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Received: 15 October 2017 Revised: 25 February 2018 Accepted: 28 February 2018
DOI: 10.1002/ptr.6076

REVIEW

A comprehensive review of phytochemical profile, bioactives

for pharmaceuticals, and pharmacological attributes of
Azadirachta indica
Sumaira Saleem1 | Gulzar Muhammad1,2 | Muhammad Ajaz Hussain2 |

Syed Nasir Abbas Bukhari3

1
Department of Chemistry, GC University
Lahore, Lahore 54000, Pakistan Azadirachta indica L. is a multipurpose medicinal tree of family Meliaceae. It occurs in
2
Department of Chemistry, University of tropical and semitropical regions of the world. Different parts of this miraculous tree
Sargodha, Sargodha 40100, Pakistan
3
are used to treat pyrexia, headache, ulcer, respiratory disorders, cancer, diabetes, lep-
Department of Pharmaceutical Chemistry,
College of Pharmacy, Jouf University, Aljouf, rosy, malaria, dengue, chicken pox, and dermal complications. The tree is popular for
Sakakah 2014, Saudi Arabia
its pharmacological attributes such as hypolipidemic, antifertility, microbicidal, antidi-
Correspondence
Muhammad Ajaz Hussain, Department of
abetic, anti‐inflammatory, hepatoprotective, antipyretic, hypoglycemic, insecticidal,
Chemistry, University of Sargodha, Sargodha nematicidal, antiulcer, antioxidant, neuroprotective, cardioprotective, and
40100, Pakistan.
Email: majaz172@yahoo.com
antileishmaniasis properties. A. indica is also rich in various phytochemicals for phar-
Syed Nasir Abbas Bukhari, Department of maceuticals such as alkaloids, steroids, flavonoids, terpenoids, fatty acids, and carbo-
Pharmaceutical Chemistry, College of hydrates. The fungicidal potential of the tree is due to the presence of azadirachtin
Pharmacy, Jouf University, Aljouf, Sakaka
2014, Saudi Arabia. and nimbin. Herein, we have compiled a comprehensive review of phytochemical pro-
Email: sbukhari@ju.edu.sa file, pharmacological attributes, and therapeutic prospective of this multipurpose tree.

KEY W ORDS

Azadirachta indica, azadirachtin, bioactives, medicinal uses, neem, pharmacological attributes,

secondary metabolites

1 | I N T RO D U CT I O N A. indica is rich in highly valuable secondary metabolites including

Azadirachta indica (A. indica), an evergreen tree of family Meliaceaeis
found abundantly in Australia, subcontinent, and other countries of
South Asia (Ahmad, Bamofleh, & Munshi, 1989; Fathima, 2004). It is
used as a traditional herbal drug all over the globe to treat various ail-
ments (Akbar, Arshad, Chaudhry, & Ahmed, 2014; Drabu, Khatri, &
Babu, 2012; Joshi et al., 2011; Prusty & Harish, 2014). Almost all parts
of this incredible tree have been used as phytomedicines for more
than 4,000 years (Krishnaswamy, 2008; Pankaj, Lokeshwar, Mukesh,
& Vishnu, 2011; Sultana et al., 2011). Folk healers have been using this
tree since long to treat skin problems, chicken pox, fever, rheumatism,
chronic syphilitic sores, ulcers, cancers, respiratory, and digestive
problems (Biswas, Chattopadhyay, Banerjee, & Bandyopadhyay,
2002; Drabu et al., 2012; Gul, Shinwari, & Afzal, 2012; Iqbal, Lateef,
Jabbar, & Gillani, 2010; Kikuchi et al., 2011; Koul, Isman, & Kelkar,
2006; Y. Sharma, Dua, & Srivastva, 2014).
isoprenoids (azadirone, protomeliacins, nimbin, azadirachtin, limo-
noids, and gedunin) and nonisoprenoids (proteins, sulphur compounds,
carbohydrates, dihydrochalcones polyphenolics, and their glycosides;
Atangwho et al., 2009; Biu, Yusufu, & Rabo, 2010; Govindachari,
1992; Koul, Isman, & Ketkar, 1990; Kraus, 1995; Olabinri, Adepoju,
Zainab, & Ahmed, 2013; Susmitha, Vidyamol, Ranganayaki, &
Vijayaragavan, 2013). Highly potential antioxidant flavonoid, genistein
7‐O‐glucoside, and (–)‐epi‐catechin (Kanwal, Ullah, Haq, Afzal, &
Mirza, 2011) are also an important constituent of seeds. Medicinal
potential of the tree can be attributed to various diverse nature sec-
ondary metabolites/bioactives, that is, terpenes, limonoids, flavonoids,
alkaloids, and saponins (Obeguwe, 2008), which mediated their role by
affecting various biological processes.
Various pharmacological attributes such as antifungal, antiviral,
antibacterial, anti‐inflammatory, antifeedant pesticides, sterilant,
antiscabic, antiallergenic, analgesic, and nematicidal are ascribed to

Phytotherapy Research. 2018;32:1241–1272. wileyonlinelibrary.com/journal/ptr Copyright © 2018 John Wiley & Sons, Ltd. 1241

1242
various parts of the tree (Girish & Shankara, 2008; Ogbuewu et al.,
2011). The extracts of leaves were observed to possess remarked
hypoglycemic, hypolipidemic, hepatoprotective, antifertility, and
hypotensive activities (Mamdouh, Mousa, Ashram, & Hamed, 2008;
Puri, 1999; Ragasa et al., 1997). Seeds are used as anthelmintic,
antileprotic, and antipoisonous agents (Iqbal et al., 2010; Drabu
et al., 2012). Seed oil exhibited spermicidal, antipyretic, antiartheritic,
diuretic, antimalarial, and hypoglycemic effects (Bhargava, Gupta,
Gupta, & Mitra, 1970; Bhide, Mehta, & Lewis, 1958; David, 1969;
Jones et al., 1994; Murthy & Sirsi, 1958; Pillai & Santhakumari,
1981; V. N. Sharma & Saksena, 1959). Flowers of the tree are used
as astringent and anthelmintic agents whereas its fruit possessed
antihemorrhodal activity. Barks and twigs are used against worm
infestation, anorexia, vomiting, and dental problems (Surbhi & Bhatt,
2016). Oils obtained from the fruits and seeds are considered as
vegetable oils. A. indica is a promising medicinal tree that deals with
multidrug resistance microbes (Aneesa, 2016; Padalia, Moteriya,
Baravalia, & Chanda, 2015).
Literature has shown that few review articles have already been
compiled to cover different aspects of A. indica (Aneesa, 2016; Haque,
Khan, & Lisa, 2016; Pankaj et al., 2011; Surbhi & Bhatt, 2016). How-
ever, there is dire need to compile a comprehensive and in‐depth
review article on this miraculous tree's medicinal uses, phytochemical
profiling, nutraceutical potential, and pharmacological applications.
Present review will bridge the knowledge gap, regarding phytochemis-
try and bioactive potential of this versatile tree among researchers
working in academia and industries (i.e., nutraceutical, pharmaceutical,
medicinal, and cosmetics).
2 | T A X O N O M Y , D I S T R I B U T I O N , A N D TR E E
G RO WTH
A. indica (neem) belongs to genus Azadirachta of family Meliaceae. It is
a tropical multipurpose evergreen tree naturally occuring in Pakistan,
India, Bangladesh, Sri Lanka, Burma, Malaysia, Thailand, Australia,
and Indonesia (Ahmad et al., 1989; Fathima, 2004; Roxburgh, 1874).
It can grow in stony and dry soils under different climatic conditions
up to an altitude of 700 m and has a long life of more than 200 years.
It is abundant in those regions where rainfall, temperature, and pH
varied from 450 to 1,200 mm, 0 to 49 °C, and 4 to 10, respectively.
However, it can also grow in those areas where annual rainfall is very
low, that is, 150–200 mm. In India, annual production of A. indica
seeds, oil, and cake is 442,300, 88,400, and 353,800 tons, respectively
(Sateesh, 1998; Jattan, Sushikumar, & Pujar, 1995; Chari, 1996;
Hedge, 1995; Uchegbu, Okoli, Esonu, & Iloeje, 2011).
A. indica grows with semistraight to straight trunk, extensive
branching, and thick bark. The maximum height and girth attained by
the mature tree is 7–15 and 3 m, respectively (Obeguwe, 2008;
Singhal & Bhatt, 2016). The tree generates oval‐shaped yellowish
seeds at the age of 4 years. The compound and imparipinnate leaves
are alternately arranged in pairs and have up to 15 narrow and
6‐cm‐long leaflets (Obeguwe, 2008). The ripened 1‐in.‐long fruit is
yellow in color. The tree produces white flowers from May to August
(Koul et al., 2006; Obeguwe, 2008).
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SALEEM ET AL.
3 | PHYTOCHEMISTRY
A. indica is a medicinal tree rich in phytochemicals such as tannins,
alkaloids, flavonoids, terpenoids, reducing sugars, glycosides, tannins,
cyclic trisulphide, unsaturated sterols, and saponins (Atangwho et al.,
2009; Biswas et al., 2002; Biu et al., 2010; Champagne, Koul, Isman,
Scudder, & Towers, 1992; Chatterjee & Pakrashi, 1994; Govindachari,
1992; Lakshmanan & Subramanian, 1996; Nwakaeze, Ifeanyichukwu,
Chika, Emmanuel, & Chinwe, 2013; Olabinri et al., 2013; Susmitha
et al., 2013; Vasantharaj, Sathiyavimal, & Hemashenpagam, 2013).
New tetracyclic triterpenoids, zafaral, and meliacinanhydride along
with two known constituents, nimocinol and isomeldenin, have been
isolated from leaves (Siddiqui, Afshan, Ghiasuddin, Naqvi, & Tariq,
1999; Siddiqui & Rasheed, 2001; Siddiqui, Rasheed, et al., 2004).
Similarly, flavonoids (genistein 7‐O‐glucoside and (–)‐epi‐catechin)
and a tetranortriterpenod, nimonol were extracted from leaves of the
tree (Gopalakrishnan, Singh, & Kasinath, 2002; Kanwal et al., 2011).
Complete screening of phytoconstituents of A. indica tree using
high‐performance thin‐layer chromatography revealed the presence of
rutin, β‐sitosterol, ellagic acid, ferulic acid, lupeol, and quercetin (Feng,
Xin‐Xin, Liang, & Feng‐Chang, 2005; Pandey, Verma, & Singh, 2014).
The extracts of leaves and bark were explored for phytochemical compo-
nents and investigated to contain stigmasterol, terpinen‐4‐ol, sugiol, 4‐
cymene, nimbiol, α‐terpinene, and vitamin E (Nand, Drabu, & Gupta,
2012). The structures of some selected biologically active phytochemi-
cals isolated from different parts of A. indica are shown in Figure 1.
V. Sharma, Bali, and Singh (1998) isolated nonterpenoidal compo-
nents such as nimbothalin and n‐tridecyl benzene from leaves using
ethanol extraction (V. Sharma et al., 1998). Leaves were explored to
contain isoprenoid, flavanone (8,3′‐di‐isoprenyl‐5,7‐dihydroxy‐4′‐
methoxyflavanone), nonisoprenoids, and meliacin (2′,3′‐
dehydrosalannol; Garg & Bhakuni, 1984, 1985). Similarly,
triterpenoids, 22,23‐dihydronimocinol, and desfurano‐6‐α‐
hydroxyazadiradione were isolated from methanolic extract of leaves
(Siddiqui, Afshan, Faizi, Naqvi, & Tariq, 2002). The leaves also
contained azadiradione (Govindachari, Gopalakrishnan, Masilamani, &
Banumathi, 2000), tetraterpenoid (14,15‐epoxynimonol; Govindachari,
Malathi, Gopalakrishnan, Suresh, & Rajan, 1999), and flavonoids par-
ticularly quercetin (Chakraborty, Uerotta, & Poddar, 1989). Table 1
shows phytochemicals isolated from various parts of A. indica.
Leaves of A. indica contained azadirachtin and related limonoids,
which are nontoxic to crop‐friendly insects, humans, and mammals
(Ignacimuthu, 2004; Schaaf, Jarvis, Esch, Giagnacovo, & Oldham,
2000). Photo‐oxidation of nimbin, salannin, and azadirachtin resulted
in the production of isonimbinolide and isosalanninolide (Jarvis,
Johnson, Morgan, Simmonds, & Blaney, 1997). The presence of
tetraanortriterpenoid, meliatetraolenone, and a compound named
odoratone was confirmed by 2D‐nuclear magnetic resonance (NMR)
in the fresh leaves (Siddiqui et al., 2003).
Essential oils were extracted by hydro‐distillation from leaves and
flowers and analysed using gas chromatography‐mass spectrometry
(GC/MS). Results of GC/MS revealed the presence of 85.6% hydro-
carbons including γ‐elemene (9.89%), caryophyllene (6.8%), β‐elemene
(33.39%), germacrene D (9.72%), and bicyclogermacrene (5.23%). Oil
extracted from flowers consisted of 63.22% hydrocarbons

SALEEM ET AL.
FIGURE 1 The structures of selected biologically active phytochemicals isolated from different parts of Azadirachta indica
(pentacosane 18.58%, tetracosane 10.65%, β‐germacrene 9.73%,
β‐caryophyllene 5.84%, and dodecene 4.54%) and 28.3% oxygenated
compounds (octadecanol 16.7%, verdiflorol 5.32%, farnesol 1.63%,
and α‐terpineol 1.51%; El‐Hawary et al., 2013). The methanolic
extract of flowers contained prenylated flavonoids (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), which showed antimutagenic activity against
Trp‐P‐I, Trp‐P‐II, and PhIP (Nakahara et al., 2002; Nakahara et al.,
2003).
Flowers were discovered to comprise structurally diverse flava-
nones (flowerine and flowerone) and triterpenoids (O‐
methylazadironolide and diepoxyazadirol). Other known constituents
present in flowers are triterpenoid (trichilenone acetate), flavanones,
nimbaflavone, 3′‐prenylnaringenin and 4‐(2‐hydroxyethyl) phenol
(Siddiqui et al., 2003). Resins of shoot apex and young leaves
contained isoprenylated flavanone (8‐prenyl‐5,7‐dihydroxy‐3′‐(3‐
hydroxy‐3,3‐dimethylbutyl)‐4′‐methoxyflavanone; Balasubramanian,
Mohan, Arumugasamy, & Udaiyan, 1993). Fresh flowers also showed
significant larvicidal activity against Anopheles stephensi owing to the
presence of sesquiterpenes, aromatic compounds, fatty acids, fatty
acid esters, steroids, few hydrocarbons, azharone, azadirone, and
isoazadironolide (Siddiqui et al., 2006, 2009).
Essential oils extracted from seeds and kernels using methanol
were analysed using different chromatographic techniques and
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1243
witnessed to contain tetranortriterpene alcohol (Gaikwad et al.,
1990; Gossé, Adjé, Niamké, Ollivier, & Ito, 2005; Momchilova et al.,
2007). The oil extracted from flowers of the tree also possessed
cubebene, copaene, humulene, δ‐cardinene, and a number of sesqui-
terpenes, which were responsible for antimicrobial activities
(Aromdee, Anorach, & Sriubolmas, 2005). The seeds of the tree
consisted of highly volatile organosulphur compounds especially di‐
n‐propyl‐ and n‐propyl‐1‐propenyl group containing di, tri, and tetra
sulphides as studied using capillary GC/MS (Balandrin et al., 1988;
Mubarak & Kulatilleke, 1990). Another compound, salannin, was iso-
lated from oil of seeds using high‐performance liquid chromatography
(Yamasaki et al., 1988). The major compounds detected in the essen-
tial oils of flowers and leaves were β‐elemene, γ‐elemene, germacrene
D, caryophyllene, and bicyclogermacrene (El‐Hawary et al., 2013). The
flower oils consisted of hydrocarbons (pentacosane 18.58%,
tetracosane 10.65%, β‐germacrene 9.73%, β‐caryophyllene 5.84%,
dodecene 4.54%, and oxygenated compounds [octadecanol 16.7%,
verdiflorol 5.32%, farnesol 1.63%, and α‐terpineol 1.51%]; El‐Hawary
et al., 2013). Figure 2 shows important antibacterial volatiles obtained
from A. indica.
The extract of seeds and kernels was carefully analysed in differ-
ent studies, and a number of bioactive compounds characterized were
azadirachtin M, azadirachtin N, 11‐epi‐azadirachtin H, and triterpenoid
(1α,7α‐diacetoxyapotirucall‐14‐ene‐3α,21,22,24,25‐pentaol) along
with known compounds, odoratone and 2β,3β,4β‐trihydroxypregnan‐
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1244 SALEEM ET AL.

