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Chapter 6

estimation of phytochemicalproperties and toxicity of the selectedmedicinal plants of North East India

This chapter deals with the in silico analysis phytochemical properties of the medicinal plants traditionally used for treating malaria in the North East India. It also deals estimation of the probable phytotoxicity associated with these plants by computational methods.

6.1 BackgroundStudies in ethnomedicinal plants associated with study of phytochemical

properties has increasing relevancy as bioprospecting tools. Traditional knowledge

about the medicinal plants along with their phytochemical and pharmacological

aspects provide significant insights into the theoretical investigations and

identification of potential novel compounds (Medeiros et al., 2013). Many natural

products obtained from the plants are used as drugs while some are used as dietary

supplements or ingredients in the cosmetic industry.

There are many empirical evidences for the efficacies of the botanical recipes

used in the codified traditional medicines such as Ayurveda, Traditional Chinese

Medicines, Unani and Siddha. In addition to these recipes, some locally used

medicinal plants are also well studied for analyzing their efficacies, pharmacological

effects and safety. Medicinal properties of these plants are due to the presence of wide

ranging bioactive principles. Identification of drug-like or lead-like compounds from

these plants would provide significant advancement in future drug development

endeavours. As drug-discovery lifecycle is an extensive and resource-consuming

process, removing non-drug like compounds in the initial stage can be a pragmatic

approach. Identification of drug-like compounds are based on the functional groups

and biochemical properties which are consistent with majority of the known drugs

(Kadam and Roy, 2007). Plants used in traditional medicines provide rich and largely

unexplored resources of therapeutic leads for the drug discovery processes.

159

One important issue pertinent with with the medicinal plant is in the toxicity

associated with the medicinal plants as such, or their derivatives or herb-drug

interactions. There are many monoherbal and polyherbal recipes which are not yet

assessed for their potential risks associated with these recipes (Heinrich, 2006). About

80% of the people all over the world are still using these botanical recipes as they are

depending on traditional medicines. In the North East India, people are still using these

ethnomedicinal plants as both monoherbal and polyherbal recipes for treating both

acute and chronic diseases. Though herbal medicinal products are considered to be

safe as compared to synthetic drugs, they are not completely safe or free from toxic

activities (Jordan et al., 2010). Assessment of these botanical recipes with regard to

toxicological properties would provide significant understanding for herbal product

safety and regulations. As such a systematic and critical approaches are needed to

assess the toxic side effects of these plants.

In recent years computational (in silico) methods are widely used both for

predicting drug likeness characters and toxicological properties in various compounds.

Modern drug discovery, including searching for novel compounds from biological

resources, incorporate computer aided approaches such as ligand docking,

pharmacophore searching, neural networking and binding free energy calculations of

potential compound towards a target receptor (Ntie-Kang et al., 2013). These

approaches rely on the chemical descriptors of the compound selected.

Implementation of these approaches need compilation of compound libraries for the

ethnomedicinal plants in the region. The present chapter deals with the applicability

of the phytochemical compound collected in the current database.

Focus of the present chapter is to assess the drug-likeness characteristics of the

compounds present in the orally administered plant extracts used for treating malaria.

Later part of this chapter deals with the toxicological prediction of these compounds

present in selected medicinal plants.

6.2 Materials and Methods

6.2.1 Data Sources

As the scope of the phytochemical properties of medicinal plants is very

extensive, the present study is limited to only a selected set of plants. Selection of the

plant was done on a specific criteria, i.e. medicinal plants which are used in the

160

treatment of malaria. Anti-malarial plants are selected as case study because malaria

have been reported from this region from long time back. On the other hand, malaria

is one of the severe disease of the tropic affecting thousands of lives in the North East

India also.

List of the medicinal plants used for treating malaria in the region was queried

from the present database of ethnomedicinal plants of North East India. Out of these

plants, only those plants which has been applied through oral administration are

selected. Overall 89 medicinal plants have been selected for the study. List of the

plants are provided along with the corresponding chemicals in the result section.

6.2.2 DataSets

Phytochemicals present in these medicinal plants are collected from available

scientific publications. For this, an extensive survey of literatures were done. Main

focus is on the chemical web resources such as ChEBI (Degtyarenko et al., 2008),

PubChem (Wang et al., 2009), ChEMBL (Gaulton et al., 2012) and similar open web

resources. Phytochemical compounds are also extracted from Dr. Duke�s Database

(Duke, 2000) and also by using Oscar 3 web mining tool (Corbett and Murray-Rust,

2006). Compound names are converted to their corresponding IUPAC name through

Cactus web server (http://cactus.nci.nih.gov/) and PubChem PUG Rest web service

(https://pubchem.ncbi.nlm.nih.gov/). Compilation of SMILES from these web server

are done through R software (R Core Team, 2014). List of the SMILES strings are

converted to corresponding SDF files by OpenBabel software (http://openbabel.org)

and Mobyl web server (Néron et al., 2009). Duplicated compounds are removed by

cross-checking with the InChIkey.

