenoids	Insecticidal activity, anti-inflammatory activity	[71], [91], [92]
176	Seeds	7-acetylneotrichilenone	Tetranortriterpenoids	n. a.	[91]
177	Seeds	7-benzoyl-17-hydroxynimbocinol	Tetranortriterpenoids	n. a.	[93]
178	Seeds	15-hydroxyazadiradione	Tetranortriterpenoids	n. a.	[93]
179	Seeds	23-deoxyazadironolide	γ-Hydroxybutenolides	n. a.	[93]
180	Seeds	Limocin E	Tetranortriterpenoids	n. a.	[93]
181	Seeds	23-epilimocin E	Tetranortriterpenoids	n. a.	[93]
182	Seeds	7a-acetoxy-3-oxoisocopala-1,13-dien-15-oic acid	Diterpenoid	n. a.	[93]
183	Dried seeds	1α-methoxy-1, 2-dihydronimbinin	Tetranortriterpenoids	n. a.	[91]
184	Dried seeds	1β, 2β -diepoxyazadiradione	Tetranortriterpenoids	n. a.	[91]
185	Seed oil	1α, 2α-epoxy-17β -hydroxyazadiradione	Tetranortriterpenoids	n. a.	[94]
186	Seed oil	Vepinin	Tetranortriterpenoids	n. a.	[95]
187	Seed oil	Mahmoodin	Tetranortriterpenoids	Effective against human pathogenic bacteria	[71], [96]
188	Seed oil	1α, 2α-epoxynimolicinol	Tetranortriterpenoids	n. a.	[94]
189	Seed oil	7-deacetylnimolicinol	Tetranortriterpenoids	n. a.	[94]
190	Seed oil	Vilasinin triacetate	Tetranortriterpenoids	n. a.	[43]
191	Seed oil	1-O-senecioyl-3-O-acetylvilasinin	Tetranortriterpenoids	n. a.	[97]
192	Seed Oil	Di-, tri- and tetra- sulfides	Sulphur containing compounds	n. a.	[98], [99]
193	Seed oil	Gedunin	Tetranortriterpenoids (meliacins/limonoids)	Antifeedant activities and growth inhibitor activity against larvae of rice leaffolder, In vitro cytotoxic activities	[71], [74], [100], [101]
194	Seed oil	7-decacetylgedunin	Tetranortriterpenoids	Antifeedant activities and growth inhibitor activity against larvae of rice leaffolder	[74], [100]
195	Seed Oil	Nimolicinol	Tetranortriterpenoids	Antibacterial to several human pathogenic bacteria	[52], [94], [96]
196	Seed oil	17-epi-Nimbocinol	Tetranortriterpenoids	n. a.	[102]
197	Neem oil	Methyl esters of 14-methylpentadecanoic acid	Fatty acids and their derivatives	n. a.	[17]
198	Neem oil	Methyl esters of ethyl palmate	Fatty acids and their derivatives	n. a.	[17]
199	Neem oil	Methyl esters of oleate	Fatty acids and their derivatives	n. a.	[17]
200	Neem oil	Salannin	Ring-C-seco-tetranotriterpenoids	Antifeeding properties	[76], [103], [104], [105], [106]
201	Neem oil	3-deacetylsalannin	Ring-C-seco-tetranotriterpenoids	Antifeeding properties	[22], [104], [107]
202	Neem oil	Salannol	Ring-C-seco-tetranotriterpenoids	Antifeeding properties	[22]
203	Neem oil	Salannol acetate	Ring-C-seco-tetranotriterpenoids	Antifeeding properties	[108]
204	Neem oil	Campesterol	Steroids	Cholesterol lowering anticarcinogenic and angiogenesis activity	[109], [110]
205	Neem oil	Sitosterol	Steroids	Anthelminthic and antimutagenic activities	[109], [111]
206	Neem oil	Fucosterol	Steroids	Cytotoxicity against breast and colon carcinoma cell line	[109], [112]
207	Neem oil	9-octadecanoic acid-hexadecanoic acid-tetrahydrofuran-3,4-diyl ester	Fatty acids and their derivatives	Antibacterial	[113]
208	Seed extract	7-decacetyl-7-benzoylgedunin	Tetranortriterpenoids	Cytotoxic activity against HL60 leukemia cells	[91], [114]
209	Seed extract	7-desacetyl-7- benzoylepoxyazadiradione	Tetranortriterpenoids	Cytotoxic activity against HL60 leukemia cells	[91], [114]
210	Seeds	Vilasinin	Tetranortriterpenoids		[22], [43]
211	Seeds	1, 3-di-O-acetylvilasinin	Tetranortriterpenoids	Insect antifeeding activity	[22]
212	Seeds	1-O-tigloyl-3-O-acetylvilasinin	Tetranortriterpenoids	Insect antifeeding activity	[115]
213	Seeds	Limbocinin	Tetranortriterpenoids	n. a.	[116]
214	Seeds	Limbocidin	Tetranortriterpenoids	n. a.	[117]
215	Seeds	4-epi-nimbin	Ring-C-seco-tetranotriterpenoids	n. a.	[117]
216	Seeds	6-deacetylnimbinal	Ring-C-seco-tetranotriterpenoids	n. a.	[118]
217	Seeds	Nimbanal (nimbinal)	Ring-C-seco-tetranotriterpenoids	n. a.	[108], [118]
218	Seeds	Nimbinol	Ring-C-seco-tetranotriterpenoids	n. a.	[118]
219	Seeds	Nimbolide	Ring-C-seco-tetranotriterpenoids	Cytotoxic activities against N1E-115 murine neuroblastoma cells, anticancerous activity against human breast cancer cells	[107], [119], [120], [121], [122]
220	Seeds	28-deoxonimbolide	Ring-C-seco-tetranotriterpenoids	Cytotoxic activities against HL60 cells	[114], [118], [123]
221	Seeds	Ochinin acetate (ochinin-3-acetate)	Ring-C-seco-tetranotriterpenoids	n. a.	[124]
222	Seeds	Azadirachtin	Ring-C-seco-tetranotriterpenoids	Most potent insect antifeedant and insect growth-regulating agent	[125], [126]
223	Seeds	2′,3′-dihydrotigloyl-azadirachtol	Tetranotriterpenoids	n. a.	[127]
224	Seeds	3-isobutyrylazadirachtol	Tetranotriterpenoids	n. a.	[127]
225	Seed extract	Azadirachtin G	Ring-C-seco-tetranotriterpenoids	n. a.	[128], [129]
226	Seed extract	3-O-acetyl-1-O-hydroxyazadirachtol	Tetranotriterpenoids	n. a.	[128], [129]
227	Seeds	11α-hydroxy-12-norazadirachtin	Tetranotriterpenoids	n. a.	[130]
228	Seeds	Azadirachtin D	Ring-C-seco-tetranotriterpenoids	n. a.	[128], [131], [132]
229	Seeds	Azadirachtin I	Ring-C-seco-tetranotriterpenoids	n. a.	[128], [131], [133]
230	Seeds	Azadirachtin F	Ring-C-seco-tetranotriterpenoids	n. a.	[128], [131], [132]
231	Seeds	1-O-Tigloyl-3-O-acetyl-11-hydroxymeliacarpinin	Tetranortriterpenoids	n. a.	[97]
232	Seeds	11 β-hydroxy-azadirachtinin	Tetranotriterpenoids	n. a.	[15]
233	Seeds	7-benzoylnimbocinol	Limonoid	Cytotoxic activity	[114]
234	Seeds	17-epiazadiradione	Limonoid	n. a.	[114]
235	Seeds	17-epi-17-hydroxyazadiradione	Limonoid	n. a.	[114]
236	Seeds	1,3-diacetylvilasinin	Tetranortriterpenoids	n. a.	[114]
237	Seeds	7-deacetylgedunin	Tetranortriterpenoids	n. a.	[114]
238	Seeds	6-deacetylnimbin	Limonoid	n. a.	[114]
239	Seeds	20,30-dihydrosalannin	Limonoid	n. a.	[114]
240	Seed oil	Salannolide	Ring-C-seco-tetranotriterpenoids	n. a.	[134]
241	Seed extract	1-O-acetyl-7-O-tigloylvilasinin	Tetranortriterpenoids	n. a.	[115]
242	Dried seeds	1-O-Tigloyl-3-O-acetyl-12α-acetoxyvilasinin	Tetranortriterpenoids	n. a.	[97], [135]
243	Dried seeds	1 – 3-di-O-acetyl-12α-acetoxyvilasinin	Tetranortriterpenoids	n. a.	[97], [135]
244	Dried seeds	7-O-Tigloyl-12α-acetoxyvilasinin	Tetranortriterpenoids	n. a.	[97], [135]
245	Seeds	1-O-acetyl-7-O-tigloylnimbidinin	Tetranortriterpenoids	n. a.	[97], [135]
246	Seeds	1, 3-di-O-acetyl-7-O-tigloyl-12β -hydroxyvilasinin	Tetranortriterpenoids	n. a.	[136]
247	Seeds	3-O-acetyl-7-O-tigloylvilasinin lactone	Tetranortriterpenoids	n. a.	[137]
248	Seeds	Azadirachtin K	Ring-C-seco-tetranotriterpenoids	n. a.	[138]