TABLE 1 Phytochemicals isolated from different parts of Azadirachta indica

Parts used Phytochemicals isolated Nature of extract References

Leaves Stigmasterol, terpinen‐4‐ol, sugiol, 4‐cymene, Dichloromethane and Nand et al., 2016
nimbiol, α‐terpinene, and vitamin E methanolic extracts
Steroid, glycoside, flavonoids, triterpenoid, Chloroform, aqueous and Rapheal, 2012; Prashanth & Krishnaiah, 2014
carbohydrate, alkaloids, and antiquinone ethanolic extracts
Zafaral, meliacinanhydride, nimocinol, and isomeldenin Ethanolic extract Siddiqui, Afshan, Gulzar, & Hanif, 2004
Nimonol Ethanolic extract Gopalakrishnan et al., 2002
Nimbothalin and n‐tridecyl benzene Ethanolic extract V. Sharma et al., 1998
Isoprenoid, flavanone Ethanol extract fractionated Garg & Bhakuni, 1984
(8,3′‐di‐isoprenyl‐5,7‐dihydroxy‐4′‐methoxyflavanone), fractioned with chloroform
nonisoprenoids, and meliacin and n‐butanol
22,23‐Dihydronimocinol and Methanolic extract Siddiqui et al., 2002
desfurano‐6‐α‐hydroxyazadiradione
Meliatetraolenone and odoratone Methanolic extract Siddiqui, Ali, Rasheed, & Kardar, 2003
Volatile compounds Oil extracted with steam El‐Hawary, El‐Tantawy, Rabeh, &
Badr, 2013
Tetracyclic triterpenes Ethanolic extract Siddiqui & Faizi, 1984; Siddiqui,
Mahmood, Siddiqui, & Faizi, 1986.
α‐Linolenic acid n‐hexane extract Nair, Gopal, & Issac, 1997
Nimonol Methanolic extract Suresh, Narasimhan, Masilamani,
Partho, & Gopalakrishnan, 1997
Roots Nimbilin and nimolinin Dichloromethane and Ara, Siddiqui, Faizi, & Siddiqui, 1989b
methanolic extracts
Flowers Prenylated flavonoids Methanolic extract Nakahara et al., 2002
Flowerine, flowerone, o‐methylazadironolide, and Methanolic extract Siddiqui et al., 2003
diepoxyazadirol
Sesquiterpenes, aromatic compounds, fatty acids n‐hexane extract Siddiqui et al., 2009
and fatty acid esters, steroids, and few hydrocarbons
Azharone, azadirone, and isoazadironolide Methanolic extract Siddiqui, Ali, & Kashif, 2006
Seeds Genistein 7‐O‐glucoside and (–)‐epi‐catechin Methanol, n‐hexane, and Kanwal et al., 2011
ethyl acetate extracts
Tetranortriterpene alcohol Seed oil Gaikwad, Mayelvaganan, Vyas, & Bhat, 1990
Organosulphur compounds Diethyl ether extract Balandrin, Lee, & Klocke, 1988
Steam volatile extract Mubarak & Kulatilleke, 1990
Salannin n‐hexane Yamasaki, Ritland, Barn, & Klocke, 1988
Azadirachtin M, azadirachtin N, 11‐epi‐azadirachtin H, Methanolic extract Luo, Ma, Wu, & Wu, 1999;
triterpenoid(1α,7α‐diacetoxyapotirucall‐14‐ene‐3α,21, Luo, Wu, Ma, & Wu, 2000
22,24,25‐pentaol), odoratone, and 2β,3β,4β‐
trihydroxypregnan‐16‐one
11‐Hydroxyazadirachtin‐B, 1‐tigloyl‐3‐acetylazadirachtinin, Methanolic extract Kumar, Srinivas, & Yakkundi, 1996
1,2‐diacetyl‐7‐tigloyl‐12‐hydroxyvilasinin, and
23‐desmethyllimocin‐B
1α‐Methoxy‐1,2‐dihydroepoxyazadiradione, Petroleum ether extract Kraus, Cramer, & Sawitzki, 1981
1β,2β‐diepoxyazardiradione, 7‐acetylneotrichilenone, dissolved in methanol
desacetyl‐7‐ benzoylazadiradione 7‐desacetyl‐7‐
benzoylepoxyazadiradione, and 7‐desacetyl‐7‐
benzoyl‐gedunin
Azadirachtin Dichloromethane extract Jarvis & Morgan, 2000
Methanolic extract Deota, Upadhyay, Patel, & Mehta, 2000
Deacetylazadirachtinol Seed oil Kubo, Matsumoto, & Matsumoto, 1986
1α,2α‐Epoxy‐17β‐hydroxyazadiradione, Methanolic extract Hallur, Sivramakrishnan, & Bhat, 2002
1α,2α‐epoxynimolicinol and
7‐deacetylnimolicinol along with epoxyazadiradione,
17β‐hydroxyazadiradione, gedunin, nimbin,
and nimolicinol
Fruit Mahmoodin, azadirachtol, and naheedin Ethanolic extract Siddiqui, Faizi, Siddiqui, & Ghaiussdin, 1992
Salimuzzalin, azadirolic acid, azadiradinol, and azadironol Ethanolic extract Siddiqui, Ghaiussdin, & Faizi, 1998
Limocinone, limocin A, limocin B, limocinol, and limocinin Ethanolic extract Siddiqui, Siddiqui, Ghiasuddin, & Faiz, 1991

16‐one (Luo et al., 1999, 2000). A previous phytochemical Presence of mahmoodin, azadirachtol, and naheedin in oil and
investigation of seeds reported the presence of 11‐ fruit coat of the tree was established using 2D NMR and chemical
hydroxyazadirachtin‐B, 1‐tigloyl‐3‐acetylazadirachtinin, 1,2‐diacetyl‐ analysis (Siddiqui et al., 1992). Later on, examination of fruit coat using
7‐tigloyl‐12‐hydroxyvilasinin, and 23‐desmethyllimocin‐B (Kumar spectroscopic techniques revealed the presence of new tetracyclic
et al., 1996). Kraus et al. (1981) isolated 1α‐methoxy‐1,2‐ triterpenoids such as salimuzzalin, azadirolic acid, azadiradinol, and
dihydroepoxyazadiradione, 1β,2β‐diepoxyazardiradione, 7‐ azadironol (Siddiqui et al., 1998). Previously, same group has con-
acetylneotrichilenone, desacetyl‐7‐benzoylazadiradione, 7‐desacetyl‐ firmed the structures oflimocinone, limocin A, limocin B, limocinol,
7‐benzoylepoxyazadiradione, and 7‐desacetyl‐7‐benzoyl‐gedunin limocinin (Siddiqui et al., 1991), isonimolicinolide, and nimolicinoic acid
from the seeds. (Siddiqui, Mahmood, Faizi, & Siddiqui, 1987) from uncrushed ripened

SALEEM ET AL.
FIGURE 2 Structures of antibacterial volatile compounds isolated
from different parts of Azadirachta indica
fresh fruit coats. A recent study showed that fresh fruit contained
azadirone, epoxyazadiradione, and azadiradione (Haldar, Phapale,
Kolet, & Thulasiram, 2013).
Tetracyclic triterpenes such as meliantriol and nimolicinol were
extracted from A. indica oil (Kraus & Cramer, 1978; Nadkarni, 1976).
The fruits and leaves consisted of tetracyclic triterpenes such
asnimbocinone, nimocin, azadirachtol, and nimocinol (Chopra, Nayar,
& Chopra, 1956; Qudrat–i–Khuda, Ghosh, & Mukherjee, 1940;
Siddiqui et al., 1986; Siddiqui & Faizi, 1984). The presence of α‐
linolenic acid from fresh leaves of the tree has also been established
(Nair et al., 1997). Suresh, Narasimhan, and Palani (1997) identified
the structure of nimonol extracted from whole green leaves by spec-
tral studies such as COSY and NOESY NMR spectroscopies. In
another study, it was concluded that the amount of azadirachitin and
salannin decreased with maturity of fruit that affected its bitter taste
(Johnson, Morgan, & Peiris, 1996). It was established that root bark
constituted two novel terpenoids, nimbilin and nimolinin (Ara et al.,
1989b).
Azadirachtin has been isolated and quantified in several reports
from the seeds of the tree (Deota et al., 2000; Jarvis & Morgan, 2000;
Kumar et al., 1996; S. M. Lee, Olsen, Schweizer, & Klocke, 1988).
Nimbidinin and nimbidic acid were also isolated from extract of seed
kernels (Mitra, Garg, & Pandey, 1971). Another study revealed the pres-
ence of nimbin and nimbolide in the leaves and seed extracts (Bokel,
Cramer, Gutzeit, Reeb, & Kraus, 1990). The extract of seeds consisted
of tetranortriterpenoid (11‐epi‐azadirachtin H), 11‐epi‐azadirachtin D,
nimbanal, and salannol‐3‐acetate as well (Ramji, Venkatakrishnan, &
Madyastha, 1996; Ramji, Venkatakrishnan, & Madyastha, 1998;
Rojatkar, Bhat, Kulkarni, Joshi, & Nagasampagi, 1989). H. W. Wang
et al. (2013) investigated the presence of three new limonoids such as
1‐benzoyl‐3‐deacetyl‐1‐detigloyl, salannin, 7‐tigloyl‐12‐oxovilasini,
azadiralactone and triterpenoid, azadirahemiacetal in the dried kernels
of the tree. Seed oil extract showed the presence of a novel limonoid,
deacetylazadirachtinol, which is a potent inhibitor in insect ecdysis
(Kubo et al., 1986). Recently, it was explored that oil from leaves
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1245
contained γ‐elemene (20.8%), germacrene‐B (20.3%), trans‐
caryophyllene (13.5%), hexadecanal (12.8%), and methyl linoleat
(10.5%; Dastan, Pezhmanmehr, Askari, Ebrahimi, & Hadian, 2009).
Oils extracted from seeds were found to contain of
1α,2α‐epoxy‐17β‐hydroxyazadiradione, 1α,2α‐epoxynimolicinol, and
7‐deacetylnimolicinol along with known epoxyazadiradione, 17β‐
hydroxyazadiradione, gedunin, nimbin, and nimolicinol (Hallur et al.,
2002). It was established that root bark constituted different terpe-
noids such as nimblin and nimolinin (Ara et al., 1989b) whereas the
stem bark contained nimbonone, nimbinone, isonimbinolide,
nimbionone, nimbionol, and nimbonolone (Ara, Siddiqui, Faizi, &
Siddiqui, 1988, 1989a, 1989b; Siddiqui, Siddiqui, Faizi, & Siddiqui,
1989; Siddiqui, Siddiqui, Faizi, & Mahmood, 1988). Some other studies
revealed the presence of margocin, margocinin, margocilin, and
nimbidiol in the root bark (Ara, Siddiqui, Faizi, & Siddiqui, 1990;
Majumder, Maiti, Kraus, & Bobel, 1987). Heartwood of the tree also
contained a valuable bioactive, that is, 24‐methylenelophenol (Banerji,
Misra, & Nigam, 1987).
4 | FOLK MEDICINAL USES
Various parts of plants such as roots, flowers, and leaves are used to
treat a number of ailments in traditional systems of medicines
(Unani‐Tibb, Ayurveda, and Chinese) owing to the presence of bioac-
tives (Anwar et al., 2016; Ashraf, Muhammad, Hussain, & Bukhari,
2016; Muhammad, Hussain, Anwar, Ashraf, & Gilani, 2015; Muham-
mad, Hussain, Jantan, & Bukhari, 2016). According to the World
Health Organization (WHO, 2002), phytomedicines are trusted by
more than 80% of people around the globe. Oil extracted from seeds
has been used in cosmetics, soaps, toothpaste, and pest repellents.
Various parts of the tree are used to cure chicken pox, dermal prob-
lems, fever, headache, leprosy, constipation, respiratory problems,
rheumatism, and gastrointestinal (GIT) disorders (Benthal, 1933;
Biswas et al., 2002; Charles & Charles, 1992; Chopra et al., 1956;
Dastur, 1964; Drabu et al., 2012; Gul et al., 2012; Kirtikar & Basu,
1935; Kirtikar & Basu, 1975; Mitra, 1963).
Leaves of A. indica are used to treat eye problems, earache,
rheumatism, anorexia, wound healing, skin infections, blood contami-
nations, nose troubles, and GIT worms. Stomach pain and fever can
be relieved using the bark of the tree (Akbar et al., 2014; Joshi et al.,
2011; Maan, Yadav, & Yadav, 2017; S. L. Patil & Patil, 2007). People
used flowers to get rid of intestinal worms and suppress bile secretion
(Anon, 1988; Benthal, 1933; Biswas et al., 2002; Chopra et al., 1956).
Similarly, people used fruits to cure haemorrhoids, urinary infections,
diabetes, leprosy and wounds (Biswas et al., 2002; Gul et al., 2012).
The therapeutic applications of twigs included remedy from cough,
haemorrhoids, diabetes, tumor, spermatorrhoea, pyrexia, and urinary
tract obstacles (Biswas et al., 2002; Gul et al., 2012).
The gum obtained from the stem is applied on skin to heal
wounds, scabies and ulcers. The gum is also considered as tonic
and stimulant (Benthal, 1933; Charles & Charles, 1992). Traditionally,
folk practitioners applied seed pulp and oil to treat leprosy and
intestinal worms (Biswas et al., 2002; Chopra et al., 1956; Drabu
et al., 2012). In Sidha, preparation consisting of A. indica and papaya

