Planta Med 2020; 86(13/14): 906-940
DOI: 10.1055/a-1107-9370
Biological and Pharmacological Activity
Reviews

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

Ravindra N. Kharwar
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
,
Vijay K. Sharma
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
2   Medical School of Kunming University of Science and Technology, Kunming, P. R. China
,
Ashish Mishra
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
,
Jitendra Kumar
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
2   Medical School of Kunming University of Science and Technology, Kunming, P. R. China
,
Dheeraj K. Singh#
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
,
Satish K. Verma
1   Mycopathology and Microbial Technology Laboratory, Department of Botany, Institute of Science, Banaras Hindu University, Varanasi, India
,
Surendra K. Gond##
3   Department of Botany, Visva-Bharati, Shantiniketan, India
,
Anuj Kumar
4   Department of Botany, Buddha PG College, Kushinagar, India
,
Nutan Kaushik
5   Amity Food and Agriculture Foundation, Amity University, Noida, India
,
Bharadwaj Revuru
6   Institute of Environmental Research (INFU), Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Dortmund, Germany
,
Souvik Kusari
6   Institute of Environmental Research (INFU), Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Dortmund, Germany
› Author Affiliations
Supported by: DST, New Delhi, India SB/EMEQ-121/2014
Supported by: Bundesministerium für Bildung und Forschung 031B0512E
 


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.


#

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].

Zoom Image
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.

Zoom Image
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].


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Antifilarial activities

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


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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].


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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.

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

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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].

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

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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].


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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]).

Zoom Image
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.


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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.


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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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Correspondence

Prof. Dr. Ravindra Nath Kharwar
Mycopathology and Microbial Technology Laboratory
Department of Botany
Institute of Science
Banaras Hindu University
Varanasi 221005, Uttar Pradesh
India   
Phone: + 91 94 15 29 00 01   
Fax: + 91 54 22 36 81 74   

 

Priv.-Doz. Dr. Souvik Kusari
Institute of Environmental Research (INFU)
Department of Chemistry and Chemical Biology
Technische Universität Dortmund
Otto-Hahn-Straße 6
44221 Dortmund
Germany   
Phone: + 49 (0) 23 17 55 40 86   
Fax: + 49 (0) 23 17 55 40 84   

Publication History

Received: 26 October 2019

Accepted after revision: 27 January 2020

Article published online:
03 March 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

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