249	Seed	3-deacetyl-11-desoxyazadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[137]
250	Seeds	11-hydroxyazadirachtin B	Ring-C-seco-tetranotriterpenoids	n. a.	[136]
251	Seeds	23-desmethyllimocin-B	Limonoids	n. a.	[136]
252	Seeds	1-tigloyl-3-acetylazadirachtinin	Ring-C-seco-tetranotriterpenoids	n. a.	[136]
253	Seeds	1,2-diacetyl-7-tigloyl-12-hydroxyvilasinin	Tetranortriterpenoids	n. a.	[136]
254	Seeds	11-epi-azadirachtin H	Ring-C-seco-tetranotriterpenoids	n. a.	[139]
255	Seeds	4α-benzoylnimbandiol	Pentanortriterpenoids	n. a.	[76]
256	Seeds	1-Tigloyl-3-acetyl-11-hydroxy-4β-methylmeliacarpin (11-epi-azadirachtin D)	Terpenoids	n. a.	[140], [141]
257	Seeds	1α-destigloyl-1α-benzoylazadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[76]
258	Oil, seeds	Glyceride of α-Linolenic acid	Fatty acids and their derivatives	n. a.	[32]
259	Seed kernels	Nimbidic acid	Ring-C-seco-tetranotriterpenoids	n. a.	[142], [143]
260	Seed kernels	1, 2-dihydro-4α, 6α-dihydroxy-A-homozadirone	Tetranortriterpenoids	n. a.	[15], [144]
261	Seed kernels	Nimbin	Tetranortriterpenoids (meliacins/limonoids)	Insecticidal activity	[12]
262	Seed kernels	Azadirachtin M	Ring-C-seco-tetranotriterpenoids	n. a.	[145]
263	Seed kernels	Azadirachtin N	Ring-C-seco-tetranotriterpenoids	n. a.	[145]
264	Seed kernels	Azadirachtin B (3-tigloylazadirachtol)	Tetranotriterpenoids	Insect growth regulating properties	[58], [146], [147], [148], [149]
265	Seed kernels	Nimbidinin	Tetranortriterpenoids	n. a.	[142], [143]
266	Neem kernel	13,14-desepoxyazadirachtin-A	Tetranortriterpenoid, ring-C-seco-tetranotriterpenoids	n. a.	[150]
267	Seed kernels	Salannolactam-21	Nitrogen containing Limonoids	Antifeedant activity	[151]
268	Seed kernels	Salannolactam-23	Nitrogen containing Limonoids	Antifeedant activity	[151]
269	Seed kernels	Azadirachtin H	Ring-C-seco-tetranotriterpenoids	Insect antifeedant and ecdysis-inhibiting activity	[131], [132], [133]
270	Neem kernel extract	Limbonin	Trinortriterpenoids	n. a.	[152], [153]
271	Methanolic extract of air-dried kernels	1-benzoyl-3-deacetyl-1-detigloyl salannin	Limonoids	n. a.	[154]
272	Methanolic extract of air-dried kernels	7-tigloyl-12-oxo vilasini	Limonoids	n. a.	[154]
273	Methanolic extract of air-dried kernels	Azadiralactone	Limonoids	n. a.	[154]
274	Methanolic extract of air-dried kernels	Azadirahemiacetal	Triterpenoid	n. a.	[154]
275	Seed oil	Nimbinene	Pentanortriterpenoids	n. a.	[22]
276	Seed oil	6-deacetylnimbinene	Pentanortriterpenoids	n. a.	[22]
277	Seed oil	6-O-acetylnimbandiol	Pentanortriterpenoids	n. a.	[22], [105]
278	Fresh twigs	6,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin	Coumarin and chalcones	n. a.	[15]
279	Twigs	7,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin	Coumarin and chalcones	n. a.	[15]
280	Twigs	Margocetin (3,4-dihydroxy-7 – 8-dimethoxy-3-methylisocoumarin)	Coumarin and chalcones	n. a.	[15]
281	Fresh twigs	6-methoxymellein (3,4-dihydroxy-6-methoxy-3-methylisocoumarin)	Coumarin and chalcones	Inhibits the growth of several fungi, yeasts and bacteria	[15], [155], [156]
282	Twigs	Isofraxidin (7-hydroxy-6-8-dimethoxycoumarin)	Coumarin and chalcones	Cytotoxic activity	[15], [157]
283	Twigs	Isonimolide	γ-Hydroxybutenolides	n. a.	[158]
284	Twigs	Isonimbolide	γ-Hydroxybutenolides	n. a.	[158]
285	Twigs	Methyl esters of eicosenoic acid	Fatty acids and their derivatives	n. a.	[17]
286	Twigs	Margosinolide	Ring-C-seco-tetranotriterpenoids	n. a.	[159]
287	Twigs	Isomargosinolide	Ring-C-seco-tetranotriterpenoids	n. a.	[159]
288	Twigs	6-deacetylnimbinolide	Ring-C-seco-tetranotriterpenoids	n. a.	[160]
289	Twigs	6-deacetyl-isonimbinolide	Ring-C-seco-tetranotriterpenoids	n. a.	[160]
290	Stem bark	1-O-Tigloyl-3-O-acetyl-11-methoxyazadirachtinin	Tetranotriterpenoids	n. a.	[97]
291	Powdered bark	22,23-dihydro-23β -methoxyazadirachtin	Tetranotriterpenoids	n. a.	[58]
292	Stem bark	Nimbosodione	Diterpenoids	n. a.	[161]
293	Stem bark	Nimbisonol	Diterpenoids	n. a.	[161]
294	Stem bark	Demethylnimbionol	Diterpenoids	n. a.	[161]
295	Stem bark	Isomargolonone	Diterpenoids	n. a.	[162]
296	Stem bark	Margolone	Diterpenoids	n. a.	[162]
297	Stem bark	Margolonone	Diterpenoids	n. a.	[162]
298	Stem bark	Margosolone	Diterpenoids	n. a.	[163]
299	Stem bark	Margosone	Diterpenoids	n. a.	[163]
300	Stem bark	Methylnimbiol	Diterpenoids	n. a.	[164]
301	Stem bark	Nimbosone	Diterpenoids	n. a.	[164]
302	Stem bark	Nimosone	Diterpenoids	n. a.	[164]
303	Stem bark	Methylnimbionone	Diterpenoids	n. a.	[164]
304	Stem bark	Nimbione	Diterpenoids	n. a.	[165]
305	Stem bark	Nimbinone	Diterpenoids	n. a.	[165]
306	Stem bark	Nimbionol	Diterpenoids	n. a.	[166]
307	Stem bark	Nimbionone	Diterpenoids	n. a.	[166]
308	Stem bark	Nimbonolone	Diterpenoids	n. a.	[167]
309	Stem bark	Nimbonone	Diterpenoids	n. a.	[167]
310	Stem bark	Nimbiol	Diterpenoids	n. a.	[168], [169], [170], [171]
311	Stem bark	Sugiol (7-oxoferruginol)	Diterpenoids	Anti-inflammatory activity	[168], [169], [170], [171], [172]
312	Stem bark	Margosinone	Polyacetates	n. a.	[173]
313	Stem bark	Margosinolone	Polyacetates	n. a.	[173]
314	Heart Wood	24-methylene-lophenol	Steroids	n. a.	[174]
315	Trunk wood	1,3-di-O-acetyl-7-O-cinnamoylvilasinin (nimbolin A)	Tetranortriterpenoids	n. a.	[175]
316	Trunk wood	Nimbolin B	Ring-C-seco-tetranotriterpenoids	Insect antifeeding activity	[175], [176]
317	Bark	Gallocatechin	Flavonoids	n. a.	[177]
318	Bark	epi-catechin	Flavonoids	Anti-inflammatory and immunomodulatory	[177]
319	Bark	Catechin	Flavonoids	Anti-inflammatory and immunomodulatory	[177]
320	Bark	epi-gallocatechin	Flavonoids	Antioxidant activity	[177], [178]
321	Bark	Gallic acid	Acids and their derivatives	n. a.	[177]
322	Bark	Fraxinellone	n. a.	Antimutagenic activity	[175], [179]
323	Bark	4,14α-dimethyl-5α-ergosta-8,24(28)-diene-3β-ol	Steroids	n. a.	[180]
324	Bark	4α-methyl-5α-ergosta-8,24(28)-diene-3β-ol	Steroids	n. a.	[180]
325	Stem bark	Methyl grevillate	Acids and their derivatives	n. a.	[167]
326	Stem bark	Isonimbinolide	Ring-C-seco-tetranotriterpenoids	Antifeedant activity	[165], [181]
327	Root bark	Azadiricin	Diterpenoids	n. a.	[182]
328	Root bark	Azadirilin	Diterpenoids	n. a.	[182]
329	Root bark	Azadirin A	Diterpenoids	n. a.	[182]
330	Root bark	Azadirin B	Diterpenoids	n. a.	[182]
331	Root bark	Nimbocinin	Diterpenoids	n. a.	[182]
332	Root bark	Nimbolicidin	Ring-C-seco-tetranotriterpenoid	n. a.	[182]
333	Root bark	Nimbocin	Hexanortriterpenoids	n. a.	[182]