1246
juice is used in India to treat dengue (V. P. Sharma, Ansari, & Razdan,
1993). The mixture of A. indica (2%) and coconut oils is applied on
skin to protect from mosquitoes and malaria (Sairam et al., 2000;
V. P. Sharma et al., 1993). Folk medicinal uses of the tree are
summarized in Table 2.
5 | P H A R M A C O L O GI CA L A T TR I B U TE S
Various clinical trials of A. indica have reported the medicinal impor-
tance of the tree. It has been revealed that biologically active primary
(carbohydrates, proteins, and fat) and secondary (alkaloids, polyphe-
nols, flavonoids, steroids, and terpenoids) metabolites are responsible
for the therapeutic potential of the tree (Ezuruike & Prieto, 2016;
Noor, Memon, & Sherwani, 2011; Saseed & Aslam, 2008; Vijayaram
et al., 2016).
5.1 | Antibacterial activity
It has been investigated that neem is rich in bioactives such assteroids,
sugars, triterpinoids, alkaloids, reducing sugars, tannins, flavonoids,
sesquiterpene lactones, and phenolic compounds (Tesso, Nisha, &
Kumsa, 2015; Boon, 2012;Vijayaram et al., 2016), which are responsi-
ble for the antibacterial properties of almost all parts of this magic tree
(Prashar, Pruthi, & Akhlaq, 2012; Priadarshini, Pankaj, Varma, & Kumar,
2013;Biswas et al., 2002; Chattopadhyay et al., 2009; Dhakal, Aryal,
Aryal, Bashyal, & Khadka, 2016; Neeta & Pankaj, 2016; Sinaga,
Ganesan, Kumar, Nair, & Gani, 2016; Aarati, Ranganath, Soumya,
Kishore, & Mithun, 2011). It has been revealed that methanolic, ace-
tonic, and aqueous extracts of leaves inhibited the growth of
Escherichia coli, Micrococcusluteus, Enterobacter, Bacillus subtilis, Pseu-
domonas aeruginosa, Klebsiellapneumoniae, Streptcoccuspyogens, and
Staphylococcus aureus when studied using agar well and disc diffusion
methods (Amin & Khan, 2011; Lall, Charan, & Bind, 2013; Salam,
TABLE 2 Folk medicinal uses of Azadirachta indica
Parts used Uses
Leaves Treatment of chicken pox, skin infections, cosmetics,
pest repellents, leprosy, intestinal infections,
respiratory disorders, constipation, and vegetables
Seeds Leprosy and GIT infections
Flowers GIT infections
Oil Cosmetics, pest repellents, leprosy, intestinal infections,
respiratory disorders, constipation, soaps,
toothpastes, and waxes
Bark Pain, malaria, cosmetics, pest repellents, leprosy,
intestinal infections, respiratory disorders,
constipation, stomachache
Twigs Pyrexia, increase in appetite, and teeth cleaner
Gum Healing of wounds, scabies, ulcer, tonic, and stimulant
Sap Cooling drink and stomach tonic
Whole tree Fever, headache, rheumatism, chronic syphilitic sores, ulcer,
skin disorders, and blood purification
Note. GIT = gastrointestinal.
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SALEEM ET AL.
Khokon, Baidya, & Mussa, 2014; Tirumalasetty, Basavaraju, &
Praveena, 2014; Vijayaram et al., 2016).
Crude extracts (chloroform, ethanol, and acetone) of leaves, roots,
and bark were found effective against multiple‐drug‐resistance bacte-
rial strains of E. coli and S. aureus when evaluated using well diffusion
method (Boon, 2012). Whole tree extracts (methanol and chloroform)
showed maximum antibacterial properties against Salmonella and Shi-
gella sp. at concentration of 2 mg/ml (Tesso et al., 2015). Methanolic
extracts of seeds also showed pronounced antimicrobial activity
(Y. Sharma et al., 2014). Crude methanolic extracts of stem, flowers,
leaves, and fruit displayed growth inhibitory effect against
Xanthomonas campestris (Britto, Hérin, & Gracelin, 2011).
Another study was focused on the detailed evaluation of antibac-
terial effects of the tree against several microbes such as P. aeruginosa,
Klebsiellaozaenae, S. aureus, Salmonella typhi, Proteus mirabilis, Salmo-
nella paratyphi B, and E. coli. Minimum inhibitory concentration (MIC)
and minimum bactericidal concentration were 5 and 50 mg, respec-
tively, for P. aeruginosa, K. ozaenae, S. aureus, and E. coli (Abalaka,
Oyewole, & Kolawole, 2012; Elkamali & Mahjoob, 2015). Hot water
and ethanolic extracts showed more prominent antibacterial potential
against S. aureus and E. coli than cold extracts (Dangana, Nasir, &
Egenti, 2016). Leaves extract dissolved in dimethylsulphoxide demon-
strated significant antimicrobial potential against Streptococcus
mutans, S. aureus, and Enterococcus faecalis (Mistry, Sanghvi, Parmar,
& Shah, 2014). In vitro antibacterial potential of A. indica or
Curcumalonga was evaluated in root canal against E. faecalis with stan-
dard drug, sodium hypochlorite (5%)/chlorhexidine (2%) using agar dif-
fusion method. No statistical difference was observed in antibacterial
activity of A. indica and sodium hypochlorite/chlorhexidine drug sug-
gesting it as significant alternative to the other root canal irrigants
(Sinha et al., 2017).
Crude extracts of seeds and bark inhibited growth of various
gram‐positive and gram‐negative bacteria (Coventry & Allan, 2001;
Garg, Perveen, Gupta, & Bajpai, 2015; Gul, Eraj, & Ashraf, 2015;
References
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002;
Kirtikar & Basu, 1935; Benthal, 1933; Anon, 1988
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002;
Kirtikar & Basu, 1935; Benthal, 1933; Dastur, 1964
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002;
Kirtikar & Basu, 1935; S. L. Patil & Patil, 2007
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002;
Benthal, 1933
Benthal, 1933; Charles & Charles, 1992
Benthal, 1933
Drabu et al., 2012; Chopra et al., 1956; Biswas et al., 2002;
Kirtikar & Basu, 1975; Charles & Charles, 1992; Mitra, 1963;
Gul et al., 2012

SALEEM ET AL.
Mandal, Mandal, & Pal, 2007; Orhue, Momoh, Igumbor, & Esumeh,
2014). Extracts of seeds, bark, fruits, and leaves were found effective
against adult mouth bacteria when studied using agar well diffusion
method (Yerima et al., 2012). Oil extracted from seeds exhibited
inhibitory effect on growth of numerous pathogens including fungi,
bacteria, and viruses (Susmitha et al., 2013; Thompson et al., 2013).
Combination of tree oil nanoemulsion and tween 20/water showed
antibacterial activity against Vibrio vulnifcus. The nanoemulsions also
caused toxicity by decreasing cellular viability of lymphocytes in
human beings when administered at a dose of 1.2–2.0 mg/ml (Jerobin
et al., 2015). Ethanolic extract (9%) of the seed oil showed high
antibacterial potential with zone of inhibition (24 mm) against E. coli
(Tambe, Pawar, & Deokar, 2016).
Moreover extract of flowers also showed bactericidal potential
against Bacillus cereus, S. aureus, Listeria monocytogenes, E. coli, and Sal-
monella infantis (Alzoreky & Nakahara, 2003). Several other studies
also confirmed the bactericidal effects of various extracts of A. indica
(Gajanan, 2012; Gnankalai & Gopap, 2016; Irshad, Butt, & Younus,
2011; Rajasekaran, 2008; Sapkota, Dasgupta, & Rawat, 2012; Singh,
Tripathi, Srivastava, Ali, & Rekhi, 2016; Thombre, Khadpekar, &
Phatak, 2012). The extracts from bark and leaves showed significant
antibacterial activity, which increased with increase in concentration;
however, seed and fruit extracts inhibited bacterial growth only at
higher concentrations in agar diffusion assay (Yerima et al., 2012). Var-
ious secondary metabolites (flavonoids, nimbolide, azadirachtin, etc.)
are responsible for antimicrobial and antioxidative potential of this
medicinal tree (Manach, Scalbert, Morand, Rémésy, & Jiménez, 2004;
Scalbert & Williamson, 2000). One of the potent antibacterial agents
present in leaves is nimbolide, which displayed results like a broad
spectrum antibiotic for B. subtilis, E. faecalis, S. epidermis, E. aerogene,
Enterobacter cloacae, and Salmonella typhimurium (Farooqui, Dey,
Singh, & Easwari, 2014).
It was discussed in the literature that polar extracts of the tree are
more antibacterial than nonpolar (Rajasekaran, 2008). The methanolic
extract of leaves showed antibacterial potential against multidrug‐
resistant bacteria, Vibriocholera, Phyllanthus emblica, and S. aureus
(Pandey et al., 2014; Thakurta et al., 2007;Haque et al., 2016; Tiwari,
Verma, Chakraborty, Dhama, & Singh, 2014; Dzulkarnain & Abdul‐
Rahim, 2014; Singh et al., 2016; Bole et al., 2010). The ethanolic
extract of leaves revealed its effectiveness against methicillin‐sensitive
and methicillin‐resistant S. aureus at concentration of 25%, 50%, 75%,
and 100% (Sarmiento, Wendy, Maramba, & Gonzales, 2011). Among
various polar and nonpolar extracts, methanolic and ethanolic extracts
were assessed effective against multidrug‐resistant clinical bacterial
isolates in agar well diffusion method (Dahiya & Purkayastha, 2012).
Synergistic effect of the tree with other plant's extracts such as
Psidium guajava, Camellia sinensis, and Calendula officinalis produced
more significant microbicidal effect against Pseudomonas spp., Vibrio
cholerae, Vibrio parahaemolyticus, Klebsiella sp., E. coli, Salmonella sp.,
and S. aureus (Farjana, Zerin, & Kabir, 2014).Similarly, P. guajava and
A. indica extracts showed higher antimicrobial activity against gram‐
positive bacteria as compared to gram‐negative bacteria except
V. parahaemolyticus, P. aeroginosa, and Aeromonas hydrophila. No sig-
nificant effects of temperature and pH were found on antibacterial
potential of extracts (Hoque, Inatsu, & Kawamoto, 2007).
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1247
A recent study showed that the antibacterial activity of ethanolic
extract of fresh leaves was prominent against E. coli, S. aureus, and
P. aeruginosa with 21‐, 16.5‐, and 10‐mm zones of inhibition, respec-
tively. It was investigated that extracts from fresh leaves inhibited
the bacterial growth more effectively than dry leaves (Azman, Sidek,
Sharudin, Halim, & Raja, 2016; Francine, Jeannette, & Pierre, 2015).
Ethanolic extract of leaves showed more significant MIC values than
twigs against methicillin‐sensitive S. aureus whereas MIC values were
comparable in case of E. coli (Ravi, Bharavi, Ravi Kumar, & Vamsi,
2015). It was reported that bactericidal potential of ethyl acetate
extract of leaves (100 μg/ml) was similar to the standard, ciprofloxacin
when evaluated against Campylobacter jejuni and Leuconostoc sp.
(Serrone & Nicoletti, 2013). MIC values of leaves extract were investi-
gated to be 6.25 and 12.5 mg/ml for P. mirabilis and E. faecalis, respec-
tively (Chaturved et al., 2011; Muhammad et al., 2015).
The growth of E. faecalis can be controlled more effectively by
aqueous extract of leaves than sodium hypochlorite (NaOCl) and pre-
scribed antibiotics (Damre, 2015; Gonmode et al., 2013; Hegde &
Kesaria, 2013). The combination of leaves extract with mucoadhesive
dental gel formulation (25 mg/g) had depicted reasonable antimicro-
bial potential against S. mutans and Lactobacilli species (Chava,
Manjunath, Rajanikanth, & Sridevi, 2012; Pai, Acharya, & Udupa,
2004). Similar results were obtained using bark and twigs of the tree
(Chaurasia, 2016; Geethashri, Manikandan, Ravishankar, & Shetty,
2014; Sundaram, Narayanan, & Vadakkepurayil, 2016). Moreover,
nonabsorbable A. indica oil chip (10%) showed significant antibacterial
properties against Porphyromonas gingivalis, a periodontal pathogen
(Vennila, Elanchezhiyan, & Ilavarasu, 2016).
Antibacterial potential of leaves was more pronounced against
S. aureus and E. coli than turmeric, tea leaves, pomegranate rind, and
myrobalan, dyes used in garment industry (Karolia & Khaitan, 2012).
The combination of aqueous leaves extract and Aloe gel was observed
to be an effective bactericidal against E. coli and S. aureus as compared
to Aloe gel and leaves extract alone (Khurshaid, Ayyoub, Asad, & Shah,
2015). Similar findings were reported for leaves extract of A. indica,
Camellia sinensis, and Maranta arundinacea (Sumathi, Thomas, &
Wesely, 2015). Herbal hand wash formulation of leaves extracts from
Ocimum sanctum, Aloe vera gel, Sapindus mukorossi fruit, A. indica,
Eucalyptus species, and citrus fruit was potently used for its antimicro-
bial properties against skin pathogens such as S. aureus, K. pneumonia,
and S. typhimurium. Among all herbal formulations, significant antimi-
crobial activity was noted for A. indica leaves extract (Kapoor, 2014;
Londhe, Kulkarni, & Lawand, 2015).
Silver nanoparticles synthesized from the extract of leaves
inhibited the growth of pathogenic bacterial strains such as
P. aeruginosa, S. typhi, S. aureus, and Streptococcus pyogenes
(Sarvamangala & Patil, 2014). Several studies conducted using metha-
nolic extracts of leaves showed potential antibacterial property against
Bacillus pumilus, P. aeruginosa, S. aureus, Candida albicans, Acacia
nilotica, Pseudomonas testosteroni, Staphylococcus epidermidis,
K. pneumoniae, B. subtilis, Proteus morganii, M. flavus, E. coli, and
S. typhimurium (Yehia, 2016; Jagtap & Chavan, 2016; Das, Chatterjee,
& Mandal, 2014; Ajayi, Omotoso, & Odejide, 2016; Nair, Kalariya, &
Chanda, 2009; Maragathavalli, Brindha, Kaviyarasi, Annadurai, &
Gangwar, 2012b; Chugh, Bharti, & Gupta, 2013; Gadien, karim,