6.2.3. Prediction of potential bioactivity

There are many rules for estimating the drug likeness of a particular compound.

In the current study, the drug likeness and lead-likeness prediction are performed by

applicating a set of rules. Before estimating drug-likeness and lead-likeness, salts and

compound mixtures are removed.

Drug likeness prediction of the compound or compound sets are important

steps for removing non-drug like compounds from the drug discovery processes. In

the current study, the test was performed to determine how many drug-like compounds

161

are present in the selected medicinal plants. There are many rules for predicting drug-

likeness at present. Lipinski�s criteria, generally referred to as the �Rule of 5� is

classical rule used for estimating the oral availability of a compounds. However,

pasing the Ro5 is not the guarantee for drug-like properties. Number of rotatable

bonds, oral bioavailability, blood-brain-barrier permeability are also important sets for

drug-likeness. Considering this combination of different filters are used for predicting

drug-likeness. Estimation is done by applying Drug-likeness Soft default filter in the

Mobyl FAF-Drugs2 web service (Lagorce et al., 2011; Néron et al., 2009). Drug

likeness of a compound is defined when there is no violation of Lipinsky�s rule,

molecular weight ranges between 100 and 600, hydrogen bond donors is < 5, hydrogen

bond acceptor is < 12, number rotatable bonds is < 11, number of rigid bonds is <30,

number of rings is < 6, size of the largest ring is < 19, polar surface area is < 180, LogP

ranges from -3 to 6, number of formal charges is < 3, sum of formal charges is 2 and

H/C Ratio ranges from 0.1 to 1.1.

Lead-likeness is a qualitative property of the compound that aside the

compound from others on the basis of their potentially to use for future drug leads. For

the present study Lead-likeness was calculated by applying Lead-likeness Soft default

filter in the Mobyl FAF-Drugs2 web service (Lagorce et al., 2011). The filter considers

physico chemical properties of compounds with molecular weight between 150 and

400, logP between -3 to 4, HBA < 7, HBD < 4, tPSA < 160, Rotatable Bonds < 9,

Rings < 4 and Stereocenters < 2.

6.2.4. Prediction of potential toxicity

Carcinogenicity and mutagenicity are major toxicological endpoints in the

human health sectors. Traditional people are using crude extracts of the plants for their

remedies. These extracts might contain toxic compounds as many medicinal plants are

known to possess various toxic compounds. Prediction of toxicity of compounds

present in the plant is an indicator of toxicity of the crude extracts. Estimations were

done by using SAR and QSAR tools. Though every model can predict the potential

toxicity of any chemical, the confidence in such predictions may be variable. It is

because each model is based on a training set of chemicals covering only a fraction of

entire chemical universe. As such, the prediction potential of such model is restricted

to its applicability domain (AD) i.e. the descriptor space. In the modelling process, it

162

is necessary to check whether the studied chemical falls within the chemical of

interest. In this modelling, those chemicals falling outside the applicability domain are

removed.

In the present study Ames mutagenicity test was done by applying quantitative

structure-activity relationship (QSAR) approach by using T.E.S.T. Version 4.1 (US

EPA, 2012) released by US Environmental Protection Agency. The present model

used a dataset of 6512 chemical compounds for evaluating in silico Ames

mutagenicity prediction methods (Hansen et al., 2009). However, the final dataset

consists of only 5743 chemicals after removing the salts, mixtures, ambiguous

compounds and compounds without CAS numbers. The TEST used a variety of QSAR

methodologies such as hierarchical clustering, nearest neighbour and Food and Drug

Administration (FDA) MDL model. In the present study, consensus model from the

different methodologies are used.

Carcinogenicity prediction was based on a SAR tool. It was done by applying

Benigni/Bossa rulebase by using carcinogenicity prediction module in the Toxtree

software (http://ecb.jrc.it/qsar/qsar-tools/). The main tool in this module is the list of

structural alerts (SAs) for carcinogenicity. The SAs for carcinogenicity are the

molecular functional groups or substructures known to be linked to the carcinogenic

activities. When one or more SAs are found to be embedded, the said compound is

flagged for carcinogenicity (Benigni et al., 2008).