334	Roots	Azadirinin	Tetranortriterpenoids	n. a.	[183]
335	Root bark	Margocilin	Diterpenoids	n. a.	[184]
336	Root bark	Margocin	Diterpenoids	n. a.	[184]
337	Root bark	Margocinin	Diterpenoids	n. a.	[184]
338	Root bark	Nimbidiol	Diterpenoids	n. a.	[185]
339	Root bark	Nimbilicin	Diterpenoids	n. a.	[182]
340	Root bark	Nimbocidin	Diterpenoids	n. a.	[182]
341	Root bark	Nimolinin	Diterpenoids	n. a.	[182]
342	Root bark	Nimbilin	Ring-C-seco-tetranotriterpenoids	n. a.	[182]
343	Wood oil	Cycloeucalenol	Triterpenes	n. a.	[186]
344	Wood oil	24-methylenecycloartanol	Triterpenes	n. a.	[186], [187]
345	Gum exudate	D-glucose	Carbohydrates and proteins	n. a.	[188]
346	Gum exudate	D-glucoronic acid	Carbohydrates and proteins	n. a.	[188]
347	Gum exudate	L-arabinose	Carbohydrates and proteins	n. a.	[188]
348	Gum exudate	L-fucose	Carbohydrates and proteins	n. a.	[188]
349	Gum exudate	Mannose	Carbohydrates and proteins	n. a.	[189]
350	Gum exudate	Xylose	Carbohydrates and proteins	n. a.	[189]
351	Gum exudate	Rhamnose	Carbohydrates and proteins	n. a.	[189]
352	Gum exudate	D-glucosamine	Carbohydrates and proteins	n. a.	[190]
353	Gum exudate	Aldobiouronic acid	Carbohydrates and proteins	n. a.	[191]
354	Gum exudate	4-O-(4-O-methyl-α-D-glucopyranosyl uronic acid)-D-galactose	Carbohydrates and proteins	n. a.	[191]
355	Gum exudate	Aldotriouronic acid	Carbohydrates and proteins	n. a.	[191]
356	Fruit coat-extract, Seed oil	Epoxyazadiradione (nimbinin),	Tetranortriterpenoids (meliacins/limonoids)	Insecticidal activity	[78], [192]
357	Fruit coat-extract, Seed oil	Azadiradione	Tetranortriterpenoids (meliacins/limonoids)	Insecticidal activity	[78], [100]
358	Seeds and leaves	1-O-cinnamoylvilasinin lactone	Tetranortriterpenoids	n. a.	[135]
359	Seeds and leaves	1-O-tigloyl-3-O-acetylvilasinin lactol	Tetranortriterpenoids	n. a.	[135]
360	Seeds and leaves	1-O-senecioyl-3-O-acetylvilasinin lactone	Tetranortriterpenoids	n. a.	[193]
361	Seeds and leaves	1-O-senecioyl-3-O-acetylvilasinin lactol	Tetranortriterpenoids	n. a.	[193]
362	Twigs and seed kernels; seed extracts	6-deactylnimbin	Ring-C-seco-tetranotriterpenoids	Anti-feeding properties	[106], [160], [194]
363	Branches and leaves	4 α-hydroperoxy-6- O-acetylnimbandiol	Triterpenoids	n. a.	[121]
364	Branches and leaves	24,25-epoxy-3 β -hydroxy-20-oxo-7-tirucallene	Triterpenoids	n. a.	[121]
365	Branches and leaves	22,23;24,25-diepoxy-3 β -hydroxy-7-tirucallene	Triterpenoids	n. a.	[121]
366	Fresh fruit coats and seeds	5α-androsta (13β Me)-7α-acetoxy-17-oxo-4,4,8-trimethyl-1,14-dien-3,16-dione (β -nimolactone)	Nonnanortriterpenoids	n. a.	[82], [93]
367	Fresh fruit coats and seeds	5α-androsta (13α Me)-7α-acetoxy-17-oxo-4,4,8-trimethyl-1,14-dien-3,16-dione (α-nimolactone)	Nonnanortriterpenoids	n. a.	[82], [93]
368	Neem oil	Cholesterol	Steroids	n. a.	[195]
369	Neem oil	Stigmasterol	Steroids	n. a.	[195]
370	Fruit coats, Flowers	Hentriacontane	Hydrocarbons	Anti-inflammatory activity	[19], [20], [64], [83], [196]
371	Aqueous extracts of powdered neem leaf, flowers	Azadirone	Tetranortriterpenoids (meliacins/limonoids)	Cytotoxic activity against a panel of human cancer cell	[47], [197], [198]
372	Leaves, oil	Meliantriol	Protolimonoids	n. a.	[199]
373	Leaves and flower	Nimbaflavone	Flavonoids	n. a.	[61], [200]
374	Neem oil and fresh fruit coatings	3,4-dihydro-4,4,5,8-tetramethylcoumarin	Coumarin and chalcones	n. a.	[17], [83]
375	Neem oil and fresh fruit coatings	3,4-dihydro-4,4,7,8-tetramethyl-coumarin-6-ol	Coumarin and chalcones	n. a.	[17], [83]
376	Leaves and twigs	Scopoletin (7-Hydroxy-6-methoxycoumarin)	Coumarin and chalcones	Antithyroid and antihyperglycemic activity	[35], [201]
377	Leaves, fruit coats	Octadecane	Hydrocarbons	n. a.	[19], [20], [83]
378	Leaves, fruit coats, flowers	Nonadecane	Hydrocarbons	n. a.	[19], [20], [64], [83]
379	Fruit coats, flowers	Isoazadironolide	γ-Hydroxybutenolides	n. a.	[61], [86]
380	Fruit coats; fresh flowers	Pentacosane	Hydrocarbons	n. a.	[64], [83]
381	Leaves, flowers, fruit coats	Nonacosane	Hydrocarbons	n. a.	[19], [20], [64], [83]
382	Fruit coats; fresh flowers	Heptacosane	Hydrocarbons	n. a.	[19], [20], [64], [83]
383	Fruit coats; fresh flowers	Octacosane	Hydrocarbons	n. a.	[19], [20], [64], [83]
384	Fruit coats; flowers	Heneicosane	Hydrocarbons	n. a.	[64], [83]
385	Fruit coats, flowers	Tricosane	Hydrocarbons	n. a.	[64], [83]
386	Oil, seeds, leaves, twigs and fruits	Glycerides and methyl esters of oleic acids	Fatty acids and their derivatives	n. a.	[202], [203]
387	Oil, seeds, leaves, twigs and fruits	Glycerides and methyl esters of stearic acids	Fatty acids and their derivatives	n. a.	[202], [203]
388	Oil, seeds, leaves, twigs and fruits	Glycerides and methyl esters of palmitic acids	Fatty acids and their derivatives	n. a.	[202], [203]
389	Oil, leaves, twigs and fruits	Glycerides and methyl esters of myristic acids	Fatty acids and their derivatives	n. a.	[202], [203]
390	Oil, leaves and twigs	Glycerides and methyl esters of arachidic acids	Fatty acids and their derivatives	n. a.	[202], [203]
391	Oil and leaves	Glycerides and methyl esters of behenic acids	Fatty acids and their derivatives	n. a.	[202], [203]
392	Oil and leaves	Glycerides and methyl esters of lignocernoic acids	Fatty acids and their derivatives	n. a.	[202], [203]
393	Leaves and twigs	Methyl esters of hexadecatrienoic acid	Fatty acids and their derivatives	n. a.	[17]
394	Leaves and twigs	Methyl esters of lauric acid	Fatty acids and their derivatives	n. a.	[17]
395	Oil/leaves	3-Deacetylazadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[97], [204]
396	Oil/leaves	2′,3′-dihydrotigloylazadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[97]
397	Oil/leaves	1-detigloyl-1-isobutylroylazadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[97]
398	Oil/leaves	1-detigloyl-1-isovaleroyl-Azadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[97]
399	Oil/leaves	1-detigloyl-1-isocaproyl-3-epoxymethacroy azadirachtin	Ring-C-seco-tetranotriterpenoids	n. a.	[97]
400	Oil/leaves	β -D-glucoside	Steroids	n. a.	[205]
401	Oil/leaves	Margocidin	Steroids	n. a.	[182]
402	Oil/leaves	Isorhamnetin	Flavonoids	In vitro antitumor activity	[15], [30], [206]
403	Oil/leaves	Kaempferol	Flavonoids	Anti-inflammatory and anti-ulcer effects	[88], [207]
404	Oil/leaves	Myricetin	Flavonoids	Antioxidant activity	[88], [208]
405	Oil/leaves	Nimbilicidin	n. a.	n. a.	[182]