1248
Elamin, & Ghada, 2015). Several previous studies also revealed the
antimicrobial potential of different parts of this magic tree (Akpata &
Akinrimisi, 1977; Almas, 1999; Badam, Joshi, & Bedekar, 1999;
Bhuiyan, Nishimura, Matsumura, & Shimono, 1997; Biswas et al.,
2002; Chopra et al., 1956; Fabry, Okemo, & Ansorg, 1998; Rao,
1987; Scalbert, 1991; Siddiqui et al., 1992). Thus, it can be concluded
from the above discussed literature that various extracts of the tree
can be used as potential antibacterial candidates against both gram‐
positive and gram‐negative bacteria. Moreover, different extracts can
also be used in combination with antibiotics against resistant bacterial
strains. Summary of antibacterial potential of leaves of A. indica is
shown in Table 3.
5.2 | Antifungal activity
Various studies carried out using extracts of leaves and oils disclosed
fungicidal properties of the tree (Kazmi, Shahzad, & Niaz, 1995;
Kleeberg, 1992; Locke, 1995; Mishra, Malik, & Tiwari, 1992; Mishra,
Parveen, Singhal, & Khan, 2005; D. Sharma, Lavania, & Sharma,
2009; Singh, Singh, & Singh, 1980). Among polar and nonpolar
extracts of leaves, stem, and fruits, chloroform and methanolic
extracts (polar) showed significant fungicidal potential against Rhizoc-
tonia solani (Bokhari et al., 2014). The seed extract also showed
fungistatic effect against Sphaerotheca fuliginea when incorporated
in growth medium (Coventry & Allan, 2001). It was also noted that
young leaves of 2–4 days age are more effective than old leaves
and twigs (Guleria & Kumar, 2006). Synergistic effect of polar
extracts of A. indica, Datura stramonium and Calotropis was effective
against Fusarium mangiferae and increased the floral yield in mango
trees (Usha et al., 2009).
Prominent reduction in the growth of Pleomorphomonas oryzae
was depicted by aqueous and ethanolic extracts of leaves and seed
oil. It was observed that seed oil showed maximum antifungal activity
followed by ethanol, cold water, and hot water extracts of leaves
(Amadioha, 2000). Seed‐borne fungi such as Aspergillus species and
Rhizopus were effectively controlled using alcoholic and aqueous
extracts of leaves (Mondali et al., 2009; Satish, Mohana, Ranhavendra,
& Raveesha, 2007). Plum fruits infected with Monilinia fructicola,
Penicillium expansum, Trichothecium roseum, and Alternaria alternata
were recovered with ethanolic extract of seed kernels (J. Wang, Jian,
Jiankang Cao, & Jiang, 2010). Seed oil of the tree inhibited the spore
germination and growth of Aspergillus (Niaz & Kazmi, 2005) and
A. alternata species (Paul & Sharma, 2002; Vir & Sharma, 1985). Mod-
erate antifungal activity was observed for oil extract against Aspergillus
fumigatus and Aspergillus niger when studied using disc diffusion
method (Bansod & Rai, 2008). Seed oil of the tree inhibited the growth
of A. niger, Aspergillus flavus, Fusarium oxysporum, Fusarium moniliforme,
Fusarium nivale, Fusarium semitectum, Drosophila hawiiensis, and
A. alternata more efficiently than oil extracts of Brassica campestris,
Nigella sativa, and Ferula assafoetida (Niaz, Sitara, Kazmi, & Qadri,
2008; Sitara, Niaz, Naseem, & Sultana, 2008). Seed‐borne infectious
diseases caused by Colletotrichome graminicola, Phoma sorghina, and
F. moniliforme were controlled by combined effect of Cymbopogon
citratus, Euclayptus camaldulensis, and A. indica essential oils (Somda,
Leth, & Sereme, 2007). Among various extracts, ethyl acetate extracts
10991573, 2018, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6076 by FUFSE - FUNDACAO UNIVERSIDADE FEDERAL DE SERGIPE, Wiley Online Library on [22/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SALEEM ET AL.
of leaves and fruits showed maximum fungicidal activity against
Alternaria solani followed by methanolic extract (Jabeen, 2013).
Ethanolic extracts of leaves and seed oil were applied to control
brown spot disease of rice caused by Cochliobolus miyabeanus. More-
over, oil extracts were observed more effective in controlling the dis-
ease (Amadioha, 2000).
Aqueous, ethanolic, and ethyl acetate extracts of leaves have
been used to control the human pathogens (A. flavus, A. fumigatus,
A. niger, Aspergillus terreus, C. albicans, and Microsporum gypseum) at
different concentrations. Ethyl acetate extract (20%) showed maxi-
mum inhibition against all human pathogens. High‐performance liquid
chromatography and NMR analysis of these extracts showed the pres-
ence of nimonol, which is thought to be responsible for such a high
antifungal activity (Mahmoud, Hassanein, Youssef, & Zeid, 2011). In
vitro application of A. indica and Nicotiana tabacum extracts showed
that N. tabacum exhibited fungitoxic effect that controlled the mycelia
growth on A. viridae and Penicillium digitatum. Extracts of A. indica led
to progressive decrease in fungal growth in concentration‐dependent
manner (Suleiman, 2011). Dry seed extracts of the tree also showed
complete inhibition of F. oxysporum growth at different concentrations
(Agbenin & Marley, 2006). Inhibition of growth of different fungi by
A. indica has also been reported in several earlier studies (Al–Abed,
Qasem, & Abu–Blam, 1993; Amadioha, 1998; Amadioha, 2003; Bhatti,
1986; Bhowmick & Vardhan, 1981; Ghewande, 1989; Govindachari
et al., 2000; Khan & Kumar, 1990; Krishna, Prasad, & Ojha, 1986;
Mirza, Hameed, Ahmad, Ayub, & Strang, 2000; Nicolls, 1970; Nwosu
& Okafor, 1995; Paul & Sharma, 2002; Qasem & Abu–Blam, 1996;
Shekhawrat & Prasada, 1991; Sinniah & Baskaran, 1981; Suresh,
Narasimhan, Masilamani, et al., 1997; Tewari & Nayek, 1991). It
becomes unambiguous from the literature that plant‐based extracts
can be used for the management of various pathogenic fungi and
development of commercial antifungal formulations. Table 4 summa-
rizes the role of different parts of A. indica used to inhibit fungal
growth.
5.3 | Pesticidal, insecticidal, antifeedant, nematicidal,
molluscicidal, and larvicidal activities
Natural pesticides are eco‐friendly, biodegradable, and safe to
nontargeted pests. One such type of biopesticides was based on
azadirachtin derived from the tree for its diverse insecticidal (Ahmed
& Grainge, 1986; Bhowmik, Chiranjib, Yadav, Tripathi, & Kumar,
2010; Debashri & Tamal, 2012; Isman, 1997; Mulla & Su, 1999;
Vendramim & Castiglioni, 2000; Waquil, Villela, & Foster, 2002),
antifeedant, toxicologically repellent, sterility inducing, and insect
growth‐inhibiting (Gahukar, 2000) properties. Nano‐gum (10 ppm)
prepared from A. indica gum was investigated as a new generation
of biopesticides, which is effective against Helicoverpa armigera
(Hub.) and Spodopteralitura (Fab; Kamaraj et al., 2017). Azadirachtin,
extracted from the seeds, showed direct toxic effects on cells and
tissues of the pests via endocrine system (Bilton et al., 1987;
Butterworth & Morgan, 1968; Feng & Isman, 1995; Immaraju, 1998;
Kraus et al., 1987; Kreutzweiser, Capell, & Scarr, 1999; Maredia,
Segura, & Mihm, 1992; Mordue et al., 1998; Prates, Viana, & Waquil,
2003; Turner et al., 1987; Vendramim & Castiglioni, 2000).
 10991573, 2018, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6076 by FUFSE - FUNDACAO UNIVERSIDADE FEDERAL DE SERGIPE, Wiley Online Library on [22/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SALEEM ET AL. 1249

TABLE 3 Antibacterial potential of leaves of Azadirachta indica

Microorganisms used
Nature of extract Gram‐positive Gram‐negative ZOI (range) Standard drug References
Methanolic X. campestris 29.20 ± 0.47 mm Neomycin and Britto et al., 2011
Kanamycin
B. cereus, B. subtilis, S. typhimurium – Kanamycin Yehia, 2016
Listeria, Monocytogenes, and E. coli Chloramphenicol
S. aureus, C. perfringens, Specillin G
and M. luteus Ampicillin
S. aureus and S. pyogens E. coli, P. aeruginosa, 7–14 mm – Vijayaram et al., 2016
and K. neumoniae,
S. aureus and E. coli and K. pneumonia 14–20 mm Amikacin Tirumalasetty et al., 2014
P. aeruginosa Augmentin
S aureus, E. faecalis, andS. mutans 11–24.67 mm 2% Chlorhexidine Mistry et al., 2014
gluconate
Ethyl acetate Leuconostoc C. jejuni 11.33–22.67 mm Ciprofloxacin Serrone & Nicoletti, 2013
Ethanolic E. faecalis and P. mirabilis, E. coli, 7.5–15.8 mm Erythromycin, Mohamed & Omer, 2015
S. aureus P. aeruginosa, and ciprofloxacin,
K. pneumonia ceftriaxone, and
gentamycin
S. aureus E. coli ‐ Ciprofloxacin Ravi et al., 2015
S. aureus 6–14 mm oxacillin Sarmiento et al., 2011
vancomycin
povidone iodine
mupirocin
S. aureus E. coli and P. aeruginosa 10–21 mm Ampicillin Azman et al., 2016
Streptococci, Staphylococci, Bacilli, M. bacilli 0–30 mm 5.25% Sodium Sundaram et al., 2016
Lactobacilli, and Enterococci hypochlorite
Aqueous B. anthracis E. coli 35–50 mm Streptomycin Jagtap & Chavan, 2016
S aureus, E. faecalis – – Geethashri et al., 2014
Acetone and S. aureus P. aeruginosa 10.50–28 mm Gentamycin Ajayi et al., 2016
ethanolic
Polar and S. aureus and E. coli and P. aeruginosa 15–22 mm Ciprofloxacin Prashar et al., 2012
nonpolar extracts B. subtilis
Pure ethanolic, B. subtilis, S. aureus, P. aeruginosa, S. typhi, 0–4 mm Ampicillin Irshad et al., 2011
acetonic, and and S. epidermitis Pseudomonas, and
methanolic K. pneumoniae,
Petroleum and B. subtilis E. coli, P. vulgaris, 5–14 mm Gentamycin Priadarshini et al., 2013
chloroform P. aeruginosa,
S. typhimurium, and
K. pneumonia
Ethanolic, aqueous, B. cereus 12–18 mm – Rajasekaran, 2008
petroleum ether,
chloroform, and
dichloromethane
Pure nimbolide B. subtilis, E. faecalis, E. aerogene, E. cloacae, 17.3–18.1 mm Ciprofloxacin Farooqui et al., 2014
and S. epidermis and S. typhimurium
S. aureus E. coli, P. aeruginosa, 5–16 mm Ciprofloxacin Amin & Khan, 2011
Enterobacter, and Streptomycin
K. pneumonia
Oil, aqueous, and S. aureus Pseudomonas species, 10–11 mm – Farjana et al., 2014
methanolic V. cholera,
V. parahaemolyticus,
Klebsiella species,
E. coli, and Salmonella
Methanolic and S. aureus and E. coli, P. aeruginosa, 12–23 mm Gentamycin Maragathavalli et al.,
ethanolic B. pumilus and S. typhimurium, 2012b

Azadirachtin inhibited cell division and protein synthesis, which
resulted in flaccid paralysis of muscles, midgut cells necrosis, loss of
nidi (regenerative cells), and lack of midgut enzyme production
(Mordue & Nisbet, 2000; Nisbet, Luntz, & Mordue, 1995; Nisbet,
Woodford, & Strang, 1996, 1998).
Azadirachtin's direct (0.35 and 1.28 mg/L) and indirect (0.3–
0.99 mg/L) effects were evaluated against Culex pipien and were
observed that adult mosquito fecundity was significantly reduced with
increase in Culex's sterility and larval developmental stage (Alouani,
Rehimi, & Soltani, 2009). Pesticides based on A. indica showed efficacy
by reducing detoxificating enzymes (Lowery & Smirle, 2000) or break-
ing resistant compounds (Trisyono & Whalon, 2000). Depending upon
the resistance mechanism, pesticides may affect blockage of enzyme
production or reduce midgut cell turnover rate (Boadu, Tulashie,
Anang, & Kpan, 2011; Nasiruddin & Luntz, 1993).
Various chromatographic and spectroscopic techniques (GC‐
13
EIMS, C‐NMR, UV, and FTIR) revealed the presence of 27 com-
pounds responsible for enhanced pesticidal properties of fruit coating
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1250 SALEEM ET AL.

TABLE 4 Antifungal potential of various parts of Azadirachta indica

Parts used Nature of extract Microorganisms used References

Leaves Aqueous P. arachidis and M. berkeleyi Ghewande, 1989
Wheat seed mycoflora Khan & Kumar, 1990
D. graminea Paul & Sharma, 2002;
B. haptosporus, B. ranarum, A. fumigatus, G. candidum, Nwosu & Okafor, 1995
and C. albicans
P. Oryzae Amadioha, 2000
Methanolic P. arachidis Suresh, Narasimhan,
Masilamani, et al., 1997
A. solani Jabeen, 2013
Leaf decoction D. graminea Bhatti, 1986
Alcoholic and aqueous Aspergillus and Rhizopus species Mondali et al., 2009
Seeds Ethanol and aqueous C. lindemuthianum Amadioha, 1998
Ethanolic M. fructicola, P. expansum, T. roseum, and A. alternata J. Wang et al., 2010
Crude seed extract F. oxysporum Agbenin & Marley, 2006
Seed oil Aqueous seed oil P. Oryzae Amadioha, 2000
Essential oil Aspergillus species Paul & Sharma, 2002
Aqueous seed
Seed oil A. fumigatus and A. niger Bansod & Rai, 2008
Acetone and n‐hexane A. niger, A. flavus, F. oxysporum, F. moniliforme, Sitara et al., 2008;
F. nivale, F. semitectum, D. hawiinesis, and A. alternata Niaz et al., 2008
Ethanol/oil C. miyabeanus Amadihoa, 2001
Fruit Methanol A. solani Jabeen, 2013
Whole tree Whole tree decoction P. infestans Mirza et al., 2000
Aqueous, ethanol, ethyl acetate A. flavus, A. fumigatus, A. niger, A. terreus, Mahmoud et al., 2011
C. albicans, and M. gypseum
Methanolic A. viridae and P. digitatum Suleiman, 2011
Aqueous Aspergillus species Satish et al., 2007

than seed extracts (Ascher, 1993; Tariq, Naqvi, Siddiqui, Rasheed, &
Faizi, 2001). Azatin killed Hypsipyla grandella larvae by direct toxicity
whereas Nim 80 disrupted growth at 1.0, 3.20 and 10% concentra-
tions (Mancebo, Hilji, Mora, & Salazar, 2002). The extracts of kernels
and leaves in polar and nonpolar solvents were observed fruitful in
agriculture against Bemisia tabaci, Amblyomma cajennense, Plutella
xylostella, Boophilus microplus, and Acarina (Williams & Mansingh,
1996). Various control/control mosquitoes and flies (Maragathavalli,
Brindha, Kaviyarasi, Annadurai, & Gangwar, 2012a; Rembold & Peter,
1981; Rochanakij & Thebtaranonth, 1985; Schmutterer, 1990). Oil
extract (10%) and aqueous suspension of seeds showed significant
mortality of Coleomegilla maculata as compared to malathion (Roger,
Vincent, & Coderre, 1995).
Leaves extracts of the tree and azadirachtin displayedsignificant
effects on soil microorganisms and plant growth‐promoting
rhizobacteria. Administration of leaves extracts (0.1 and 0.4 g/ml)
and azadirachtin (1.25 and 2.5 μg/ml) inhibited in vitro activity of soil
growth‐promoting rhizobacteria. Two months treatment of soil with
azadirachtin reduced number of microorganisms in soil whereas leaves
extracts enhanced both soil microorganism and rhizosphere's activities
(Sarawaneeyaruk, Krajangsang, & Pringsulaka, 2015). Growth
disrupting effect of seed extracts in water and organic solvents was
observed at imaginai stage of Aedes aegypti larval development. The
effectiveness of the extracts for prolongation of larval period
increased with decrease in polarity of solvents (Zebitz, 1984).
NeemAzal, a commercial insecticide based on A. indica extracts,
was tested against Rhyzopertha dominica, Sitophilus oryzae, and
Tribolium confusum in rye, whole, and peeled oats at concentrations
of 50, 100, and 200 ppm of azadirachtin for 1, 2, 7, and 14 days.
The treated substrates were kept at the same condition for additional
45 days. The tested grains showed increase in mortality rate of insects
with increase in concentration and exposure time, except for
T. confusum on whole and peeled oats (Athanassiou, Kontodimas,
Kavallieratos, & Veroniki, 2005). Susceptibility test of Chrysoperla
carnea was observed for azadirachtin, diflubenzuron, pyriproxyfen,
and tebufenozide at different dosage frequencies in laboratory.
Results showed that pyriproxyfen and tebufenozide were ineffective
against C. carnea, whereas azadirachtin and diflubenzuron were effec-
tive at a dose of 24.5 and 6.9 mg per insect, respectively (Medina,
Budia, Tirry, Smagghe, & Vinuela, 2001). Aqueous extract (10%) of rip-
ened seeds prevented the attack of termites on cassava and melon
plants or cassava tubers (Umeh & Ivbijaro, 1999).
Extracts of seed kernels and leaves in methanol–chloroform mix-
ture showed substantial insecticidal activity and morphogenic effect
against H. armigera (Jaglan, Khokhar, Malik, & Singh, 1997). Sodium
dodecyl sulphate‐poly acrylamide gel electrophoresis of A. indica
treated third and fourth instar larvae of H. armigera exhibited the
suppression of head polypeptide up to 22, 26, 40, and 56 kDa with
alteration of polypeptide pattern in dose‐dependent pattern (Neoliya,
Dwijendra, & Sangwan, 2007). Biological activity of 6β‐hydroxygedunin
separated from A. indica was assessed against H. armigera and
Spodoptera litura alone or in combination with other limonoids
(gedunin, salannin, nimbinene, and azadirachtin) in artificial diet assay.
Growth inhibitory effect was observed with 24.2 and 21.5 ppm of 6β‐
hydroxygedunin and in combination with other limonoids, respectively.
This study revealed the potential of nonazadirachtin limonoids via two
different action modes, feeding deterrence and physiological toxicity of
various insects (Koul, Multani, Singh, Daniewski, & Berlozecki, 2003).
Extracts of A. indica and malathion reduced the population of
Macrosiphum euphorbiae, Myzus persicae, and Nasonovia ribisnigri under
greenhouse conditions (Fournier & Brodeur, 2000). Insecticides based
on A. indica retarded the growth of pathogen, Erysiphe pisi, and