The oral rat LD50 endpoint represent the amount of the chemical that can kill

the half of the rat when fed orally. The dataset for the endpoint was downloaded from

the ChemIDplus database (http://chem.sis.nlm.nih.gov/chemidplus/). The final oral rat

LD50 dataset contained 7413 chemicals. Toxicity was measured according to the

following range (Ruiz et al., 2012) - Super toxic (<5 mg/kg), Extremely toxic (5�50

mg/kg), Very toxic (50�500 mg/kg), Moderately toxic (500�5,000 mg/kg), Slightly

toxic (5,000�15,000 mg/kg) and Practically non-toxic (>15,000 mg/kg).

163

6.3 Results

6.3.1 Phytochemical Properties

In the initial stage, 1605 molecules have been used as initial dataset. Total

number of molecules was reduced to 1217 after removal of salts and complex

mixtures. After removal of salt and complex mixtures, 1217 molecules have been

filtered as input dataset. Relative percentage of these compound datasets are provided

in the following figure.

It was observed that distribution of MW of the molecules exhibit highest

frequency in 101 to 200 Da. Molecular weight <500 Da contribute about 90% in the

current filtered collection. Graphical distribution of the MW is provided in the Figure

35.

Figure 35 : Distribution of molecular weight among the total filtered dataset, drug-like and lead-like compounds

0

50

100

150

200

250

0

150

300

450

600

750

900

1050

1200

1350

1500

1650

1800

1950

2100

2250

2400

More

Freq

uency

MW (Da)

Distribution of MW (Da) among different groups

Total FilteredCompound

164

In the study it was observed that about 70.31% of the total filtered compounds

are Lipsinki compliant while 89.14% showed < 2 violations. Lipinski�s violations of

the total filtered compounds are provided in the Figure 36.

Figure 36 : Percentage of filtered compounds which violate Lipinski's rule

A dataset of chemical for virtual screening with higher diversity is better to

reduce redundancy and enhancing the coverage of biological activity. To study

diversity of selected phytochemical dataset, classical multidimensional scaling was

done in R software. The results are provided in the following figure.

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

0 1 2 3 4

Percentage

ofCo

unts

Lipinski violations

165

Figure 37 : Multidimensional plot showing distribution of compound in chemical space

The pair-wise scatter plots of selected molecular descriptors of the filtered

compound library are shown in the following figures. The plots also showed the

regions of Lipinski compliant area. It shows the comparative population density area

between Lipinski compliant area and non-compliant area with regard to that

descriptors.

166

Figure 38 : Pairwise comparison of mutual relationships between molecular descriptors

Note : (A) MW versus log p, (B) MW versus HBA, (C) MW versus HBD, (D) MW versus NRB; MW in Da; LCA - Lipinski compliant area

For estimating drug-likeness a total of 1217 filtered molecules have been

checked. Out of these 711 molecules have been rejected while another 341 molecules

are put in intermediate category. Only 164 molecules are found to be compliant with

the drug-likeness criteria. Out of these 68 compounds are complaint with lead-likeness

criteria. Compounds passed drug-likeness criteria are provided in the Table 36 and

molecular structure in Figure 39.

167

(+)-Angelicoidenol (1) (+)-Borneol (2) 1,2,3,9-tetrahydro-5-methoxypyrrolo-(2,1-b)-

quinazoline-3-ol (3)

1,3,3-trimethylbicyclo{2.2.1}-heptan-2-ol (4)

1,8-cineole (5) 2-(methyl-amino)-benzyl-alcohol (6)

2,3,5-trimethylpyrazine (7) 2,3-dihydrobenzofuran (8)

2-methyl-5-phenyl-pyridine (9)

2-methyl-pentanoic-acid (10) 2-pentylpyridine (11)

2-phenyl-pyridine (12) 3-(4-methyl-hexyl)-pyridine (13)

3-(4-methyl-phenyl)-pyridine (14) 3-alpha-Acetoxytropane (15)

3-butyl-pyridine (16)

168

3-heptyl-pyridine (17) 3-hydroxy-ethyl-hexanoate (18) CH3

O

O �

CH3

3-methyl-butyl-benzoate (19) 3-methyl-butyric-acid (20) 3-methylcarbazole (21)

H 3C

N

3-octyl-pyridine (22) 3-pentyl-pyridine (23)

3-phenyl-pyridine (24) 3-propyl-pyridine (25) 4-hydroxy-2-piperidinecarboxylic acid

(26)

4-phenyl-pyridine (27) 4-quinazolone (28) 5-acetyl-2-methyl-pyridine (29)

5-hexyl-2-methyl-pyridine (30) 9-acetamido-3,4-dihydropyrido-(3,4-b)-indole

(31)

169

9-carbethoxy-3-methylcarbazole (32)

Acetophenone (3) Acetyl-choline (34)

Achyranthine (35) Adhatodine (36)

Alpha-cedrol (37) Amyl-acetate (38)

Aneurine (39) Anisotine (40)