Selected Bioactive Principles of Neem and Their Specific Activity

Anti-inflammatory, analgesic, and antipyretic activities

Kaempferol, reported from neem as well as from a different, unrelated plant Rhamnus procumbens, was found to have anti-inflammatory and anti-ulcer activities [83], [207]. Anti-inflammatory and immunomodulatory activity was observed in 2 flavonoids, catechin and epi-catechin, reported from the bark of the neem tree [177]. Nimbidin, a major active component of the Azadirachta indica seed oil, was found to significantly inhibit some of the functions of macrophages and neutrophils relevant to the inflammatory responses both in vitro as well as in vivo, signifying anti-inflammatory and anti-arthritic potential of the compound [209]. In another study, the effect of aqueous extract of neem leaves (400 mg/kg body weight) was compared with that of dexamethasone (0.75 mg, intraperitoneal) in rats, which demonstrated statistically significant reduction by extract, albeit less pronounced compared to dexamethasone [210]. Crude ethanol extract of neem leaves yielded anti-inflammatory responses by suppression of paw edema induced by carrageenan and reduced cotton pellet-induced granuloma formation in chronic model rats [211]. Furthermore, the ethanol extract obtained from A. indica leaves (1 g/kg w/w) showed significant antinociceptive effect by inhibition of abdominal writhes produced by acetic acid. A. indica extract also showed statistically significant antipyretic effect (p < 0.05) at 1 g/kg and 500 mg/kg dose level on yeast-induced pyrexia in rats [211].

Immunostimulant activities

Neem oil is shown to selectively activate the cell-mediated immune mechanisms that elicit an enhanced response to subsequent mitogenic or antigenic challenges by acting as a non-specific immunostimulant [212]. Pre-treatment of rats with an odorous and volatile fraction of neem oil, coded NIM-76, was found to increase polymorphonuclear leukocytes, with a decrease in lymphocyte count displaying immunomodulatory efficacy [213].

Radiosensitizing effects

Neem oil was found to increase the radiosensitivity of the Balbc/3 T3 cells and severe combined immunodeficiency (SCID) cells during x-irradiation under aerobic conditions [214]. Application of neem oil reduced the G2 + M phase of the cell cycle, thereby inhibiting the repair of cells from lethal damage [214].

Hypoglycemic activities

Neem kernel powder, in combination with glibenclamide, yielded significant antidiabetic and antihyperlipemic effects in alloxan diabetic rats [215]. Antihyperglycemic effect of aqueous neem leaf extract was also observed in insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus animal models [216]. Mixed water extracts of Abroma augusta roots, when combined with the leaves of A. indica and given orally to alloxan diabetic rats, showed hypoglycemic action with decreased formation of lipid peroxides estimated as thiobarbituric acid reactive substance along with increased antioxidants in erythrocytes [217]. Extracts of A. indica combined with extracts of Vernonia amygdalina (Del.) was found to have enhanced anti-diabetic effect in albino Wistar rats [218]. Ethanolic extracts of A. indica in streptozotocin-induced hyperglycemia normalized the glucose level and reversed dyslipidemia [219]. Hypoglycemic action of ethanolic neem leaf extract was evaluated in diabetic rats, which demonstrated that after treatment for 24 h with a single dose of 250 mg/kg extract reduced glucose (18%), cholesterol (15%), triglycerides (32%), urea (13%), creatinine (23%), and lipids (15%) [220]. Further, in a multiple-dose study that lasted for 15 days, reduction of creatinine, urea, lipids, triglycerides, and glucose were observed [221]. In the year 2012, a new tetranortriterpenoid named meliacinolin was isolated from chloroform extract of dried neem leaves, which demonstrated in vivo inhibition of α-glucosidase and α-amylase enzyme activities in streptozotocin-nicotinamide-induced type 2 diabetes in mice [55]. Inhibition of both these enzymes offers an effective strategy of lowering the levels of postprandial hyperglycemia that prevents the digestion of carbohydrates, offering promising potential of meliacinolin as an antidiabetic agent [55].

Anti-ulcer effects

The aqueous leaf extract of neem showed anti-ulcer properties in stressed rats by preventing mast cell deregulation and increasing the amount of adherent gastric mucus [221]. Neem leaf extract exhibited anti-ulcer activity on gastric lesions in rats by blocking acid secretion through inhibition of H⁺-K⁺-ATPase and by preventing oxidative damage and apoptosis [222].

Antifertility effects

Prolonged antifertility effects were observed by a single intrauterine administration of neem oil in female Wistar rats [223]. In another study, a single dose of 50 µl of neem oil on each side of the lumen of the vas deferens of male Wistar rats acted as a long-term male contraception [224]. The neem oil fraction NIM-76 was shown to have spermicidal activity in vivo not only in rats but also in rabbits and rhesus monkeys; NIM-76 was further found to affect the motility of sperm leading to the observed infertility [225], [226]. Aqueous extract of old and tender neem leaf was found to immobilize and kill 100% human spermatozoa within 20 s [227].

Antimalarial activities

Gedunin, a tetranortriterpenoid isolated from neem, was reported to be active against Plasmodium falciparum, the causative organism of malaria [228]. The antimalarial activity of the limonoids (meldenin, isomeldenin, nimocinol, and nimbandiol) isolated from the ethanolic extract of fresh neem tree was reported to be active against chloroquine-resistant P. falciparum strain K1 [229]. Schwikkard and van Heerden (2002) discussed the antimalarial activity of neem compounds such as the limonoid gedunin, meldenin, and azadirachtin [230]. NeemAzal, a commercial neem seed extract containing the limonoid azadirachtin as the main component, was found to block the activity of rodent malarial parasite, Plasmodium berghei, in its vector Anopheles stephensi [231].

Antiretroviral activities

An acetone-water extract of neem leaves was found to prevent the invasion of human lymphocytes by human immunodeficiency virus (HIV), thereby protecting the target cells without any adverse effects [232]. The acetone-water extract significantly increased CD4 cell count in HIV I or HIV II patients that also led to a substantial increase in mean body weight, hemoglobin concentration, lymphocyte differential count with no adverse effects, and abnormalities in kidney and liver function parameters [233].

Antifungal activities

Khan and Shah (1992) tested leaf extracts of A. indica on wheat seed mycoflora and noted considerable reduction in seed mycoflora vis-à-vis better seed germination [234]. Suresh et al. (1997) studied the antifungal activity of polar extract and the impure HPLC fractions of green leaves of A. indica against groundnut rust disease (causal agent Puccinia arachidis Speg.) [235]. Govindachari et al. (1998) also showed the synergistic effect of various neem terpenoids on different fungal pathogens [236]. Minimum inhibitory concentration (MIC) of neem seed extract was found to be 31 µg/ml against clinical isolates of dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum nanum) [237]. Wang et al. (2010) reported a significant reduction in the growth of the pathogens Monilinia fructicola, Penicillium expansum, Trichothecium roseum, and Alternaria alternata by neem seed kernel extracts [238].

Antibacterial activities

Mahmoodin, a novel limonoid, isolated from neem oil, showed significant antibacterial activity against various Gram-positive and Gram-negative bacteria [71]. Aquaneem, an emulsified product prepared from the neem kernel, exhibited antibacterial activity against Aeromonas hydrophila and Pseudomonas fluorescens as well as Myxobacteria sp., which are pathogenic to fish [239]. Moreover, SaiRam and co-workers (2000) studied the antimicrobial activity of the extract NIM-76 against certain bacteria, fungi, and Poliovirus and compared the same with neem oil [240]. The results revealed that NIM-76 inhibited the growth of various bacterial pathogens tested including Escherichia coli and Kleibsiella pneumoniae. The extract also showed antifungal activity against Candida albicans and antiviral activity against Poliovirus replication in Vero cell lines. Overall, NIM-76 showed stronger anti-microbial activity as compared to the neem oil. Neem seed kernel extract was found to be active against Bacillus mycoides, B. thuringiensis, B. subtilis, Nocardia sp., and Corynebacterium fascians in in vitro assays [241]. In another study, neem mouthwash was found to show antibacterial activity against salivary levels of Streptococcus mutans and Lactobacillus [242]. Neem leaf extract gel also showed antiplaque activity [243]. Polyester/cotton blend fabric treated with neem extract was reported to have antibacterial activity against both Gram-positive (Bacillus subtilis) and Gram-negative bacteria (Proteus vulgaris) [244]. Neem oil was also found to be active against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa, and Escherichia coli [245], [246]. The tetranortriterpenoid, nimolicinol, isolated from neem, was reported to be moderately antibacterial against several human pathogenic bacteria [93], [95]. The antibacterial activity of neem leaf extract and various phytoconstituents of neem such as alkaloids, steroids, tannins, glycosides, flavonoids, and saponins were evaluated and confirmed to have antibacterial efficacies, with crude flavonoids revealing maximum antibacterial activities [247]. 9-Octadecanoic acid-hexadecanoic acid-tetrahydrofuran-3,4-diyl ester obtained from neem oil was found active against Staphylococcus aureus, Escherichia coli, and Salmonella sp. in in vitro assays [113]. M-Octadecanoic acid-3,4-tetrahydrofuran diester, isolated from the petroleum ether extract of neem oil, also showed potent antibacterial activity [248]. Alcoholic extracts of neem leaves were found to be active against the human bacterial pathogens Bacillus pumillus, Pseudomonas aeruginosa, and Staphylococcus aureus [249].