SALEEM ET AL.
enhanced the intercellular protein concentration due to elevated
activity of phenylalanine ammonia lyase when evaluated in detached
leaves and intact plant of Pisum sativum (Singh, Pandey, Guddewar,
& Malik, 1997). Grains of maize treated with Plectranthus glandulosus
powder and A. indica seed powder showed low mortality rate of
Sitophilus zeamais as compared to A. indica seed oil. Significant reduction
in progeny emergence was observed for A. indica than P. glandulosus
extracts (Nukenine, Tofel, & Adler, 2011). Synergistic effect of
azadirachtin‐based insecticide, especially A. indica seed extract or com-
mercially available 5% NeemAzal T with S. feltiae was an integrated
approach for controlling B. zonata in field trials (MahMoud, 2007).
Comparative analysis of various bio‐insecticides (A. indica and
Gliricidia sepium based) for their damage to crop, growth inhibition,
and crop yield was evaluated in maize crop. Crop yield was higher in
A. indica treatment, but shoots of maize were more affected by
G. sepium‐based insecticide (Montes–Molina et al., 2008). Biopesti-
cides derived from aqueous leaves extract of Melia azedarach and
A. indica enhanced the mortality rate ofCotesia plutellae and Diadromus
collaris (Charleston, Kfir, Dicke, & Vet, 2005). Evaluation of A. indica‐
based insecticides against Liriomyza huidobrensis (pea leaves miner)
revealed that reduction in pupal development and adult eclosion was
more significant in soil drenching than leaves dipping techniques
(Weintraub & Horowitz, 1997). In another investigation, extracts of
seeds controlled the growth of Callosobruchus maculatus, Sitophilus
oryzae, and Cylas puncticollis more effectively than leaves extracts in
maize (Makanjuola, 1989).
In Nigeria, various extracts of neem are applied to control brown
cocoa mirids (Sahlbergella singularis), the most damaging insect for
development of cocoa prospects (Asogwa, Ndubuaku, Ugwu, & Awe,
2010). Synchronization of commercial insecticides derived from
A. indica such as Agroneem, Ecozin, and Neemix with noncommercial
A. indica leaves powder reduced survival of eggs and larvae of
Spodoptera exigua (Greenberg, Showler, & Liu, 2005). In field trials,
aqueous extracts of seeds and leaves reduced the population of
Megalurothrips sjostedti in cowpeas with increased yields. These
extracts showed adverse effects on biology of Maruca testulalis
(Ivbijaro, 1990; Tanzubil, 1991). The extract of seeds in methanol
(5%) was effective in cowpea pest management because it delayed
the flowering time (Egho & IIondu, 2012).
Antifeedant properties of seed oils depicted significant
deterrential effectson H. abietis when studied in field and laboratory
trials (Thacker, Bryan, McGinley, Heritage, & Strang, 2003). NeemAzal,
insecticide based on A. indica extracts, affected the emergence of
adult parasitoids of Trichogramma cacoeciae when studied in hosts
such as S. cerealella and C. pomonella at 1.33 ppm of active ingredient
per milliliter (Saber, Hejazi, & Hassan, 2004). Antifeedant activity of
Z. subfasciatus against P. vulgaris seeds treated with hydroalcoholic
extract of A. indica leaves enhanced insect's inability of ingestion along
with loss of appetite. However, the extract produced negative effects
on growth and germination of seeds in concentration‐dependent man-
ner (El‐Aswad, Abdelgaleil, & Nakatami, 2004; Silva, Crotti, & Cunha,
2007). Various earlier reports also confirmed the pesticidal or
antifeedant properties of various extracts or pure compounds isolated
from A. indica (Adhikary, 1985; Jilani & Sexena, 1990; Kearney, Allan,
Hooker, & Mordue, 1994; Shin–Foon & Yu–Tong, 1993).
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1251
A. indica oil and extracts of different parts (leaf, seed, flower, bark,
etc.) displayed significant nematicidal properties when studied against
root dips and seed treatments (Akhtar, 2000). Ethyl acetate and
ethanolic extracts of the tree were explored against Haemonchus
contortus eggs and larvae at doses of 0.19, 0.78, 3.12, 12.5, and
50 mg/L. It was observed that ethyl acetate extract (50 mg/L) retarded
egg hatching (51.31%) and larval development (68.10%) whereas
ethanolic extract inhibited egg hatching (99.77%) and larvicidal activity
(87.11%) at 3.12‐ and 50‐mg/L concentrations, respectively (Costa
et al., 2007). The nematicidal–nematostatic activity of azanema and
azadirachtin (1%) was investigatedagainst Meloidogyne incognita. Nem-
aticidal/‐nematostatic potential of azadirachtin was very low even at
recommended or higher doses as compared to Azanema (Ntalli,
Menkissoglu–Spiroudi, Giannakou, & Prophetou–Athanasiadou,
2009).
Azadirachtin protected the ash trees by inhibiting larval develop-
ment and adult emergence of emerald ash borer (Arnason, Philogene,
Donskov, & Nozzolillo, 1985; Ley et al., 1989; Mckenzie et al.,
2010). Seed oil (Okumu, Knols, & Fillinger, 2007) and fresh flower
extract of the tree in n‐hexane possessed larvicidal properties against
A. stephensi. Therefore, it can be effectively used as anti‐malarial agent
in treatment of malaria. GC‐EIMS analysis of flower's extract revealed
thepresence of five sesquiterpenes, three aromatics, seventeen fatty
acids, five fatty acid esters, three steroids and eight hydrocarbons
(Siddiqui et al., 2009).
In field trials, it was noticed that seed extracts of the tree are bet-
ter pest controller than pyrethrum used by organic farmer (Isman,
Koul, Arnason, Stewart, & Salloum, 1991). Various extracts of seed
kernels exhibited toxicity against mites such as Phytoseiulus persimilis,
Athias‐Henriot and Tetranychus cinnabarinus (Mansourv, Ascher, &
Omari, 1987). Aqueous extract of whole tree and its seed kernels
showed larvicidal effect against A. aegypti at 2 and 8 mg/L after
24 hr. The extractinhibitednymph and adult's emergency owing to
damage on the epithelial columnar cells, perturbation of alimentary
flow, beginning of vacuolization at apical level and bursting posterior
cells of gut. Therefore these extracts can be effectively used as anti‐
malarial agents (Khalid, Duddect, & Gonzalez–Sierra, 1989; Ndione,
Faye, Ndiaye, Dieye, & Afoutou, 2007).
Application of seed extracts reduced the population of
Dendroctonus ponderosaeby decreasing larval densities at dosage
greater than 0.25 g (azadirachtin) per tree (Nauman, Rankin, & Isman,
1994). AZT, NeemAzal and azadirachtin when applied at 1‐μg/ml dose
rate, produced larvicidal effects and delayed development of surviving
larvae with no morphogenetic abnormalities in P. xylostella (Verkerk &
Wright, 1993). Various concentrations of seed oil (1.0, 94 and 100%)
decreased the survival of adult M. persicae and N. ribis‐nigri signifi-
cantly when applied to leaves discs of lettuce (Lowery & Isman, 1995).
Longevity of M. fimbriolataalong with morphological and physio-
logical changes in the eggs was controlled by aqueous seed extracts
(Garcia, Grisoto, Vendramim, & Botelho, 2010). Effect of A. indica oil
(0.006, 0.05 and 0.4%) on survival and development of S. frugiperda
caterpillars was witnessed to cause mortality at dose of 0.4%. More-
over, degeneration of epithelial lining of midgut and peri‐trophic
matrix was observed at all concentrations (Roel et al., 2010). Methano-
lic extract of A. indica exhibited larvicidal activity against A. stephensi

1252
after 24 (LC50 15.25 ppm; LC90 46.79 ppm) and 48 hr (LC50
12.70 ppm; LC90 45.56 ppm) intervals for each concentration. The
results showed that methanolic extract was more potent larvicidal
than synthetic insecticides (Batabyal, Sharma, Mohan, Maurya, &
Srivastava, 2007).
A. indica based insecticide was investigated against A. stephensi
(0.35 and 1.81 mg/L) and C. quinquefasciatus (0.69 and 3.18 mg/L) in
laboratory and field trials. Pupal mortality was significantly higher with
prevention of adult emergence of larvae (Vatandoost & Vaziri, 2004).
Comparative larvicidal activity of ethereal leaves extracts of A. indica,
O. gratissimum and H. suavoelens was studied against Culex mosquito
in laboratory. Mortality rate observed for A. indicawas 100%, more
than O. gratissimum and H. suavoelens extracts (Okigbo, Okeke, &
Madu, 2010). Azadirachtin applied at low concentration to roots of
Brassicanapus sub sp napus enhanced the mortality with decreased
longevity and fecundity of cabbage aphid at the stage of ecdysis in
concentration dependent manner (Pavela, Barnet, & Kocourek, 2004).
Artemisia annua and A. indica leaves extracts in ether and n‐hex-
ane were collected by cold, reflux and soxhlet extractions for investi-
gating their larvicidal activities against A. stephensi. In case of
A. indica, crude extracts obtained by soxhlet showed 100% mortality
(after 48 hr) at 250 ppm whereas reflux extracts didn't causeany con-
siderable mortality at 250 ppm (Tonk, Bartarya, Kumari, & Srivastava,
2006). Ethanolic extracts from ripened fruit kernels of Melia azedarach
and A. indica were analysed against larvae of A. aegypti in temperature
variation model. Howeverat 30.8°C, it was increased to 100% for
A. indica extracts (Wandscheer et al., 2004). Amalmagation of
petroleum ether extracts of A. indica, Pongianaglabra and Annona
squamosa seedskilled the larvae of Culex quinquefaciatus, A.stephensi
and A.aegypti more significantly thanA. indica alone (George &
Vincent, 2005).
Significant molluscicidal effect of various extracts (leaves, cake,
oil, bark) and A. indica based pesticides (achook and nimbecidine)
was noticedagainst Lymnaea acuminata and Indoplanorbis exustus in
time and dose‐dependent manner (Singh, Singh, & Singh, 1996). It
was discovered that extracts of the bark, root and leaves were found
active against L. aurora at dose of 500 mg/kg after 48 hr. However
extracts caused mortality of A. marginata atdose of 700 mg/kg
after72 hr (Ebenso, 2003).
Water, methanol and ethyl acetate extracts of Entada leptostachya
and A. indica exhibited molluscicidal, cercericidal and miracicidal activ-
ities against Biomphalaria pfeifferi, Schistosoma mansoni cerceriae and
miracidia. Niclosamide was used as positive control. Results showed
that only methanolic extract of E. leptostachya and aqueous extract
of A. indica were found to have cercericidal and miracicidal activities
(Michael, Musila, Kutima, & Kareru, 2013). The molluscicidal effect of
aqueous extract of leaves was reasonable and caused mortality
ofLymnaea auricularia and I. exustusafter 96 and 72 hr, respectively.
Similarly, bark and whole tree extracts were investigated to
havesignificant molluscicidal activity (Alam, Kaur, Singh, Haque, &
Rath, 2011). Methanolic extract of whole tree was more effective
againstL. auricularia and I. exustusfollowed by seed, leaves and bark
extracts (Alam et al., 2011).
In another study, it was disclosed that aqueous extracts of A. indica
is more efficient as a mollusicidal agent than Aloe secundiflora, Aspilia
10991573, 2018, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6076 by FUFSE - FUNDACAO UNIVERSIDADE FEDERAL DE SERGIPE, Wiley Online Library on [22/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SALEEM ET AL.
pluriseta, Balanites aegyptiaca, and Amaranthus hybridus (Mwonga,
Waniki, Dorcas, & Piero, 2015). Azadirachtin extracted from the seeds
increased the mortality rate of golden apple snail depending upon con-
centration and polarity of solvent (Massaguni & Latip, 2015). It can be
concluded that extracts of the tree can act as cost‐effective pesticides
to get rid of pests. This eco‐friendly management of pests will surely
add to the economy of the country. These cheaper extracts will prove
fruitful for the eradication of different larvae and treatment of various
infections.
5.4 | Antileishmaiases and anthelmintic activities
The leishmaniases are a parasitic disease caused by Leishmania. Differ-
ent extracts of A. indica (leaves, seeds, flowers, and fruits) exhibited
prominent antileishmaiases activity. Ethanol, dichloromethane, and
aqueous extracts of leaves and seeds exhibited in vitro activity against
promastigotes and Leishmania amazonensis. Ethanolic extract was effi-
cient against leishmaniases with minimal cytotoxic effects (Carneiro,
2012). Crude powder and aqueous extracts of seeds administered
(1–3 g/kg of body weight) to sheep infected with GIT nematodes
showed significant anthelmintic activity at higher concentration (Iqbal
et al., 2010). Thus A. indica may be the potential candidate for the
treatment of parasitic‐based cutaneous and infectious diseases after
more careful investigations using animal models and volunteers.
5.5 | Antidiabetic activity
Diabetes mellitus (DM) is a chronic metabolic disorder, which is char-
acterized by hyperglycemia, hyperlipemia, negative nitrogen balance,
glycosuria, dyslipidemia, and ketonemia. DM enhanced the peripheral
resistance to insulin action and is associated with blindness, kidney
failure, cardiovascular, and nervous disorders (Hafeel & Suma, 2003;
Szkudelski, 2001). Around the globe, people (80%) prefer herbal treat-
ment for diabetes due to lesser side effects (Jackson & Bressler, 1981;
Halim, 2003; Nishan & Subramanian, 2014;Ezuruike & Prieto, 2016).
Various parts of A. indica had been actively used for hypoglycemic
or antihyperglycemic activities (Alzohairy, 2016; Nagashayana,
Jagadeesh, & Revankar, 2014; P. Patil, Patil, Verma, & Adake, 2011;
Shori & Baba, 2011). The possible mechanism for antidiabetic activity
of the tree is the elevated production of insulin (Singh, Singh, Geroge,
& Joseph, 2010) or inhibition of epinephrine action on glucose metab-
olism, resulting in increased utilization of peripheral glucose
(Chattopadhyay, 1996; Chattopadhyay, Chattopadhyay, Nandy,
Podder, & Maitra, 1987). It was inspected that active phytochemicals,
for example, azadirachtin present in seeds and leaves are helpful in
delaying or preventing onset of disease (Kar, Choudhary, &
Bandyopadhyay, 2003; Khosla, Bhanwra, Singh, Seth, & Srivastva,
2000; Atangwho et al., 2009; Arika, Nyamai, Agyirifo, Ngugi, & Njagi,
2016; Tiwari & Rao, 2002;Semwal, Gupta, Singh, Kumar, & Giri, 2009).
Ether extracts of seed kernels and husk of A. indica showed deter-
rence effect on oxidative stress when investigated in streptozotocin
(STZ) induced diabetes in rats. Serum creatine phosphokinase
increased in diabetic rats was significantly decreased by treatments
with above said extracts. Increase in activity of superoxide dismutase
(SOD) and catalase (CAT) during lipid peroxidation (LPO) of red blood