170

Aporphine (41) Ascorbigen (42)

Atropine (43) Benzoic acid (44)

Benzoic-acid-pentyl-ester (45) Benzoxazolinone (46)

Benzyl-acetate (47) Benzyl-alcohol (48) Betaine (49)

Biotin (50) Borneol-acetate (51)

Borneol-methyl-ether (52) Bornyl-acetate (53)

Brassinolide (54) Butanoic-acid-methyl-ester (55)

171

Butyl-acetate (56) Butyl-benzoate (57) Butyl-hexanoate (58)

Caffeine (59) Capric-acid (60) Caproic-acid-methyl-ester

(61)

Caprylic-acid (62) Carbazole (63) Choline (64)

Cis-2,3-dimethyl-5,6-dithia-

cyclo(2,2,1)heptane-5-oxide (65) Cis-3,5-diethyl-1,2,4-

trithiolane (66) Cis-hexan-3-ol (67)

Citropten (68) Cotinine (69) Coumarin (70)

Crategolic acid (71) Delta-decalactone (72) Delta-dodecalactone (73)

172

Delta-octalactone (74) Diisopropyl-trisulfide (75) Diphenylamine (76)

Dipropyltetrasulfide (77) Dipropyl-trisulfide (78) Dodecanoic-acid (79)

D-quercitol (80) Ephedrine (81) Ethyl-benzoate (82)

H3 C O CH3

O Ethyl-octanoate (83) Gamma-glutamyl-leucine (84)

Gamma-glutamyl-phenylalanine (85) Gamma-glutamyl-phenylalanine-ethyl-ester

(86)

Gamma-L-glutamyl-isoleucine (87) Gamma-L-glutamyl-l-valine (88)

Gamma-nonalactone (89) Gamma-octalactone (90)

173

Glucosan (91) Heptan-2-ol (92) Hexahydro-2H-azepin-2-one

(93)

Hexahydro-3h-1,3-Diazepine-2,4-

Dione (94) Hexan-1-ol (95) Histamine (96)

Hydroxycinnamic-acid (97) Isoamyl-acetate (98) Isobutyl-acetate (99)

Isobutyl-caproate (100) Isobutyl-isovalerate (101)

Isocaespitol (102) Isofebrifugine (103)

Isomenthol (104) Isopropyl-propyl-trisulfide (105)

Ligustrazine (106) Longamide (107)

174

H 3 C

O

HN

HN CH3

O

Marmesin (108) Melatonin (109) Menthol-acetate (110)

Methyl-butyrate (111) Methyl-caprylate (112)

Methyl-cis-propenyl-trisulfide (113) Methyl-heptanoate (114)

Methyl-heptenol (115) Methyl-nicotinate (116)

Methyl-N-methyl-anthranilate (117) Methyl-propyl-tetrasulfide (118)

Methylpropyl-trisulfide (119) Methyl-salicylate (120)

Mevalonic-acid (121) M-methyl-acetophenone (122)

Mukonine (123) Myosmine (124)

175

Neodecanoic-acid (125) N-heptanol (126)

Niacin (127) Nicotine (128) N-methyl-aniline (129)

N-N-dimethyl-3-methyl-aniline (130) N-N-dimethyl-aniline (131)

N-nonanol (132) N-octanol (133)

Nonan-2-ol (134) Noratropine (135)

Octan-1-ol-acetate (136) Octan-2-ol (137)

Octan-3-ol (138) Pantothenic-acid (139)

P-cymen-8-ol (140) Peganine (141) Pipecolic-acid (142)

176

Piperamine (143) Prolamine (144) Pseudotropine (145)

Quinic-acid (146) Quinoline (147) RAA (148)

N

O

NH2

O

Squamolone (149) Stachydrine (150)

Thiamin (151) Toddalolactone (152)

Triacetin (153) Tridecanoic-acid (154)

Trigonelline (155) Tropone (156)

Undecan-2-ol (157) Undecanoic-acid (158)

177

Vasicinone (159) Vasicoline (196)

Vasicolinone (161) Withasomnine (162)

Xanthanol (162) Xylitol (164) Figure 39: Structures of compound passing drug-likeness parameter

Network graph of plants possessing these drug-likeness compounds are

provided in the Figure 40.

179

Detail list of the compounds compliant to drug-likeness criteria and lead-

likeness criteria are presented along with the plants possessing them in the Table 36.