Antiviral activities

Foliar application of neem seed oil, when compared with neem seed oil-free extract, inhibited transmission of potato virus Y to sweet pepper by the green peach aphid, Myzus persicae (Sulzer) suggesting that the oil interferes with virus transmission [250]. A methanolic extract fraction of leaves of neem showed antiviral activity against the Coxsackie B group of viruses [251]. Crude aqueous extract of neem leaves was reported both in vitro and in vivo to display antiviral activity against the replication of Dengue virus type-2 [252]. Aqueous neem bark extract, at concentrations ranging from 50 to 100 µg/ml, when pre-incubated with herpes simplex virus type 1 (HSV-1), considerably blocked its entry into cells; additionally, virions treated with the extract failed to bind to the cells, suggesting role of the extract either as an attachment-blocker or having direct anti-HSV-1 property. Furthermore, cells treated with extract also inhibited herpes simplex virus type 1 glycoprotein-mediated cell-cell fusion and polykaryocytes formation, signifying an additional role of the bark extract at the viral fusion step [253]. The crude acidic extract of leaves and seeds and alkaline extract of seeds were found to show high antiviral activity against HSV-1 when compared with the well-known antiviral drug acyclovir [254].

Anticarcinogenic activities

Azadirone, a limonoidal constituent isolated from methanolic extract of neem flowers, was found to be a potent cytotoxic agent with good in vitro and in vivo activities [255]. The studies also revealed that the α,β-unsaturated enone moiety, or its equivalent conjugated system of A-ring, C-7 acetyloxy/chloroacetyloxy or keto group of B-ring and the furan moiety, are the structural requirements for the potent activity of azadirone and its analogs [255]. Four prenylated flavanones, 5,7,4′-trihydroxy-8-prenylflavanone, 5,4′-dihydroxy-7-methoxy-8-prenylflavanone, 5,7,4′-trihydroxy-3′,8-diprenylflavanone, and 5,7,4′-trihydroxy-3′,5′-diprenylflavanone, were isolated by activity-guided fractionation from the methanolic extract of the flowers of neem, which acted as potent antimutagens against Trp-P-1 (3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole) in the Salmonella typhimurium TA98 assay [61]. Aqueous extract of neem was found to show chemopreventive potential when given to Syrian male hamsters having 7,12-dimethylbenz[a]anthracene (DMBA) induced buccal pouch carcinogenesis by modulation of lipid peroxidation, antioxidants, and detoxification systems [256]. Pre-treatment with ethanolic neem leaf extract significantly lowered the concentration of lipid peroxides and increased antioxidant levels on induced oxidative stress by the potent gastric carcinogen N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) in male Wistar rats suggesting its chemoprotective effects [257]. Significant anticarcinogenic potential was also found in leaf extracts of A. indica in a tumor model system (p < 0.005 to p < 0.001) [258]. Subapriya et al. (2005) suggested that the chemopreventive effects of ethanolic neem leaf extract might be mediated by the induction of apoptosis [259]. Treatment of rats by aqueous neem extracts significantly decreased the proliferating cell nuclear antigen labeling indices of colon epithelium and aberrant crypt foci, suggesting a chemopreventive role in the short-term colon carcinogenesis bioassay [260]. Nimbolide, a triterpenoid extracted from the flowers of the neem, was found to have antiproliferative activity and apoptosis-inducing property against U937, HL-60, THP1, and B16 cancer cell lines [261]. The acidic extract of leaves and neutral extract of seeds possessed anticancer activity, inhibiting Ehrlich ascites carcinoma cell line growth and IC₅₀ values were 669.43 and 724.63 µg/ml, respectively [254]. 7-Deacetyl-7-benzoylepoxyazadiradione, 7-deacetyl-7-benzoylgeduin, and 28-deoxonimbolide exhibited potent cytotoxic activity against HL60 leukemia cells while 4 other compounds (7-benzoylnimbocinol, epoxyazadiradione, gedunin, and ohchinin acetate) exhibited cytotoxic activity against 1 or more cell lines [114]. Cytotoxic activities of nimbolide isolated from branches and leaves against HL-60 have also been reported [121]. Sulfonoquinovosyldiacylglyceride, a water-soluble constituent of dried neem leaves, showed anti-cancerous activity in human leukemic cell lines U937 and K562 with IC₅₀ of 9 µg/ml [49]. Nimbolide was shown to exert apoptotic activity in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cell lines activating caspase-8, caspase-9, caspase-3, and cleavage of PARP [122]. Induction of apoptosis in human breast cancer cells by nimbolide ratifies its future in cancer treatment as a chemotherapeutic agent [122]. NIM-76, a volatile fraction of neem oil, was reported to have no mutagenic effects and regarded as safe concerning genotoxic potential in humans [262]. In vitro inhibition of growth of mouse sarcoma was found on treatment with neem leaf glycoprotein (25 µg/mice/wk subcutaneously for 4 wks) [263]. This anti-tumor immunity inhibiting the growth of mouse sarcoma was reported to be associated with increased expression of CD69, CD44, and Ki67 on CD8+ T cells [263]. Neem leaf glycoprotein showed no toxicity to various physiological functions of Swiss mice and Sprague-Dawley rats even though type 1 cytokines increased in serum with a decrease in type 2 cytokines and total IgG content in leaf glycoprotein-treated mice [264]. Change in type 1 cytokines were associated with increased anti-tumor immunity [264]. Neem oil limonoids were found to induce caspase-dependent and apoptosis-inducing factor-mediated apoptosis, as well as autophagy in cancer cells [265].

Hepatoprotective activities

Aqueous leaf extracts of neem significantly prevented changes in the serum levels of bilirubin, protein, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, and prevented the histological changes, thus having an antihepatotoxic activity against the damage induced by antitubercular drugs in rats [266]. Chattopadhyay and Bandyopadhyay (2005) discussed the possible mechanism of hepatoprotective activity of neem leaf extracts against paracetamol-induced hepatic damage in rats and concluded that hepatoprotective activity was possibly due to its potent antioxidant activity [267]. Mercury-induced oxidative damage in hepatic tissues was improved with neem leaf extract through its antioxidant effects [268].

Antioxidant activities

Sithisarn et al. (2006) compared free radical scavenging activity of Siamese neem tree leaf extracts against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and reported that most active extract was obtained with the leaf decoction method showing antioxidant activity with half-maximal effective concentration (EC₅₀) of 31.4 µg/ml [269]. In another study, significant antioxidant properties were observed in leaf and bark extracts/fractions of neem, while bark was found to possess higher phenolic content than the leaves [270].

Effects on CNS

Anxiolytic activity of leaf extracts of A. indica was studied in rats [271]. Neem extracts could attenuate anxiogenic and appetite-suppressant effects of stress by decreasing the brainʼs 5-hydroxytryptamine and 5-hydroxyindolacetic acid concentration in albino Wistar rats [272]. The pharmacotherapeutic value of neem leaves was also seen in anxiety disorders of albino Wistar rats [273].

Molluscicidal activities

Singh and co-workers (1996) showed the effect of leaf, bark, cake, neem oil, and the neem-based pesticides, achook and nimbecidine of neem, against the snails Lymnaea acuminata and Indoplanorbis exustus and found that pure azadirachtin was more toxic compared to synthetic molluscicides [274]. In another study, crude extracts of bark, roots, and leaves of neem at 500 mg/kg and 700 mg/kg were found lethal to edible tropical land snails Archachatina marginata and Limicolaria aurora (Jay) after exposure for 72 h and 48 h, respectively [275].