SALEEM ET AL.
cells was regained in diabetic rats after insulin treatments, but this was
not observed with extracts of A. indica. This study provided another
proof that A. indica extracts can prevent onset of hyperglycemia.
Therefore, A. indica provides double protection against diabetes.
Moreover, there was significant improvement in SOD, CAT, and LPO
profile, which protected from cardiac damage (Gupta, Kataria, Gupta,
Murganandan, & Yashory, 2004).
Another study focused on DM type II concluded that powder, and
aqueous and ethanolic extracts of seeds when administered at high
dose of 2 g thrice a day showed significant antidiabetic activity
(Waheed, Minana, & Ahmad, 2006). Ethanolic extracts of leaves even
at very low concentrations (10–100 μg/ml) exhibited maximum inhib-
itory effect on α‐amylase activity (Chattopadhyay, 1999;
Dineshkumar, Analava, & Manjunatha, 2010; Gholap & Kar, 2004).
Similarly, ethanolic extract (500 mg/kg) of leaves lowered the blood
glucose with improved pancreatic β cells in STZ‐induced diabetic rats
(Akinola, Martins, & Dini, 2010). Likewise, aqueous extract of leaves
possessed hypoglycemic effect, which was observed by determination
of glucose level in the normoglycemic medium in human blood cells
(Martínez et al., 2014). Another study showed that administration of
ethanolic extract of leaves (1 g/kg) significantly reduced the elevated
blood glucose level by 36.91% in glucose‐loaded rats and 30.20% in
alloxan induced diabetic rats (Akter, Mahabub–Uz–Zaman, & Rahman,
2013).
Some studies showed synergistic effects of A. indica when
administered with other plants. The comparative effect of A. indica
and Spirulina leaves extracts in alloxan induced diabetic mice
revealed the increment in leukocytes showing antidiabetic properties
(Akter, Rahman, Mostofa, & Chowdhury, 2014). Later on, mixed
powder of leaves from Moringa olifera and A. indica showed antidia-
betic potential (Kumari, 2010; Ojiako & Chikezie, 2014). Chloroform,
methanolic, and aqueous extracts of A. indica and Bougainvillea
spectabilis also showed enhanced glucose tolerance and glucose‐6‐
phosphate dehydrogenase activity with reduced intestinal glucosi-
dase activity. Regeneration of insulin‐producing cells and consistent
rise of plasma insulin and C‐peptide levels were observed on treat-
ment with combinations of A. indica chloroform and B. spectabilis
aqueous and methanolic extracts (Bhat, Kothiwale, Tirmale,
Bhargava, & Joshi, 2011).
In continuation of antidiabetic study of A. indica in STZ‐induced
DM, another investigation was carried out to elucidate the effect of
hyperglycemia on cardiovascular diseases. Literature showed that
leaves extract of the tree reduced total cholesterol (low‐density lipo-
protein cholesterol and very low‐density lipoprotein cholesterol, total
lipids, and triglycerides) in serum; however, high‐density lipoprotein
(HDL) cholesterol levels remained unchanged (Chattopadhyay &
Bandyopadhyay, 2005). This and some other studies further indicated
that A. indica extracts (250 mg/kg, 16 weeks) not only treat diabetes
but also protect heart by improving several parameters of lipid profile
(Das, Mostofa, Hoque, Das, & Sarkar, 2010; Halim, 2002). Hypoglyce-
mic activity of seed oil is significant at a dose of 2.5 ml/kg; however,
the effect reduced with increase in concentration (Khosla et al.,
2000). Another study on seed oil showed significant reduction in
blood glucose levels along with improved glucose tolerance in rats
(Nagashayana et al., 2014).
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1253
Root bark (P. Patil, Patil, Mane, & Verma, 2013), flowers (Jayasree
et al., 2013), and fruit extracts (Rao, Madhuri, & Prasad, 2012) have
also shown antidiabetic potential in rat models; however, their activity
is relatively less than that of leaves extracts. In another study, diabetic
rats were treated with diabetic control saline, bitter leaves extract in
combination with A. indica tree, A. indica extract, bitter leaves extract,
and chlorpropamide for 24 days. Percentage reductions in blood glu-
cose as compared to their initial values at the end of treatment were
71.05%, 44.95%, 88.63%, and 75.83% for combined extract (A. indica
and bitter leaves), A. indica, bitter leaves, and chlorpropamide, respec-
tively (Ebong, Atangwho, Eyong, & Egbung, 2008). This enhanced
activity was due to synergistic effects of aforesaid extracts (Halim,
2002). Atangwho, Ebong, Egbung, Akpaso, and Asuquo (2010) studied
the synergism of aqueous extracts of Vernonia amygdalina and A. indica
protected from diabetes induced liver damage and might exert its
antihyperglycemic action by induced islet cell regeneration (Atangwho
et al., 2010). Likewise, aqueous extract of powder roots and leaves of
A. Augusta and A. indica (200‐mg/kg body weight) administered to
alloxan diabetic rats once a day for 8 weeks resulted in substantial
lowering of blood glucose, serum lipids, and formation of LPO as esti-
mated by thiobarbituric acid reactive substance test and increased
antioxidants (SOD, CAT, glutathione peroxidase, and glutathione
transferase) in erythrocytes. There was significant reduction in LPO
in the heart, liver, kidney, and muscles of diabetic rats after treatment
with A. indica aqueous leaves extract. It also prevented decrease in
body weight (Atangwho et al., 2010).
Hypoglycemic potential of A. indica was also confirmed in several
previous reports (Chakraborty et al., 1989; Chattopadhyay, 1999; El‐
Hawary & Kholief, 1990; Murty, Rao, Rao, & Murty, 1978; Pillai &
Santhakumari, 1981; Sen, Mediratta, & Ray, 1992; Sonia &
Scrinivasan, 1999). From the above discussion, antidiabetic potential
of tree cannot be denied. The tree is rich in phytochemicals required
to counteract glucotoxicity in β cells and suppress the secretion of glu-
cagon from α‐cells of pancreas.
5.6 | Antipyretic, analgesic, antinociceptic,
antiproliferative, antimelanogenesis, and anti‐
inflammatory activities
Nonsteroidal anti‐inflammatory drugs are used to reduce inflammation
with side effects such as osteoarthritis acceleration. To avoid side
effects, phytomedicines such as extracts and decoctions are exten-
sively used as antipyretic, analgesic, and antinociceptic agents (Apu,
Bhuyan, Prova, & Muhit, 2012; Umashanker & Shruti, 2011; Vishal,
Ganesh, Mukesh, & Ranjan, 2014). Crude ethanolic extract of leaves
when administered to albino mice for 24 hr at dose of 1,100 and
500 mg/kg showed anti‐inflammatory effect similar to standard
diclofenac sodium in concentration‐dependent manner (Zaman et al.,
2009). Aqueous extract of leaves at dose of 400 mg/kg administered
to rats once in a day for a week displayed reasonable anti‐inflamma-
tory effect but less than dexamethasone (Mosaddek & Rashid, 2008).
Methanolic, ethyl acetate, and n‐hexane extracts of leaves depicted
significant anti‐inflammatory and analgesic activities in rats, and
results were comparable to indomethacin (Dinda & Kumar, 2011). Sim-
ilarly, aqueous extract of leaves also demonstrated significant

1254
analgesic and anti‐inflammatory activities in thermal and chemical
induced pain models in rats (Buchineni et al., 2014).
Besides leaves, extracts of stem barks also showed anti‐inflamma-
tory activity due to the presence of various tetranortriterpenoids
(Vikrant & Arya, 2011). Methanolic and n‐hexane extracts of seeds
contained salannin, which showed potent inhibitory effect on 12‐O‐
tetradecanoylphorbol‐13‐acetate induced inflammation in mice
(Akihisa et al., 2009; Akihisa et al., 2011). Another compound, sodium
nimbinate, from various extracts of A. indica showed inhibitory effect
against carrageenan induced edema and methanal induced arthritis in
rats (Bhargava et al., 1970; Brahmachari, 2004; Okpanyi & Ezeukwu,
1981). Nimbolide is an important phytochemical isolated from the
tree, which considerably reduced the expression of inflammatory cyto-
kines interleukin (IL‐6, IL‐8, and IL‐12,) and nuclear factor (TNF‐α) in
intestinal epithelial cell line. Nimbolide inhibited NF‐κB signaling in
intestinal epithelial cells and macrophages and improved experimental
colitis in mice (Seo et al., 2016).
Total polysaccharides (TP) and fractioned ion exchange residue
extracted from tegument of seeds were evaluated for anti‐inflamma-
tory activities using acute inflammation model in Wistar rats.
Fractioned ion exchange residue residue showed more prominent
activity than TP, which rationalized the traditional use of A. indica as
anti‐inflammatory agent (Pereira, Silva, Silva, Assreuy, & Pereira,
2012). Nimbidin, a tetranortriterpenes extracted from seed oil, pos-
sessed anti‐inflammatory and antiarthritis activities (Kaur, Sarwar‐
Alam, & Athar, 2004; Ojha, 2016). Alcoholic extract of leaves also
exhibited anti‐inflammatory, antipyretic, analgesic, and antiulcerogenic
activities (Koley, Lal, & Tandan, 1994). Anti‐inflammatory activity of
methanolic leaves extract was mediated by nuclear factor‐κB (NF‐κB)
pathway, which could be linked as controlling unit for cancer,
inflammation, and apoptosis in living beings (Schumacher, Cerella,
Reuter, Dicato, & Diederich, 2011). Epoxyazadiradione, purified and
isolated from the seeds, exhibited anticancer activity against human
cervical cancer (HeLa) cell line. Increase in activity of caspase IX and
release of active cytochrome‐c with inhibition of nuclear translocation
factor in HeLa cells was noted. The results were comparable to
standard drug, cis‐platin which suggested epoxyazadiradione as an
alternative chemotherapeutic agent (Shilpa et al., 2017). Seed extract
showed significant activity against chronic and acute inflammatory
diseases. The results were similar to standard drugs, phenylbutazone,
and prednisolone. Nimbidin (40 mg/kg) showed enhanced activity
than phenylbutazone (100 mg/kg) in acute inflammation; however,
it increases with increase in concentration (Pillai & Santhakumari,
1981).
Polyherbal formulation of extracts from leaves of A. squamosa,
A. indica, and rhizome of C. longa showed significant anti‐inflamma-
tory activity, and results were comparable to diclofenic sodium
against carrageenan induced rat paw edema (Jain, 2015). Analgesic
effect of leaves (500 mg/kg) and seed oil extract (2 ml/kg) was
evaluated using glacial acetic acid induced writhing and tail flick
response to heat stimulus model in rats. Analgesic effect of A. indica
leaves was found more promising (Khosla et al., 2000). Different
doses of seed oil (0.25, 5, 1, and 2 ml/kg) showed significant
analgesic effect in dose‐dependent fashion (Kumar, Agrawal, Patnaik,
& Patnaik, 2012).
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SALEEM ET AL.
Analgesic effect of leaves extract was assessed in albino rats by
tail flick response to thermal stimulation model. Increase in tail flick
latency in rats with concentration may operate through central analge-
sic system by opioid receptor pathway (Bhattacharya et al., 2014).
Alcoholic extract (70%) of root bark also showed significant analgesic
effect by affecting central and peripheral centers when administered
at 200, 400, and 800 mg/kg doses to Wistar rats (P. Patil et al.,
2011; P. R. Patil, Patil, Verma, Vijayanath, & Surpur Rajeshawri,
2012). Oral administration of polyherbal formulation of extracts of
mature A. indica leaves and rhizomes of C. longa showed anti‐inflam-
matory and analgesic activities similar to standards, indomethacin
and tramadol hydrogen chloride (M. C. Sharma, Sharma, & Kohli, 2010).
Antinociceptic and analgesic activities of various extracts of
A. indica might involve central, peripheral, or complex neural mecha-
nism including opioid and nonopioid pathways in rats (Khanna,
Goswami, Sen, & Ray, 1995). Evaluation of antinociceptic activity of
crude ethanolic extract of A. indica was done by acetic acid writhing
and hot plate tests. Results showed that this extract did not possess
significant protective effect against heat induced and cumulative
writhing pain when compared with standard antinociceptive drugs,
morphine, or diclofenac sodium (Zaman et al., 2009). Ethanolic
extract of leaves demonstrated more prominent dose‐dependent
antinociceptic activity than extracts of roots, leaves, bark (stem and
root), and seeds at a dose of 100 mg/kg by tail flick model in rats
(Khanam, Singh, Ahmad, & Zia‐ur‐Rahman, 2011; Patil et al., 2012).
Limonoids extracted from the tree represented antimelanogenesis
properties on B 16 melanoma cell in mice (Akihisa et al., 2011).
Various parts of A. indica had been used as antipyretic and
antinociceptic agents since antiquity, but their mode of action and bio-
active components for these effects were unknown (Bhowmik et al.,
2010; Choudhury, Bawari, & Singha, 2010). Antipyretic effect of crude
ethanolic extract of leaves at concentration of 1,000, 500, and
100 mg/kg produced concentration‐dependent antipyretic activity in
albino rats. Results were similar to that of standard drug, paracetamol
(Zaman et al., 2009). These findings supported the utilization of vari-
ous extracts of tree to get rid of inflammations. However, isolation
of active phytochemicals responsible for anti‐inflammatory activity
and development of new drugs is demanding. Similarly, extensive
research is required to prove that tree possessed antiproliferative
activity.
5.7 | Antiulcer, nephroprotective, hepatoprotective,
and antioxidant activities
Hyper‐secretion in stomach is due to uncontrolled release of acid from
the parietal cells of gastric mucosa (Hersey & Sachs, 1995; Sachs, Shin,
Briving, Wallmark, & Hersey, 1995). During ulceration, production of
peptic juice, oxidative damage by reactive oxygen species and apopto-
tic cell death was significant. The gastroduodenal ulceration can be
controlled by inhibiting hyper‐secretion of gastric acid, scavenging
reactive oxygen species, blocking apoptosis, and stimulating cell prolif-
eration for effective healing (Bhattacharjee, Bhattacharjee, Gupta, &
Banerjee, 2002; Kwiecien, Brzozowski, & Konturek, 2002; Szabo &
Tarnawski, 2000; Watanabe, Takagi, Koga, Kamiya, & Miwa, 2000).
Aqueous extract of leaves when administered at 150, 300, and