Table 36: Drug-liken and lead-like compounds with corresponding plants

Sl No

Chemical_name Plants Lead Like

1 (+)-Angelicoidenol Zingiber officinale 2 (+)-Borneol Zingiber officinale 3 1,2,3,9-tetrahydro-5-methoxypyrrolo-

(2,1-b)-quinazoline-3-ol Justicia adhatoda +

4 1,3,3-trimethylbicyclo{2.2.1}-heptan-2-ol

Hyptis suaveolens

5 1,8-cineole Cymbopogon citratus, Cyperus rotundus, Helianthus annuus, Hyptis suaveolens, Ocimum tenuiflorum, Piper nigrum, Zingiber officinale

+

6 2-(methyl-amino)-benzyl-alcohol Citrus sinensis 7 2,3,5-trimethylpyrazine Cocos nucifera 8 2,3-dihydrobenzofuran Centella asiatica, Murraya koenigii 9 2-methyl-5-phenyl-pyridine Citrus sinensis + 10 2-methyl-pentanoic-acid Piper nigrum 11 2-pentylpyridine Citrus sinensis 12 2-phenyl-pyridine Citrus sinensis + 13 3-(4-methyl-hexyl)-pyridine Citrus sinensis 14 3-(4-methyl-phenyl)-pyridine Citrus sinensis + 15 3alpha-Acetoxytropane Datura metel +

16 3-butyl-pyridine Citrus sinensis 17 3-heptyl-pyridine Citrus sinensis 18 3-hydroxy-ethyl-hexanoate Citrus sinensis + 19 3-methyl-butyl-benzoate Carica papaya + 20 3-methyl-butyric-acid Piper nigrum 21 3-methylcarbazole Murraya koenigii + 22 3-octyl-pyridine Citrus sinensis 23 3-pentyl-pyridine Citrus sinensis 24 3-phenyl-pyridine Citrus sinensis + 25 3-propyl-pyridine Citrus sinensis 26 4-hydroxy-2-piperidinecarboxylic acid Acacia farnesiana 27 4-phenyl-pyridine Citrus sinensis + 28 4-quinazolone Dichroa febrifuga 29 5-acetyl-2-methyl-pyridine Citrus sinensis 30 5-hexyl-2-methyl-pyridine Citrus sinensis 31 9-acetamido-3,4-dihydropyrido-(3,4-b)-

indole Justicia adhatoda +

32 9-carbethoxy-3-methylcarbazole Murraya koenigii 33 Acetophenone Piper nigrum 34 Acetyl-choline Piper nigrum

180

35 Achyranthine Achyranthes aspera 36 Adhatodine Justicia adhatoda + 37 Alpha-cedrol Zingiber officinale 38 Amyl-acetate Carica papaya 39 Aneurine Acorus calamus + 40 Anisotine Justicia adhatoda 41 Aporphine Annona squamosa + 42 Ascorbigen Momordica charantia 43 Atropine Datura metel 44 Benzoic acid Nyctanthes arbor-tristis 45 Benzoic-acid-pentyl-ester Helianthus annuus + 46 Benzoxazolinone Scoparia dulcis 47 Benzyl-acetate Melia azedarach + 48 Benzyl-alcohol Carica papaya 49 Betaine Achyranthes aspera, Citrus sinensis,

Justicia adhatoda

50 Biotin Nasturtium officinale 51 Borneol-acetate Centella asiatica, Helianthus annuus,

Zingiber officinale

52 Borneol-methyl-ether Zingiber officinale 53 Bornyl-acetate Murraya koenigii, Zingiber officinale 54 Brassinolide Citrus sinensis, Helianthus annuus 55 Butanoic-acid-methyl-ester Carica papaya 56 Butyl-acetate Carica papaya 57 Butyl-benzoate Carica papaya + 58 Butyl-hexanoate Carica papaya + 59 Caffeine Citrus sinensis + 60 Capric-acid Citrus sinensis, Cocos nucifera,

Cymbopogon citratus, Helianthus annuus, Momordica charantia, Zingiber officinale

+

61 Caproic-acid-methyl-ester Helianthus annuus 62 Caprylic-acid Citrus sinensis, Cocos nucifera,

Cymbopogon citratus, Zingiber officinale

63 Carbazole Murraya koenigii + 64 Choline Allium cepa, Carica papaya, Citrus

sinensis, Helianthus annuus, Piper nigrum, Plantago major, Syzygium cuminii, Withania somnifera

65 Cis-2,3-dimethyl-5,6-dithia-cyclo(2,2,1)heptane-5-oxide

Allium cepa +

66 Cis-3,5-diethyl-1,2,4-trithiolane Allium cepa + 67 Cis-hexan-3-ol Zingiber officinale 68 Citropten Citrus medica + 69 Cotinine Carica papaya + 70 Coumarin Ageratum conyzoides 71 Crategolic acid Syzygium cuminii