Insecticidal activities

The neem tree is well known for its insecticidal properties, which has been documented in a large assortment of studies. Insect growth-regulating properties were found in 23-O-methylnimocinolide and 1, 7-O-deacetyl-23-O-methyl-7α-O-senecioylnimocinolide [39] belonging to γ-hydroxybutenolides group of compounds. Siddiqui et al. (2002) reported desfurano-6-α-hydroxyazadiradione and 22, 23-dihydronimocinol as having insecticidal activity against the fourth instar larvae of mosquito (Anopheles stephensi) [36]. Two nitrogen-containing limonoids, salannolactam-21 and salannolactam-23, have been reported from neem seed kernels, which possess antifeedant activities [151]. Various tetranortriterpenoids–meliatetraolenone, zafaral, 6a-O-acetyl-7-deacetylnimocinol, meliacinol, 17-β-hydroxyazadiradione, azadironic acid, limocin-A, limocin-B, epoxyazadiradione, mahmoodin, gedunin, 7-decacetylgedunin, 1, 3-di-O-acetylvilasinin, 1-O-tigloyl-3-O-acetylvilasinin, nimbin, azadiradione, and 7-deacetylazadirone–isolated from different tissues of neem have been reported to either have insecticidal activities or insect anti-feeding activities (see [Table 1]). Additionally, azadirachtin and related compounds, such as 6-deactylnimbin, nimbolin B, salannin, 3-deacetylsalannin, salannol, and salannol acetate, have been isolated from various tissues of neem and also have insecticidal or insect anti-feeding properties. Insect growth-regulating activity was observed in desfuranoazadiradione, an octanortriterpenoid isolated from fresh fruit coats [77], [82]. Meliacinin, a dinortriterpenoid isolated from fruit coats, was found to be toxic against mosquito (Anopheles stephensi) [77], [78]. β-sitosterol, a steroid, has also shown insecticidal potential [276], [277]. Odoratone (protolimonoid), isolated from methanolic extract of fresh leaves, has demonstrated a lethal effect on the fourth instar larvae of mosquitoes (A. stephensi) [56]. Larvicidal properties of neem oil were also reported against A. stephensi, Culex quinquefasciatus, and Aedes aegypti [278].

Neem-based shampoos, amended with neem seed extract, are effective against all stages of head lice [279]. Extracts of neem oil [280], petroleum ether extracts of neem oil, and its 4 fractions separated by column chromatography [281] were reported to be lethal in in vitro assays against rabbit mite Sarcoptes scabiei var. cuniculi larvae. Further, octadecanoic acid-tetrahydrofuran-3,4-diyl ester isolated from an active fraction of the chloroform extract of neem oil was reported to have acaricidal in vitro activity against S. scabiei larvae [282]. Neem oil microemulsion was very effective against Sarcoptes scabie var. cuniculi larvae in vitro [283].

Antifilarial activities

Alcohol and aqueous extracts of flowers of A. indica showed inhibition of cattle filarial parasite Setaria cervi [284].

Synthesis and biological sources of azadirachtin

In addition to its remarkable insecticidal activity, azadirachtin also exhibits a range of other biological properties. The first complete structure of azadirachtin was elucidated by Nakanishi and coworkers in 1975 [285] using extensive NMR spectroscopy, which was further revised by Kraus in 1985 [87], who proposed a C13 – C14 epoxide. However, it took 22 y for azadirachtin to be produced by total synthesis [286], [287]. Initially, Veitch and co-workers discussed the probable route leading to the successful synthesis of azadirachtin [288]. This was followed by Jauch (2008) [286] and Ley et al. (2008) [287] who reported the full mechanism of complete chemical synthesis of azadirachtin. Meanwhile, another group focused on the biotechnological approaches for the production of azadirachtin; its production was reported using A. indica cell suspension cultures [289]. Further, azadirachtin biosynthesis could be induced in hairy root cultures of A. Indica [290], which was enhanced in hairy root cultures of A. indica by Satdive et al. in 2007 [291]. Production of azadirachtin in neem callus and suspension cultures has also been reported [292]. Another method of androgenic culture of A. indica showed increased azadirachtin production [293]. In 2012, Kusari and coworkers reported the biosynthesis of azadirachtin by an endophytic fungus, Eupenicillium parvum, isolated from neem [294].

Endophytic microorganisms (endophytes)

Endophytes are one of the predominant classes of microorganisms, which reside inside healthy tissues of host plants; endophytes include bacteria, fungi, nematodes, and viruses. Fungal endophytes (or endophytic fungi) are a dynamic and multitrophic group of microorganisms that are ubiquitous in plants thriving in every ecological niche ([Fig. 3]). Fungal endophytes have been found associated with algae [295], lichens [296], mosses [297], ferns [298], conifers [299], large trees [300], small trees [301], palms [302], [303], mangroves [304], halophytes [305], grasses [306], marine sponges [307], and seagrasses [308] to name a few. Endophytic fungi were isolated from every plant tissue including bark, flower, leaves, petioles, root, seed, and twigs [7], [309], [310], [311]. Further, endophytic fungi are well-established producers of a plethora of bioactive compounds and extracellular enzymes such as amylase, cellulase, chitinase, chitosonase, laccase, lipase, pectinase, and protease [312], [313], [314], [315]. Being colonizers of host tissues, the endobiome plays a crucial role in creating an extra layer of protection to their host during several adverse conditions [316], [317], [373]. They also modulate host metabolism for enhanced production of high-value secondary metabolites in medicinal plants like Withania, Coleus, Papaver; this positive modulation is a result of significant-high expression of genes and transcription factors of biosynthetic pathways [318], [319], [320]. Occasionally, few endophytic species mimic host metabolic pathways and produce host signature metabolites independently [294]. Therefore, unmatched beneficial traits of the endophytes were well recognized by research communities, and several of these endophytes have been utilized for several industrial and agricultural purposes.

Fig. 3 General representation of coexistence of and interaction between neem plants and associated endophytic microorganisms.

Fungal endophytic diversity of A. indica

Following-up the cues on ethnobotanical history of neem, Rajagopal and Suryanarayanan (2000) investigated and isolated endophytic fungi from green and senescent leaves of A. indica from Chennai, India, continuously for 2 y on a monthly basis. They reported 5 selected endophytes, 4 of which were sterile forms and the fifth was identified as Fusarium avenaceum [321]. They proposed that the restricted number of endophytic fungal genera and the absence of common endophytic fungi in the neem leaves could be due to the antifungal metabolites present in the leaves. The frequency of colonization of green leaves by endophytes was maximal during the rainy season although no new endophyte species could be discovered. It was found that the occurrence of foliar endophytes was influenced by seasonal changes [311], [322]. Since this was also found to be the case with the foliar endophytes of neem, it was suggested that the occurrence of foliar endophytes in tropical trees was influenced by the environment, soil type, and chemistry of the host tissue [321]. Mahesh and co-workers (2005) studied endophytic mycoflora harboring the inner bark of A. indica and reported 77 endophytic fungal isolates belonging to 15 genera [323]. Among them, 71.4% were hyphomycetes, followed by 18.2% coelomycetes, 6.5% ascomycetes, and 3.9% sterile mycelia. The colonization frequency was found to be 38.5%. Although Rajagopal and Suryanarayanan (2000) recovered only Fusarium avenaceum and 4 sterile forms of endophytes [321], Mahesh and co-workers (2005) were able to recover endophytic genera such as Curvularia, Cochlonema, Gliomastix, and Verticillium sp. [323]. Later, the same group identified endophyte diversity in bark segments of A. indica, which exposed high species richness with an average of 20 species, and prevalent colonization of Trichoderma and Chaetomium globosum was observed [324]. Verma and co-workers (2007) studied the fungal endophytes of A. indica in several of its natural habitats in India and recovered a total of 233 isolates of endophytic fungi, representing 18 fungal taxa from segments of bark, stem, and leaves [310]. Interestingly, in the whole study, the authors observed that hyphomycetes were the most prevalent group (62.2%), followed by the coelomycetes (27.4%) and a minor percentage by mycelia-sterilia (7.7%). The leaf samples from all locations were nearly constant in their endophytic composition, whereas the bark samples showed maximum diversity at different locations. This study also revealed, for the first time, that endophytes of genera Periconia, Stenella, and Drechslera were associated with A. indica. Not only was the endophytic fungal colonization frequency higher in leaves (45.5%) than bark (31.5%), but the maximum species richness and frequency of colonization also were as well [310]. Shao and coworkers (2008) have studied the distribution of endophytic fungi in A. Indica from Yuanjiang county of Yunnan Province, PR China [325]. They isolated a total of 372 endophytic fungal strains from the stem, leaves, and fruits. Colletotrichum was found to be the most dominant genera, followed by Alternaria and Xylaria. Another group characterized 85 endophytic fungi belonging to 10 genera, which were isolated from 200 segments of fresh A. indica leaves collected from the Panchmarhi biosphere reserve [326]. Here, the most dominant endophytes observed were Trichoderma, Pestalotiopsis, and Penicillium sp.