SALEEM ET AL.
600 mg/kg body weight to three groups of Wistar rats decreased
ulceration induced by pyloric ligation, aspirin, and cold restraint stress
in dose‐dependent manner (Bhajonia, Meshrama, & Lahkarb, 2016).
Antioxidant potential of stored aqueous crude extract of leaves
decreased with time and temperature due to significant decrease in
total phenolics and vitamin C content; however, increase in ferulic acid
was observed (Ullah, Khan, Hussain, Ullah, & Rehman, 2017).
Nimbidin, a compound extracted from A. indica, exhibited gastric
antisecretory activity in pylorus ligated rats and cats. This activity of
nimbidin was similar to H‐receptor antagonists (Pillai & Santhakumari,
1984).
Azadiradione, isolated from ethanolic extract of seeds, demon-
strated potent antiulcer activity by inhibition of H /K ‐ATPase via its
+ +
cytoprotective and antisecretory effect in cold restraint, aspirin, alco-
hol, and pyloric ligation induced ulceration model (Singh et al., 2015).
Extracts of leaves exhibited good protection against ulceration by
decreasing serum alanine aminotransferase, aspartate aminotransfer-
ase, gamma glutamyl transpeptidase, alkaline phosphatase, total biliru-
bin, creatinine, uric acid, and urea in cisplatin induced model. The
study led to conclude that leaves can prevent hepatotoxicities and
nephrotoxicities (Ezz‐Din, Gabry, Farrag, & Abdel Moneim, 2011).
Methanolic extract of root bark was investigated for
antiulcerogenic activity in mice. Significant decrease in gastric acid vol-
ume, pH, free acidity, total acidity, and ulcer index was observed. The
results were comparable to that of standard drug, sucralfate (Kiranmai,
Kumar, & Ibrahim, 2011). Gastric ulcerations induced by pyloric liga-
tion, aspirin, and cold stress were reduced by administration of aque-
ous extract of leaves at dose of 150, 300, and 600 mg/kg of body
weight. Results showed the dose‐dependent relationship between
antiulcer activity and leaves extract concentrations (Bhajonia et al.,
2016). Aqueous extract of leaves administered to mice at particular
dose of 0.5, 1, and 2 mg/kg under different murine physiological sys-
tems was observed to stimulate hematological systems as evidenced
by increase in total count of red blood cells, white blood cells, plate-
lets, and hemoglobin percentage. Histological evaluation disclosed
that serum alkaline phosphatase, serum glutamic oxaloacetic transam-
inase, and serum glutamic–pyruvic transaminase were not increased in
mice proving its nonhepatotoxic nature (Haque & Baral, 2006).
Aqueous extract of the bark exhibited potent antisecretory and
antiulcer effects in animal models with no significant adverse effects
(Bandyopadhyay et al., 2002). The lyophilized powder of bark extract
administered to patients suffering from duodenal and esophageal ulcer
for 10 days at dose of 30 mg twice daily caused a significant decrease
in gastric acid secretion. Complete healing of duodenal ulcers was
proved using barium metal X‐ray or endoscopy (Bandyopadhyay
et al., 2004). Antiulcer activities of aqueous extract of leaves were
studied in rats, and the most probable mechanism of action was
the inhibition of gastric lesions in dose‐dependent manner
(Chattopadhyay et al., 2004). Aqueous extract of leaves showed
gastro‐protective activity by hormonal and cell‐mediated immune
responses in rats, which depend upon concentration (Ray, Banerjee,
& Sen, 1996).
Methanolic extract of leaves were evaluated for its antisecretory
and antihemorrhagic activities against MDRS, V. cholerae. There was
an observed 27.7%, 41.1%, 43.3%, 57.0%, and 77.9% decrease in
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1255
gastric secretion at a dose of 100, 200, 300, 450, and 1,800 mg/kg
in rats, respectively. Oral administration of extracts inhibited hemor-
rhage at a dose equal to or greater than 300 mg/kg in rats (Thakurta
et al., 2007). Hepatoprotective effect of alcoholic extract of leaves
was noteworthy against carbon tetrachloride induced liver damage in
mice using silymarin as standard drug (Kalaivani et al., 2009). Powder
or aqueous slurry of leaves (0.5 g/kg of body weight) when adminis-
tered to Wistar rats having CCl4 induced liver damage exhibited com-
plete recovery of all biochemical parameters (GPT, bilirubin, alkaline
phosphate, GOT, glucose, total protein, and cholesterol; Pingale,
2010). Aqueous extract of leaves showed protection and healing
against gastric ulcer in diabetic and nondiabetic rats. Various extracts
of A. indica reduced mucosal proton activity and pepsin secretion as
compared to omeprazole (Dorababu et al., 2006).
Potential antioxidant properties of extracts had been evaluated
against coccidiosis caused by Eimeria papillata. It was observed that
leaves produced hepatoprotective activity and healed preexisting liver
damage due to oxidative stress (Dkhil, AL–Quraishy, Abdel Moneim, &
Delic, 2013). Polyherbal formulation prepared from extracts of
Glycyrrhiza glabra, Garcinia cambogia, deglycyrrhizinated licorice, and
A. indica effectively cured naproxen, histamine, cysteamine, and etha-
nol induced ulcer (Purohit & Kushwaha, 2013). Thus, A. indica can be
the good choice of traditional healers for the treatment of liver, kid-
ney, and GIT disorders with lesser side effects than available drugs.
Moreover, free radical scavenging potential of different extracts sup-
ported the medicinal importance of the tree.
5.8 | Neuroprotective and cardioprotective activities
Flavonoids, present in seeds of A. indica, were investigated for their
neuroprotective effect on rat pheochromocytoma‐12 cell line.
Ethanolic extract of seeds when applied to neurons pre‐exposed with
neurotoxin (6‐Hydroxydopamine) created neuroprotective effects.
Therefore, extracts of the tree can be used in treatment of
neurological disorders (Y. Sharma et al., 2014). Finely grounded whole
tree significantly lowered the cerebral hypoperfusion induced func-
tional disturbance in rats when administered at dose of 500 mg/kg
for 15 days. Reactive changes in brain histology were effectively
attenuated with A. indica treatment (Yanpallewar, 2005). The extract
of leaves caused the substantial attenuation of cell inflammation,
concentration of reactive oxygen and nitrogen species with the
inhibition of tumor necrosis (TNF‐α) and interleukin‐6 factors (J. W.
Lee et al., 2017). Presence of flavonoids in seed extracts produced
neuroprotective effects on rat PC‐12 (Pheochromocytoma) cell line.
Thus A. indica seed extracts can be used as a supplement for the
patients suffering from Parkinson's and other neurological disorders
(Y. Sharma et al., 2014).
Pretreatment of tumor‐bearing mice with aqueous extract of
leaves protected against cardiotoxicity induced by doxorubicin. Anti-
oxidants present in extract played a modulatory effect on the defen-
sive system of body to protect it from cardiotoxicity (Koul, Goyal, &
Bharati, 2014). Cardioprotective potential of aqueous extract of leaves
was investigated against isoprenaline induced myocardial infarction in
rats. Isoprenaline control group showed elevation in total cholesterol
and triglycerides levels with decrease in HDL level. However,

1256
administration of extract at dose of 250, 500, and 1,000 mg/kg with
vitamin E significantly restored all hemodynamic, biochemical, and
histopathalogical parameters (Peer, Trivedi, Nigade, & Deshpande,
2007). Crude powder of leaves protected cardiovascular system of
anesthetized guinea pigs and rabbits by causing hypotension and min-
imizing negative chronotropic effect in dose‐dependent manner
(Chattopadhyay, 1996). Various extracts of the tree helped in control-
ling cardiovascular problems by improving lipid profile (Chattopadhyay
& Bandyopadhyay, 2005; Das et al., 2010; Halim, 2002). Literature
unveiled that tree is rich in flavonoids, which inhibited LPO and
reduced the effects of neurotoxins. Thus, isolation of bioactives
responsible for neuroprotective and cardioprotective activities is
required.
5.9 | Antifertility activity
Various contraceptives with different modes of action were developed
from synthetic and natural sources to prevent the sperm fusion with
ovum by generating hormonal changes in female and spermicidal
activity in male. Whole A. indica tree possessed good spermicidal
potential and created reversible infertility in female reproductive sys-
tem (Asif, 2013). Azadirachtin, extracted from the tree, exhibited no
oviposition with traces of ecdysteroids in ovaries of Locusta migratoria
female at dose of 10 mg for 15 days. Oogenesis inhibition and pres-
ence of ecdysteroid was controlled by interference of azadirachtin
with the neuroendocrine control of hormone synthesis (Rembold &
Peter, 1981).
The seed oil extracted using polar and nonpolar solvents were
studied for its quantitative effects on follicular development in female
albino rats. Significant reduction was observed in number of follicles at
different stages of growth and differentiation (Roop, Dhaliwal, &
Guraya, 2005). Effect of azadirachtin and A. indica oil on oviposition,
feeding behavior, and tunneling of Coptotermes formosanus was stud-
ied by Grace and Yates (1992). Subsequent observation of experiment
exhibited that C. formosanus avoided contact with A. indica oil treated
sand/paper and loss of appetite (Grace & Yates, 1992). Comparable
efficacy of herbal acaricides extracted from A. squamosa and A. indica
was investigated in B. microplus. A. indica was most efficient infertility
agent without harming ovaries and changing oviposition in female
subjects (Magadum, Mondal, & Ghosh, 2009).
Controlled amount of A. indica and peanut oil was given
viaintrauterine route to Wistar female rats for investigation of their
comparative efficacy as antifertility agents. A. indica oil was more effi-
cient in controlling fertility without harming ovaries than peanut oil.
Intrauterine administration of A. indica oil induced preimplantation
blocking of fertility (Upadhyay, Kaushic, & Talwar, 1990). Aqueous
extract of leaves administered at a dose of 1 ml per male rat for
1 month induced male infertility due to secretion of spermatogenesis
and testicular functioning androgenic hormone (Deshpande,
Mendulkar, & Sadre, 1980). The above discussion indicated that vari-
ous extracts of tree had spermicidal potential. It also inhibited release
of ovum owing to hormonal changes. Thus, these extracts can be used
as birth control pills to delay pregnancy. However, preclinical and clin-
ical trials are demanding. Table 5 shows preclinical trials of different
extracts of A. indica.
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SALEEM ET AL.
6 | SAFETY EVALUATION
Toxicity of A. indica oil and oleic acid based nanocapsules was
evaluated by Pasquoto‐Stigliani et al. (2017). Cytotoxic and
genotoxic analysis showed elevation of toxicity with increase in oleic
acid concentration. Phytotoxic analysis of pure oil formulation
showed non‐detrimental effect on photosynthesis and stomatal
conductance whereas formulation having A. indica oil and oleic acid
reduced the net photosynthesis and stomatal conductance in maize
plants (Pasquoto‐Stigliani et al., 2017s). Azadirachtin, a biopesticide
when orally administered to male rats at concentration of 500,
1,000, and 1,500 mg/kg per day for 90 days did not produce any
toxic effect in blood parameters (Raizada, Srivastava, Kaushal, &
Singh, 2001). Unprocessed aqueous extract of seed oil showed
lowest toxicity when administered to the albino rats (Boeke et al.,
2004).
Topical application of seed oil (5%) did not exhibit detrimental
effect on survival and emergence of predator larvae however it signif-
icantly reduced the emergence of parasitoids. Thus, A. indica‐based
insecticide can be used for integrated pest management to aphid pred-
ators and parasitoids (Lowery & Isman, 1995). Compounds isolated
from A. indica having lower molecular weight than azadirachtin exhib-
ited no toxicity to Spodoptera littoralis, Schistocerca gregaria, and
Oncopeltus fasciatus; however, azadirachtin significantly reduced the
growth of above mentioned species (Aerts & Mordue, 1997). Toxicity
of seed oil to Amblyomma variegatum demonstrateddirect relation with
concentration and time (Ndumu, George, & Choudhury, 1999). It was
observed that aqueous extract of leaves increased the glutamate oxa-
loacetate transaminase (GOT) and glutamate pyruvate transaminase
(GPT) activities when fed to fish, Cirrhinus mrigala for 24 hr. The
extract increased the K+ ions concentration in plasma however con-
centrations of Cl‐ and Na+ ions were decreased. Moreover
haemoglobin, red blood cells, mean cell haemoglobin and volume were
decreased along with increase in white blood cells (Saravanan,
Ramesh, Malarvizhi, & Petkam, 2011).
Suspension of methanolic extract of flowers was prepared in pro-
pylene glycol and fed to Wistar rats at dose of 6, 9, and 12 g/kg body
weight to evaluate acute toxicity. Evaluation of subacute toxicity was
carried out by feeding suspension of methanolic extract in tragacanth
at dose of 150, 750, and 1,500 mg/kg body weight. Blood chemistry
and histopathology of visceral organs exhibited no prominent change.
It was noted that alkaline phosphatase, creatinine and potassium ion
concentrations were greater in female whereas in male rats, the levels
of aminotransferase and blood urea nitrogen were lower than control
groups. It was concluded that LD50 was greater than 12 g/kg body
weight (Kupradinun et al., 2010). For the evaluation of acute toxicity,
rats were injected with aqueous extracts of leaves and seeds for
48 hr. It was observed that death rate of rats was increased with
increase in concentration of extracts and LD50 values were 6.2 and
9.4 ml/kg for leaves and seeds respectively. Higher doses of leaves
(0.1 and 0.92 g/ml) and seeds (0.2 g/ml) caused 100% death. Thus it
can be concluded that injection of aqueous extracts of seeds and
leaves demonstrated acute toxicity (Bakr, 2013).
Ethanolic extract of leaves of the tree was administered to Swiss
albino mice for the investigation of acute toxicity. No mortality was
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SALEEM ET AL. 1257

TABLE 5 Preclinical trials of Azadirachta indica

Preclinical trial Parts used Nature of extract Dose of extract Model used References
Antidiabetic Seed kernels Ether extract 0.55–0.90 g/kg Wistar rats Gupta et al., 2004
activity of body weight
Seed oil 2.5 ml/kg Rabbits Khosla et al., 2000
Seed oil 500 mg/kg of body weight Albino rats Nagashayana
et al., 2014
Ethanolic extract 500 mg/kg Rats Akinola et al., 2010
Aqueous extract 0.01–1.4 mg Human blood cells Martínez et al., 2014
Ethanolic extract 1 g/kg of body weight Rats Akter et al., 2013
Flower Ethanolic extract 100 mg/kg of body weight Wistar albino rats Jayasree et al., 2013
Fruit extract Aqueous extract 500 mg/kg of body weight Rabbits Rao et al., 2012
Roots Aqueous extract 200 mg/kg body weight Rats Atangwho et al., 2010
Anti‐inflammatory Leaves Ethanolic extract 1,100 and 500 mg/kg Albino mice Zaman et al., 2009
activity Aqueous extract 400 mg/kg Rats Mosaddek &
Rashid, 2008
Methanol, ethyl acetate, 100 mg/kg Mice Dinda et al., 2011
and n‐hexane
Stem bark Methanolic extract 0.09–0.26 mg per ear Mice Akihisa et al., 2009
Seed Methanolic fraction 0.1 mg/kg Wistar rats Pereira et al., 2012
Analgesic activity Root bark Alcoholic extract 70% Wistar rats Patil et al., 2011
Antinociceptic activity Root/stem/leaf, Ethanolic extract 100 mg/kg Rats Khanam et al., 2011
and seed
Antipyretic activity Leaves Ethanolic extract 100–1,000 mg/kg Rats Zaman et al., 2009
Insecticidal/pesticidal Leaves Aqueous extract 0.1 and 0.4 g/ml Rhizobacteria Sarawaneeyaruk
activity et al., 2015
Aqueous extract 10.7–32 μl/100 ml C. plutellae Charleston et al., 2005
D. collaris
Seed Aqueous extract 10% Cassava and maize Umeh & Ivbijaro, 1999
plants
Seed oil 2 and 3 ml/kg C. maculatus Ivbijaro, 1990
Methanol 5% Cowpea pest Egho & IIondu, 2012
Powder Pure P. glandulosus Nukenine et al., 2011
Leaves and Mixture of ethanol ‐ Natural foods Jaglan et al., 1997
seed and chloroform
Antifeedant activity Seed Pure seed oil ‐ H. abietis Thacker et al., 2003
Nematicidal Activity Whole Ethanol and ethyl 0.19–50 mg/L H. contortus Costa et al., 2007
acetate extract
Leaves Dry powder 11.2‐μg/g dry mass A. planipennis Mckenzie et al., 2010
Seed Aqueous extract 2 and 8 mg/L A. aegypti Ndione et al., 2007
Seed oil 1.0%, 94%, and 100% Aphids Lowery & Isman, 1995
Larvicidal activity Whole Oil extract 0.006%, 0.05%, and 0.4% S. frugiperda Roel et al., 2010
Methanolic 15.25, 12.70, 46.79, and A. stephensi Batabyal et al., 2007
45.56 ppm
Leaf Petroleum ether 35–40% Mosquito larvae Okigbo et al., 2010
Ether and n‐hexane 20 ppm A. stephensi Tonk et al., 2006
Fruit Ethanolic extract 0.0033 to 0.05 g% A. aegypti Wandscheer
et al., 2004
Seed Petroleum ether ‐ Mosquitoes George &
Vincent, 2005
Molluscicidal/ Whole Crude extract 350, 500 and 700 mg/kg A. marginata, Ebenso, 2003
Cercericidal activity L. aurora
Water, methanol and 80 mg/L B. pfeifferi, Michael et al., 2013
ethyl acetate extracts S. mansoni
Methanolic extract 10 g/50 ml L. auricularia, Alam et al., 2011
I. exustus
Aqueous extract 80 mg/L B. pfeifferi Mwonga et al., 2015
Seed Methanolic extract 21.008–53.654 mg/ml Golden apple snail Massaguni & Latip, 2015
Antileishmaiases Ethanol, dichloromethane 0.6–1.2 μg/ml L. amazonensis Carneiro, 2012
activity and aqueous extract
Root bark Methanolic extract 100–500 mg/kg Albino mice Kiranmai et al., 2011
Leaf Aqueous extract 150, 300 and 600 mg/kg Wistar rats Bhajonia et al., 2016
of body weight
Aqueous extract 0.5, 1 and 2 mg Mice Haque et al., 2006
Methanolic extract 100–100 mg/kg Rat Thakurta et al., 2007
Aqueous extract 500 mg/kg Rat Dorababu et al., 2006
Neuroprotective Seed Ethanolic extract 5 g/50 ml Rat Y. Sharma et al., 2014
activity Whole tree Powder 500 mg/kg Rat Yanpallewar, 2005
Leaf Aqueous extract 250, 500, and 1,000 mg/kg Rat Peer et al., 2007