181

72 Delta-decalactone Cocos nucifera + 73 Delta-dodecalactone Cocos nucifera 74 Delta-octalactone Carica papaya, Cocos nucifera 75 Diisopropyl-trisulfide Allium cepa 76 Diphenylamine Allium cepa + 77 Dipropyltetrasulfide Allium cepa + 78 Dipropyl-trisulfide Allium cepa + 79 Dodecanoic-acid Zingiber officinale 80 D-quercitol Cissampelos pareira 81 Ephedrine Sida rhombifolia + 82 Ethyl-benzoate Carica papaya + 83 Ethyl-octanoate Carica papaya + 84 Gamma-glutamyl-leucine Allium cepa 85 Gamma-glutamyl-phenylalanine Allium cepa 86 Gamma-glutamyl-phenylalanine-ethyl-

ester Allium cepa +

87 Gamma-l-glutamyl-isoleucine Allium cepa 88 Gamma-l-glutamyl-l-valine Allium cepa 89 Gamma-nonalactone Cocos nucifera + 90 Gamma-octalactone Carica papaya 91 Glucosan Citrus sinensis 92 Heptan-2-ol Cocos nucifera, Zingiber officinale 93 Hexahydro-2h-Azepin-2-One Helianthus annuus 94 Hexahydro-3h-1,3-Diazepine-2,4-Dione Annona squamosa 95 Hexan-1-ol Zingiber officinale 96 Histamine Helianthus annuus 97 Hydroxycinnamic-acid Plantago major + 98 Isoamyl-acetate Carica papaya 99 Isobutyl-acetate Carica papaya 100 Isobutyl-caproate Piper nigrum + 101 Isobutyl-isovalerate Piper nigrum + 102 Isocaespitol Acorus calamus 103 Isofebrifugine Dichroa febrifuga 104 Isomenthol Helianthus annuus 105 Isopropyl-propyl-trisulfide Allium cepa 106 Ligustrazine Cocos nucifera 107 Longamide Piper longum + 108 Marmesin Aegle marmelos + 109 Melatonin Allium cepa, Zingiber officinale + 110 Menthol-acetate Zingiber officinale 111 Methyl-butyrate Citrus sinensis 112 Methyl-caprylate Zingiber officinale + 113 Methyl-cis-propenyl-trisulfide Allium cepa + 114 Methyl-heptanoate Piper nigrum 115 Methyl-heptenol Cymbopogon citratus

182

116 Methyl-nicotinate Carica papaya 117 Methyl-n-methyl-anthranilate Citrus sinensis + 118 Methyl-propyl-tetrasulfide Allium cepa 119 Methylpropyl-trisulfide Allium cepa + 120 Methyl-salicylate Carica papaya, Murraya koenigii + 121 Mevalonic-acid Allium cepa, Citrus sinensis 122 M-methyl-acetophenone Piper nigrum 123 Mukonine Murraya koenigii + 124 Myosmine Carica papaya 125 Neodecanoic-acid Allium cepa + 126 N-heptanol Melia azedarach 127 Niacin Achyranthes aspera, Aegle marmelos,

Allium cepa, Annona squamosa, Carica papaya, Centella asiatica, Citrus sinensis, Cocos nucifera, Helianthus annuus, Mangifera indica, Momordica charantia, Murraya koenigii, Nasturtium officinale, Piper nigrum, Plantago major, Syzygium cuminii, Zingiber officinale

128 Nicotine Carica papaya, Withania somnifera + 129 N-methyl-aniline Citrus sinensis 130 N-n-dimethyl-3-methyl-aniline Citrus sinensis 131 N-n-dimethyl-aniline Citrus sinensis 132 N-nonanol Zingiber officinale 133 N-octanol Zingiber officinale 134 Nonan-2-ol Zingiber officinale 135 Noratropine Datura metel 136 Octan-1-ol-acetate Zingiber officinale + 137 Octan-2-ol Zingiber officinale 138 Octan-3-ol Carica papaya 139 Pantothenic-acid Allium cepa, Annona squamosa, Carica

papaya, Citrus sinensis, Mangifera indica, Zingiber officinale

+

140 P-cymen-8-ol Murraya koenigii, Piper nigrum, Zingiber officinale

+

141 Peganine Justicia adhatoda + 142 Pipecolic-acid Momordica charantia, Zingiber officinale 143 Piperamine Piper nigrum 144 Prolamine Zingiber officinale + 145 Pseudotropine Withania somnifera 146 Quinic-acid Allium cepa, Citrus sinensis, Cocos

nucifera, Helianthus annuus, Withania somnifera

147 Quinoline Annona squamosa 148 RAA Justicia adhatoda 149 Squamolone Annona squamosa 150 Stachydrine Citrus sinensis

183

151 Thiamin Achyranthes aspera, Aegle marmelos, Allium cepa, Annona squamosa, Carica papaya, Centella asiatica, Citrus sinensis, Cocos nucifera, Helianthus annuus, Mangifera indica, Momordica charantia, Murraya koenigii, Piper nigrum, Syzygium cuminii, Zingiber officinale