Rajagopal and Suryanarayanan (2000) found that even though the endophytic genera Phomopsis, Phyllosticta, and Xylaria are ubiquitous and commonly isolated from many hosts, these were absent from the leaves of the neem plants under their study [321]. However, these genera were found to be endophytic in neem leaves by other studies [310], [323], [325]. Dominant endophytes fungi isolated from the inner bark of A. indica from South India were Trichoderma, Penicillium, and Pestalotiopsis spp. [323], while those from North India were typically Phomopsis oblonga, Cladosporium cladosporioides, Pestalotiopsis sp., Trichoderma sp., and Aspergillus sp. [310]. Further, isolated species had exhibited inhibitory properties against Trichophyton, Microsporum [327]. In China, Colletotrichum was reported as the most dominant genus, followed by Alternaria and Xylaria [325]. This clearly indicates that endophyte diversity and species richness are not only dependent on specific hosts but also are location and niche specific. This further illustrates the importance of sampling different tissues of a given plant at several locations to obtain an enormous species diversity of endophytes. Taken together, endophytic fungal diversity in neem has been found to be highest in stems (42%), followed by bark (20%), while leaves and fruits harbor a similar percentage of endophytic fungi (19%) ([Fig. 4]). With the isolation of endophytic fungi from roots and fruits of neem, in addition to previous isolation and characterization from leaves, stems and bark, Verma and colleagues completed sampling of all organs of selected neem trees for their endophytic microflora [7], [300], [303]. Overall, a unique diversity pattern emerges from these studies: endophytic fungi isolated from A. indica belong mostly to the hyphomycetes, followed by coelomycetes and finally, ascomycetes [310], [313], [321], [323], [325].

Fig. 4 Percentage of the endophytic fungi isolated from different parts of neem.

Endophytic actinomycetes of A. indica

In addition to endophytic fungi, neem plants have been studied for the presence of associated endophytic actinomycetes. Kharwar and coworkers characterized 55 endophytic actinomycetes from 20 different samples, 60% of which showed in vitro inhibitory activity against 1 or more pathogenic fungi or bacteria [313]. Actinomycetes were most commonly recovered from roots (54.5% of all isolates), followed by stems (23.6%), and finally, leaves (21.8%). The dominant genus was Streptomyces (49.09% of all isolates), while Streptosporangium (14.5%), Microbispora (10.9%), Streptoverticillium (5.5%), Sacchromonospora sp. (5.5%), and Nocardia (3.6%) were also isolated. In another study, Gohain and coworkers identified the actinomycetes diversity of 6 medicinal plants collected from Gibbon wildlife sanctuary, Assam, and revealed that A. indica possesses the high Shannon diversity index (1.49) with predominance of Streptomyces species and Streptomyces significantly expressed Polyketide synthase-II (PKS) gene [328]. Endophytic actinomycetes species isolated from A. indica improved plant growth of tomato through the production of siderophores and Indole acetic acid, and inhibited the growth of the pathogen Alternaria alternata that causes blight disease in tomato [324]. Further, an actinomycete Micromonospora costi has been isolated from A. indica from Thailand. The unique characteristics of this species include the presence of meso-diaminopimelic acid in peptidoglycan and the presence of phospholipids like diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylinositol in the plasma membrane [329].

Metabolomics of Endophytes

In 1993, the landmark discovery of biosynthesis of the anticancer compound paclitaxel (Taxol) by endophytic Taxomyces andreanae [330] captured the attention of the scientific community towards endophytes as a treasure trove of novel, unique, bioactive natural products. A considerable number of discoveries followed the remarkable work, which cemented the virtually inexhaustible biosynthetic capabilities of endophytic fungi. Some important compounds produced by endophytic fungi are antifungal compounds such as cryptocandin A [331], cryptocin [332], ambuic acid [333], [334], pestaloside [335] and jesterone [336]; antibacterial compounds such as cytosporone A [337], [338] and javanicin [314]; anticancer compounds such as torreyanic acid [339], vincristine [340], chaetoglobosin A [341], penicillenols A1 and B1 [342], and camptothecin [343]; antioxidants like pestacin [344] and isopestacin [345]; and immunosuppressant subglutinols A and B [346] and HIV-1 integrase inhibitors [347]. Several reviews exemplify the vast chemical diversity of compounds produced by endophytes isolated from various plants prospected from different parts of the world [313], [348], [349]. Recently, Chutulo et al. (2018) briefly reported the metetabolites produced by endophytes isolated from neem plant and their activities [350]. The bioactive compounds produced by endophytes not only have an ecological significance but also provide a scientific handle to study the biochemical and molecular blueprints associated with their production [351]. Herein, we present detailed elaboration on the recent developments in compounds identified from the endophytic fungi of neem plant.

Bioactive natural compounds of endophytic fungi isolated from A. indica

Over 30 compounds have already been reported to be produced by neem-associated fungal endophytes. For instance, chlorinated oxazinane derivatives, 10-membered lactones, solanapyrone analogues, naphthaqinones, anthraquinones, napthodianthrone derivatives, and ring-C-seco-tetranortriterpenoids are some of the essential compound classes reported to be biosynthesized by endophytes associated with neem ([Fig. 5] and [Table 2]).

Fig. 5 Bioactive natural compounds isolated from endophytic fungi of A. indica.

Table 2 Major bioactive compounds derived from endophytic fungi of Azadirachta indica.

Sl. No.	Compound	Derivative	Activity	Endophytic fungi	Reference
n. a.: not available
1	1-[(2R*,4S*,5S*)-2-chloro-4-methyl-1,3-oxazinan-5-yl]ethanone (1)	Chlorinated oxazinane derivate	Nematicidal	Geotrichum sp.	[352]
2	1-[(2R*,4S*,5R*)-2-chloro-4-methyl-1,3-oxazinan-5-yl]ethanone (2)	Chlorinated oxazinane derivate	Nematicidal	Geotrichum sp.	[352]
3	[2,3-dihydro-2-(1-methylethenyl)-1-benzofuran-5-yl]methanol (3)	Benzofuran derivative	n. a.	Geotrichum sp.	[352]
4	1-(2,4-dihydroxyphenyl)-ethanone (4)	Polyphenol	Nematicidal	Geotrichum sp.	[352]
5	8α-Acetoxy-5α-hydroxy-7-oxodecan-9-olide (5)	10-membered lactone ring	Antifungal	Phomopsis sp.	[353]
6	7α, α-Dihydroxy-3,5-decadien-10-olide (6)	10-membered lactone ring	Antifungal	Phomopsis sp.	[353]
7	7α-Acetoxymultiplolide A (7)	10-membered lactone ring	Antifungal	Phomopsis sp.	[353]
8	8α-Acetoxymultiplolide A (8)	10-membered lactone ring	Antifungal	Phomopsis sp.	[353]
9	Multiplolide A (9)	10-membered lactone ring	Antifungal	Phomopsis sp.	[353]
10	Solanapyrone N (Methyl 4-Amino-6-[(1R,2S,4aR,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2-methylnaphthalen-1-yl]-2-oxo-2H-pyran-3-carboxylate) (10)	Solanapyrone analogues	Antifungal	Nigrospora sp.	[354]
11	Solanapyrone O (11)	Solanapyrone analogues	Antifungal	Nigrospora sp.	[354]
12	Solanapyrone C (12)	Solanapyrone analogues	Antifungal	Nigrospora sp.	[354]
13	Nigrosporalactone (13)	Lactones	Antifungal	Nigrospora sp.	[354]
14	Phomalactone (14)	Lactones	Antifungal	Nigrospora sp.	[354]
15	Javanicin (15)	Naphthaqinone	Antibacterial	Chloridium sp.	[314]
16	Chrysophanol (16)	Anthraquinone	Antibacterial	Aspergillus aculeatus	[355], [356]
17	Emodin (17)	Napthodianthrone derivative	Antibacterial, anticancerous	Aspergillus aculeatus	[355], [357], [358]
18	Succinic acid (18)	Dicarboxylic acid	Weak insecticidal activity against Plutella xylostella	Aspergillus aculeatus and Xylaria sp.	[355], [359]
19	1,5-Dimethyl citrate (19)	Oxobutanoate	n. a.	Aspergillus aculeatus	[352]
20	5-hydroxymellein (20)	Isocoumarin	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
21	5-methylmellein (21)	Isocoumarin	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
22	5-carboxymellein (22)	Isocoumarin	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
23	Hymatoxin C (23)	Diterpene	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
24	Hymatoxin D (24)	Diterpene	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
25	Halorosellinic acid (25)	Ophiobolane sesterterpene	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
26	Cerebroside C (26)	Sphingolipids	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
27	(2S,3S,4R,2′R)-2-(2′-Hydroxytetracosanoylamino)-octadecane-1,3,4-triol (27)	Ceramides (Lipids)	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
28	Cerevisterol (28)	Steroids	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
29	Adenosine (29)	Purine nucleoside	Weak insecticidal activity against Plutella xylostella	Xylaria sp.	[359]
30	Azadirachtin A (30)	Ring-C-seco-tetranotriterpenoids	Insecticidal activity	Eupenicillium parvum	[294]
31	Azadirachtin B (31)	Ring-C-seco-tetranotriterpenoids	Insecticidal activity	Eupenicillium parvum	[294]