(Continues)

1258
TABLE 5 (Continued)
Preclinical trial Parts used Nature of extract
Antimelanogenesis/ Seed Crude powder and
Anthelmintic activities aqueous extract
Antifertility activity Azadirachtin: isolated
from A. indica
Seed Seed oil
Leaf Aqueous
observed even at dose of 2 g/kg body weight (Kanagasanthosh,
Shanmugapriyan, & Kavirajan, 2015). Oil obtained from seeds by
pressing was applied topically on nymphs and adults of predator,
Podisus nigrispinus. With increase in oil concentrations, mortality rate
was increased in the third, fourth, and fifth instar nymphs. The oil also
caused malformations in legs, wings, and scutellum (Zanuncio et al.,
2016). Various concentrations of bioneem oil were administered to
fish, Danio rerio and microcrustacean, Daphnia magna to evaluate
acute and chronic toxicity, respectively. The median lethal
concentration (LC50–96h) and the median effective concentration
(EC50–48h) were found to be 0.22 and 0.17 ml/L for D. rerio and
D. magna, respectively. The size and reproduction of microcrustacean
also varied with varying concentrations of bioneem oil (Maranho et al.,
2014). Pretreatment of rats with the tree extracts significantly
reduced genotoxicity and apoptosis in rats induced by sodium
arsenite with increase in activities of glutathione‐S‐transferase,
CAT, SOD, and reduced glutathione as compared to the group that
received only sodium arsenite. Histopathological analysis suggested
that liver showed infiltration signs of inflammatory cells with deaths
of hepatocytes in sodium arsenite intoxicated rats whereas the
opposite was observed in case of A. indica extract (Oyagbemi
et al., 2017).
Vegetable oil obtained from seeds or fruits were given to Kun-
ming mice of either sex to evaluate acute and subacute toxicities
(28 days). LD50 of the oil was investigated to be 31.95 g/kg during
acute toxicity study. Gain in body weight, food, and water consump-
tion was not affected by neem oil. There was not observed prominent
difference in serum biochemistry even at dose of 1,600 mg/kg. Histo-
pathology studies showed that the kidney, liver, and testicles are
affected up to a dose of 1,600 mg/kg body weight (Deng et al.,
2013). Ethanolic extract of stem bark at dose of 50, 100, 200, and
300 mg/kg body weight was administered to Wistar rats for 21 days
to evaluate toxicity. Significant decrease was noted in white blood
cells, platelets, serum triacylglycerol, and HDL cholesterol. Moreover,
serum globulins, serum cholesterol, low‐density lipoprotein choles-
terol, and bilirubin levels were increased significantly. Food and water
intake, and activities of alkaline phosphatase, alanine, and aspartate
transaminases were also disturbed. Thus, ethanolic extract cannot be
considered safe for oral use at above mentioned doses (Ashafa,
Orekoya, & Yakubu, 2012).
Different products of neem (1% Suneem, formulated neem oil,
and neem powder) caused inhibition of nymphs and adults emergency
of A. aegypti. The products also caused damage to epithelial columnar
cells, agitation of alimentary flow, and bursting of gut cells (Ndione
et al., 2007). Six different concentrations (0.5%, 1%, 1.5%, 2%, 2.5%,
and 3%) of methanol and hexane extracts of leaves were evaluated
for toxicity indiamondback moth, P. xylostella. It was explored that
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SALEEM ET AL.
Dose of extract Model used References
1–3 g/kg of body weight Sheep Iqbal et al., 2010
10 mg L. migratoria Rembold & Peter, 1981
3–6 mg/kg of body weight Albino mice Roop et al., 2005
1.0 ml per rat Male rat Deshpande et al., 1980
mortality rate (61.67%) was significant even at very low concentration
(0.5%). Mortality rate was 100% at 3% concentration. The LC50 values
were investigated to be 0.61% and 3.95% for methanolic and hexane
extracts, respectively. Thus, population of P. xylostella can be con-
trolled using neem extracts (S. Sharma & Singh, 2014). Administration
of unextracted neem seed kernel (75, 150, and 225 g/kg) and raw
neem seed kernel (75 g/kg) to chicks slowed down the growth owing
to poor ingestion and digestion. Intake of unextracted neem seed ker-
nel enlarged the lungs, liver, and kidneys. Ingestion of raw neem seed
kernel induced anaemia and increased activity of aminotransferase
(Uko & Kamalu, 2006).
Extracts of seeds and powder of leaves were tested for direct
and residual toxicities against red floor beetle, Triboliumcastaneum.
Direct toxicity of seed extracts was noted to be 53.13% at a concen-
tration of 100 μg per insect. Leaf powder exhibited 50.06% residual
toxicity. Thus, neem seed extracts and leaf powder can be used to
control red floor beetle (Islam & Talukder, 2005). Male Wistar rats
were divided into three groups, A, B, and C. Group A labelled as con-
trol group and receive normal saline solution, Group B was adminis-
tered with 1 ml of ethanol (50%) for 12 hr whereas Group C was
given aqueous extract of leaves (500 mg/kg) after administration of
1 ml of 50% ethanol for 21 days. Ethanol treated rats (Group B)
showed marked mucosal lesion of stomach and ileum whereas Group
C showed significant regenerative properties in ethanol induced
mucosal damage (Ofusoria, Falanab, Ofusoric, & Caxton‐Martinsa,
2010). Methanolic extract administered to rats exhibited significant
reduction in hypertension and genotoxicity induced by sodium
fluoride (Omόbὸwálé et al., 2017). Summary of toxicological studies
is shown in Table 6.
7 | CLINICAL TRIALS
A group of patients suffering from gastroduodenal ulcer was treated
with aqueous extract of bark at dose of 30 mg twice a day for 10 days
and 10 weeks separately. Patients treated for 10 days showed signif-
icant decrease in gastric acid secretion along with reduction in pepsin
activity whereas 10 weeks treatment led to complete healing of gas-
troduodenal ulcer monitored by barium meal X‐ray or endoscopy
(Bandyopadhyay et al., 2004). Efficacy of leaf extract (25 mg/g of den-
tal gel) was observed for 6 weeks in male of age group 20–30 years.
Results showed significant decrease in salivary bacterial count, plaque
formation in comparison with 0.2% of chlorhexidine gluconate (Pai
et al., 2004).
Forty‐four patients divided into two groups were administered
with leaves and chlorhexidine (0.12%) for 7 days. It was revealed that
all clinical tests (plaque index, gingival bleeding index, cariogenic
 10991573, 2018, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ptr.6076 by FUFSE - FUNDACAO UNIVERSIDADE FEDERAL DE SERGIPE, Wiley Online Library on [22/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SALEEM ET AL. 1259

TABLE 6 Toxicological studies of various parts of Azadirachta indica

Plant part used Nature of extract Study duration LC50 Effect noted Test animal References
Leaves Aqueous 24 hr 1.035 g/L Acute toxicity C. mrigala Saravanan et al., 2011
Flowers Methanolic 90 days >12 g/kg Acute and subacute toxicity Rats Kupradinun et al., 2010
Leaves Aqueous 48 hr 6.2 ml/kg Acute toxicity Rats Bakr, 2013
Seeds Aqueous 48 hr 9.4 ml/kg Acute toxicity Rats Bakr, 2013
Leaves Ethanolic 14 days – Acute toxicity Wistar rats Kanagasanthosh et al., 2015
Neem oil Neem oil 6 days 41.92 g/ml Acute toxicity P. nigrispinus Zanuncio et al., 2016
Bioneem oil Bioneem oil 96 hr 0.22 ml/L Acute toxicity D. rerio Maranho et al., 2014
Bioneem oil Bioneem oil 21 days 0.17 ml/L Chronic toxicity D. magna Maranho et al., 2014
Neem oil Neem oil 14 days 31.95 g/kg Acute and subacute toxicity Kunming mice Deng et al., 2013
Neem oil Neem oil 28 days – Subacute toxicity Kunming mice Deng et al., 2013
Stem bark Ethanolic 21 days – Toxicity implications Wistar rats Ashafa et al., 2012
Leaves Methanolic 6 days 0.61% extract Toxicity effects P. xylostella S. Sharma & Singh, 2014
Leaves Hexane 6 days 3.95% extract Toxicity effects P. xylostella S. Sharma & Singh, 2014
Seed kernel Seed kernel 35 days – Toxicity implications Cockerelchicks Uko & Kamalu, 2006
Seeds Aqueous 72 hr 74.27 μg per insect Contact toxicity T. castaneum Islam & Talukder, 2005

TABLE 7 Clinical trials of various parts of Azadirachta indica

Biological activity Plant part used Administration route Duration of study Dose References

Antiulcer Bark Oral 10 weeks 30–60 mg twice a day Bandyopadhyay et al., 2004
Antiplaque Leaves Oral 6 weeks 25 mg/g Pai et al., 2004
Gingival inflammation and Leaves Oral 30 days 25% extract Botelho et al., 2008
antiplaque
Acute toxicity Neem oil Oral 2 days 12 ml Sinniah, Baskaran, Looi, Looi,
& Leong, 1982
Antidiabetic Leaves Oral – 2 tablets Alam et al., 1990
Allergenic effect Pollen Skin prick test Once – Chakraborty et al., 1998
Acute renal failure Leaves Oral and – – Kadiri et al., 1999
intravaginally
Encephalopatic Neem oil Oral Once 5 ml Lai, Lim, & Cheng, 1990

bacteria, and gingival index) exhibited no statistical difference in
activity of chlorhexidine and extract of leaves (Botelho et al., 2008).
Mouthrinse of A. indica used by 45 patients having plaque induced
gingivitis showed same effect as chlorhexidine (Chatterjee, Saluja,
Singh, & Kandwal, 2011). Leaves of the tree were used to treat DM
in India. It caused severe side effects such as necrosis, hemolysis,
and hepatotoxicity. Three out of 53 patients treated with leaves
expired (Alam, Siddiqui, & Husain, 1990; Kadiri, Arije, & Salako,
1999). Patients suffering from respiratory allergy when exposed to
pollens of A. indica enhanced the intensity of allergy (Chakraborty,
Gupta‐Bhattacharya, Chakraborty, Lacey, & Chanda, 1998). Table 7
shows the clinical trials of various parts of the tree.
8 | C O N C L U S I O N S A N D F U T U RE
P R O S P EC T S
Among other plants of family Meliaceae, researchers are more enchanted
towards A. indica owing to its demanding therapeutic uses and broad
spectrum pharmacological attributes. Folk healers used various extracts
of the tree to treat pyrexia, cancer, small pox, diabetes, ulcer, headache,
rheumatism, skin complications, GIT infections and healing of wounds.
Antifungal, antibacterial, anti‐inflammatory, sterilant, antiscabic, antialler-
genic, analgesic, nematicidal, antipyretic, and so forth, properties of vari-
ous parts of A. indica, are significant. Phytochemicals responsible for
these activities should be isolated and then synthesized commercially.
Various extracts of A. indica lowered the cholesterol, improved
the lipid profile, and protected vital organs such as the heart and liver.
It is also noted that it repaired the damaged liver cells due to diabetes.
Literature revealed that extracts of the tree particularly leaves extracts
not only treat diabetes but also prevent from reoccurrence of diabe-
tes. Thus, there is need to isolate bioactives for the preparation of
commercial formulations.
It is skin food and protects the body from several fungal and bac-
terial infections along with its skin whitening properties. It is highly
valuable as it may be added into yogurt and different foods to get
its plethora of potential benefits. It is also useful to treat contagious
diseases such as small pox along with several other skin diseases. Its
food products and several cosmetics products may be designed to
get commercial benefits, for example, leaves extract based soaps and
cosmetics, oil extract based formulations for skin diseases, seed and
husk based formulation.
Regarding its antibacterial properties, it is noted that A. indica
extracts are as powerful as marketed antibiotics. Various studies

1260
confirmed its potential against bacteria and fungi. Researchers are
invited to isolate these secondary metabolites and develop new eco-
nomical and safer drugs for which bacteria and fungi are not resistant.
Literature indicated that extracts containing flavonoids are used to
treat diabetes. Efforts are required for the isolation of active phyto-
chemicals and their mechanism of action.
Research witnessed that extracts containing tetranortriterpenoids
possessed admirable anti‐inflammatory activity. The identification of
these active components is required so that anti‐inflammatory drugs
with lesser cost and side effects can be developed. Similarly, extracts
of the tree are used to kill insects. New economical pesticides can
be synthesized after isolation and identification of constituents
responsible for insecticidal potential. We concluded that A. indica
has plenty of potential to treat huge number of diseases by the devel-
opment of its relevant herbal formulations hence areas are of high
commercial importance as well. There existed a great potential for
the synthesis of isolated bioactives in laboratories on a commercial
basis. There is also great opportunities for researcher to develop
nutrapharmaceuticals.
CONF LICT OF INT E RE ST
The authors have declared that there is no conflict of interest.
ORCID
Muhammad Ajaz Hussain http://orcid.org/0000-0003-4570-6616
Syed Nasir Abbas Bukhari http://orcid.org/0000-0001-8125-7972
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How to cite this article: Saleem S, Muhammad G, Hussain
MA, Bukhari SNA. A comprehensive review of phytochemical
profile, bioactives for pharmaceuticals, and pharmacological
attributes of Azadirachta indica. Phytotherapy Research.
2018;32:1241–1272. https://doi.org/10.1002/ptr.6076