+

152 Toddalolactone Toddalia asiatica + 153 Triacetin Carica papaya + 154 Tridecanoic-acid Cocos nucifera 155 Trigonelline Allium cepa 156 Tropone Acorus calamus 157 Undecan-2-ol Zingiber officinale 158 Undecanoic-acid Cocos nucifera 159 Vasicinone Justicia adhatoda + 160 Vasicoline Justicia adhatoda + 161 Vasicolinone Justicia adhatoda + 162 Withasomnine Withania somnifera + 163 Xanthanol Xanthium strumarium + 164 Xylitol Allium cepa, Carica papaya

Summary of the various physico-chemical properties of the filtered

compounds, drug-like and lead-like compounds are provided in the Table 37.

Table 37: Summary of the physico-chemical properties of all filtered ocmpounds, drug-like and lead-like compounds with various subsets

Library name Library Size MW (Da) log P HBA HBD NRB

All filtered compounds

1217 287.014 3.214 3.802 1.727 4.709

Drug-Like 164 177.030 1.701 2.506 1.084 3.066 Lead-Like 68 196.850 2.140 2.412 0.721 3.250

Note : MW (Da) � mean of Molecular weight in Dalton, log p � mean of the logarithm of the calculated octan-1-ol�water partition coefficient; HBA - mean number of hydrogen bond acceptors, HBD - mean number of hydrogen bond donors and NRB - mean number of rotatable bonds.

6.3.2 Toxicity Estimation

From the initial set of 1605 compounds, 1347 compounds are selected by

removing ubiquitous compounds such as sugars, amino acids. These compounds are

more than those for the drug likeness prediction by including compound mixtures,

salts. Results of the with regard to Ames mutagenicity test, Oral Rat Lethal Dose LD50,

184

carcinogenicity results are provided in the following section. Network graph of the

plants possessing toxic properties are shown in Figure 41

In the present study, 137 compounds out of 1347 compounds are predicted to

be positive in Ames mutagenicity test. In the test of carcinogenicity, 238 compounds

are observed to positive in genotoxic carcinogenicity while 87 compounds are

predicted to be positive in non-genotoxic carcinogenicity.

Compounds showing mutagenicity positive are listed along with the predicted

values in the Table 38. In this section compound which are predicted to cause

carcinogenicity (both genotoxic and nongenotoxic) are listed. Only the compounds

with predicted results are shown.

186

Table 38 : In silico mutagenicity and carcinogenicity results of the compound dataset

Sl No Compound plants GC NGC Mut 1 (-)-Cubebin Piper nigrum - + - 2 (+)-Calamusenone Acorus calamus + - - 3 (+)-Verbenone Verbena officinalis + - - 4 (E,e)-2,4-heptadienal Murraya koenigii + - - 5 (Z)-2-hexenal Murraya koenigii + - + 6 1,1,4-

trimethylcyclohepta-2,4-dien-6-one

Piper nigrum + - -

7 1,2-bis(4-allyl-2-methoxyphenoxy)-3-(4-hydroxy-3-methoxyphenyl)-3-methoxypropane

Ocimum tenuiflorum + - -

8 1,3,6-trigalloylglucose Terminalia chebula - + - 9 1,3,7,8-

tetrahydroxyxanthone Swertia chirata - - +

10 1,8-cineole Cymbopogon citratus, Cyperus rotundus, Helianthus annuus, Hyptis suaveolens, Ocimum tenuiflorum, Piper nigrum, Zingiber officinale

- + -

11 1,8-dihydroxy-2-methylanthraquinone-3-o-beta-d-galactopyranoside

Melia azedarach + - +

12 1,8-dihydroxy-3,7-dimethoxyxanthone

Swertia chirata - - +

13 10-dehydrogingerdione Zingiber officinale + - - 14 10-gingerdione Zingiber officinale + - - 15 17-epiazadiradione Azadirachta indica, Melia azedarach + - 16 1-allyl-4-(5-allyl-2-