Two new chlorinated, epimeric 1,3-oxazinane derivatives possessing nematicidal activity were characterized from Geotrichum sp. residing endophytically in leaves of neem [352], namely 1-ethanone (1) and 1-[(2R*,4S*,5R*)-2-chloro-4-methyl-1,3-oxazinan-5-yl]ethanone (2), an epimer of the first. Another nematicide active against the nematodes Bursaphelenchus xylophilus and Panagrellus redivivus, identified as [2,3-dihydro-2-(1-methylethenyl)-1-benzofuran-5-yl]methanol (3), was also reported from Geotrichum sp. in addition to 1-(2,4-dihydroxyphenyl)-ethanone (4) [352]. Ten-membered lactones viz. 8a-acetoxy-5a-hydroxy-7-oxodecan-9-olide (5), 7a,8α-dihydroxy-3,5-decadien-10-olide (6), 7α-acetoxymultiplolide A (7), 8α-acetoxymultiplolide A (8), and multiplolide A (9) have been reported from Phomopsis sp. isolated from stems of A. indica. These compounds exhibited antifungal activities against Aspergillus niger, Botrytis cinerea, Fusarium avenaceum, Fusarium moniliforme, Helminthosporium maydis, Penicillium islandicum, and Ophiostoma minus [353]. Multiplolide A (9), previously isolated from the fungus Xylaria multiplex [360], was also isolated from endophytic Phomopsis sp. associated with neem [353]. The main difference between multiplolide A (9) and 7α,8a-dihydroxy-3,5-decadien-10-olide (6) is that the epoxide moiety at C-3 and C-4 in the former is substituted by a double bond in the latter [360]. Solanapyrones have been previously reported as phytotoxins from Ascochyta rabiei [361], [362], [363] and Alternaria solani [364], [365]. Interestingly, 2 analogs solanapyrone N (10) and solanapyrone O (11) were isolated from Nigrospora sp. recovered from stems of A. indica, with both being structurally different in the substitution pattern of the a-pyrone unit compared to other solanapyrones [354]. Solanapyrone N (10), solanapyrone O (11), solanapyrone C (12), nigrosporalactone (13), and phomalactone (14) were shown to possess antifungal activities [354]. Structurally-related analogs of solanapyrones have also been isolated from an unidentified marine fungus associated with the surface of the green alga Halimeda monile, which demonstrated anti-algal activity [366]. Wu et al. [367] isolated guanine sesquiterpenes and isopimarane diterpenes from Xylaria sp. isolated from A. indica, and these compounds have shown inhibitory activities against Candida albicans, Hormodendrum compactum, and Pyricularia oryzae with MIC values ranging between 16 µg to 256 µg/ml. Similarly, 5 new guanine sesquiterpenes were further isolated from Xylaria sp. which also possesses antipathogenic activities [368]. Recently, Chatterjee et al. [369] identified the metabolites produced by Alternaria alternata isolated from A. indica showing inhibitory activities against Gram-negative and Gram-positive bacteria.

The highly functionalized antibacterial naphthaquinone, javanicin (15), has been reported from an endophytic fungus Chloridium sp. isolated from roots of A. indica [314], which displayed strong inhibition of Pseudomonas aeruginosa and P. fluorescens. Chrysophanol (16), emodin (17), succinic acid (18), and 1,5-dimethyl citrate (19) were obtained from the broth extract of an endophytic fungus Aspergillus aculeatus, a resident of A. indica [355]. Chrysophanol (1,8-dihydroxy-3-methylanthracenedione) (16), an anthraquinone responsible for antimicrobial efficacy against Bacillus subtilis and Staphylococcus aureus, was detected in the extract of Colubrina greggii [356]. Emodin (17) and related compounds were previously described as having significant inhibitory activities against P-388 leukemia in mice [357]. Emodin (17), postulated as the primary precursor in the endophytic biochemical pathway to the naphthodianthrone derivative hypericin, also showed antimicrobial activity against the Gram-positive bacterium Staphylococcus aureus, Gram-negative bacteria Klebsiella pneumoniae f. sp. ozaenae, Pseudomonas aeruginosa, Salmonella enterica f. sp. enterica, and Escherichia coli, and fungal organisms Aspergillus niger and Candida albicans [358]. Eleven compounds, namely 5-hydroxymellein (20), 5-methylmellein (21), 5-carboxymellein (22), hymatoxin C (23), hymatoxin D (24), halorosellinic acid (25), cerebroside C (26), (2S,3S,4R,2′R)-2-(2′-hydroxytetracosanoylamino)-octadecane-1,3,4-triol (27), cerevisterol (28), adenosine (29), and succinic acid (18) have been reported to be produced by endophytic Xylaria sp. YC-10 isolated from the stems of A. indica collected in Yuanjiang County, Yunnan Province, P. R. China [359]. Although all the compounds exhibited weak insecticidal activity against Plutella xylostella, 9 of these compounds were reported from Xylaria for the first time [359]. Further, Verma et al. [370] attempted to synthesize silver nanoparticles from the extracts of endophytic fungus Aspergillus clavatus and tested against human pathogens such as Candida albicans, Pseudomonas fluorescens, and Escherichia coli, and they were effective against pathogens at 9.7 µg/ml (minimum fungicidal concentration) and 5.83 µg/ml (minimum inhibitory concentration). Kusari et al. (2012) identified and quantified azadirachtin A (30) and B (31) as biosynthetic products of a novel neem-associated endophytic fungus, Eupenicillium parvum [294]. This study highlighted an interesting plant-endophyte association where plant “mimetic” compounds are produced by endophytes to render similar functional traits in their ecological habitats.

Outlook

A. indica (neem) and its endophytic microflora represent an extensive repertoire of diverse natural products having different biological activities. On the one hand, neem (host plant) is a rich source of compounds such as the azadirachtins and related tetranortriterpenoids. On the other hand, endophytes associated with neem have a massive potential in synthesizing bioactive and chemically novel compounds. It is noteworthy that a large number of diverse endophytic fungi and actinomycetes have been isolated from A. indica in a relatively small period. Concomitantly, a large number of compounds have been isolated from neem and its endophytes, even though their biochemistry and overall ecological connotations are not clearly understood. Except for a few studies, endophytic microorganisms of neem remain poorly investigated. Recently, an epigenetic study was conducted to induce the antimicrobial activity and production of cryptic metabolites from Streptomyces coelicolor (AZRA 37) of neem plant, and the increased antimicrobial activity coupled with induced protein production were registered [371]. Extensive research is required to assess the hidden endophytic populations of neem. In particular, endophytic actinomycetes associated with neem can serve as a precious and reliable resource of novel compounds, given that they are well-known prolific producers of bioactive metabolites [372]. It has already been firmly established that endophytes have unique functions in hosts such as plant protection, nutrient supply, phosphate solubilization, and mineral transport. Besides, endophytic fungi can also confer a profound impact on the host system by not only enhancing growth and fitness but also strengthening their tolerances to abiotic and biotic stresses. It has been proposed that during evolution, some co-existing endophytes and their host plants have established a unique relationship with one another and significantly influenced the formation of secondary metabolites in plants such as neem. These findings open new platforms for enhancing growth as well as for improved production of valuable metabolites using endophytes in the host plant. However, mechanisms underlying plant-endophyte interaction are still open to future research. It is known that during endophyte infection, selected plant-specific metabolites play a significant role in colonization and the establishment of endophytic interactions. These substances not only play a crucial role in defense and competition but also might be needed for specific interaction and communication with the endophyte(s). As highlighted in this review, endophytic associations have been studied, using a birdʼs-eye view from the host plantʼs side, which resulted in detailed and comprehensive knowledge related to various microbes associated with different species or cultivars. However, how the host plant (A. indica) responds varies depending on the endophyte strain and plant environment. The mechanisms behind such selective priming remains obscure. Extricating the changes in transcriptome and, subsequently, metabolome – both of neem as well as associated endophytes – under the influence of abiotic and biotic environmental factors will throw light into the genetic and biochemical mechanisms underlying neem-endophyte interactions.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

RNK thankfully acknowledges the head and coordinator of CAS and FIST in Botany, BHU, Varanasi, for facilities; DST-PURSE, UGC-UPE, BHU, Varanasi, CSIR and UGC, New Delhi, for financial support and funding as JRF and SRF, and DST, New Delhi for financial support (SB/EMEQ-121/2014). Research in the laboratory of SK is supported by the German Federal Ministry of Education and Research (BMBF; grant no. 031B0512E); German Academic Exchange Service (DAAD); the Ministry of Innovation, Science, Research, and Technology of the State of North Rhine-Westphalia; German Research Foundation (DFG); and TU Dortmund, Germany.

^# Present Address: Department of Botany, Harish Chandra PG College, Varanasi, India

^## Present address: Department of Botany, MMV, Banaras Hindu University, Varanasi, India

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