hydroxy-3-methoxyphenoxy)-3-(4-allyl-2-methoxyphenoxy)-5-methoxybenzene

Ocimum tenuiflorum + - -

17 1-hydroxy-3,5,8-trimethoxyxanthone

Swertia chirata - - +

18 1-methyl-2-(2-propenyl)-benzene

Murraya koenigii + - -

19 1-o-caffeoyl-beta-d-glucose

Allium cepa + - -

20 1-propyltrithio-propane Allium cepa - - + 21 2-(3-methyl-but-2-enyl-

amino)-purin-6-one Cocos nucifera - - +

22 2-(methyl-amino)-benzyl-alcohol

Citrus sinensis + - +

23 2,3-dehydrosomnifericin Withania somnifera + -

187

24 2,4,5-trimethoxybenzaldehyde

Acorus calamus + - -

25 2',4'-dihydroxy-2,3',6'-trimethoxychalcone

Scutellaria discolor + - -

26 2,5-dimethoxyquinone Acorus calamus + - - 27 2,6-

dimethoxybenzoquinone Rauvolfia serpentina + - -

28 2,6-dimethyl-oct-7-ene-2,3,6-triol

Carica papaya - + -

29 2-hydroxy-6-methylcarbazole

Murraya koenigii + - +

30 2-methyl-but-2-en-1-al Allium cepa + - - 31 2-methyl-butan-1-al Carica papaya + - - 32 2-methyl-butanal Murraya koenigii + - - 33 2-methyl-pent-2-en-1-al Allium cepa + - + 34 2-methyl-pentanoic-acid Piper nigrum - + - 35 2-phenyl-pyridine Citrus sinensis - - + 36 3-(5-allyl-2-hydroxy-3-

methoxyphenyl)-1-(4-hydroxy-3-methoxyphenoxy)-prop-1-ene

Ocimum tenuiflorum + - -

37 3,4-dihydroxy-6-(n-ethyl-amino)-benzamide

Piper nigrum + - +

38 3,4-dimethyl-2,5-dioxo-2,5-dihydrothiophene

Allium cepa + - -

39 3,5,6-trihydroxy-7,3',4'-trimethoxy-flavone

Citrus medica - + -

40 3,6-digalloylglucose Terminalia chebula + + - 41 3-cyclohexen-1-

carboxaldehyde Hyptis suaveolens + - -

42 3-glucosylquercetin Centella asiatica - + - 43 3-methylcarbazole Murraya koenigii + - + 44 3-phenyl-benzaldehyde Zingiber officinale + - + 45 3-phenyl-pyridine Citrus sinensis - - + 46 3-tigloylhydroxytropane Withania somnifera + - 47 4-campesten-3-one Melia azedarach + - - 48 4-phenyl-benzaldehyde Zingiber officinale + - - 49 4-phenyl-pyridine Citrus sinensis - - + 50 5alpha-Androst-9(11)-

En-12-One Hyptis suaveolens + - -

51 5-hydroxy-3,6,7,3',4'-pentamethoxyflavone

Verbena officinalis - + -

52 5-hydroxytryptamine Carica papaya, Momordica charantia - - + 53 6,7-dimethoxy-2,2-

dimethylchromene Ageratum conyzoides - - +

54 6-dehydrogingerdione Zingiber officinale + - - 55 6-gingerdione Zingiber officinale + - -

188

56 6-hydroxy-7-methoxy-coumarin

Melia azedarach + - -

57 6-shogaol Zingiber officinale + - - 58 9-carbethoxy-3-

methylcarbazole Murraya koenigii + - +

59 9-formyl-3-methylcarbazole

Murraya koenigii + - +

60 Aceteugenol Acorus calamus + - - 61 Acoragermacrone Acorus calamus + - - 62 Adhatodine Justicia adhatoda + - - 63 Aframodial Zingiber officinale + - - 64 Ageratochromene Ageratum conyzoides - - + 65 Ajmaline Rauvolfia serpentina - + - 66 Aknadicine Stephania japonica + - - 67 Aknadinine Stephania hernandifolia + - - 68 Aloe-emodin Oroxylum indicum + - + 69 Alpha-cyperone Cyperus rotundus + - - 70 Alpha-fagarine Aegle marmelos - + - 71 Alpha-rotunol Cyperus rotundus + - + 72 Anisotine Justicia adhatoda + - + 73 Anolobine Annona squamosa - + + 74 Anonaine Annona squamosa - + + 75 Antheraxanthin Carica papaya, Citrus sinensis + - - 76 Anthranilic-acid-methyl-

ester Citrus sinensis + - -

77 Anthraquinone Oroxylum indicum + - + 78 Apohyoscine Datura metel + - - 79 Aporphine Annona squamosa - - + 80 Arabinose Allium cepa, Helianthus annuus + - - 81 Arvenin-iii Picorrhiza kurooa + - - 82 Asaronaldehyde Acorus calamus + - - 83 Ascaridol Chenopodium ambrosioides - + - 84 Astragalin Centella asiatica, Melia azedarach,

Nyctanthes arbor-tristis, Piper nigrum - - +

85 Aurapten Aegle marmelos + - - 86 Auraptene Citrus sinensis + - - 87 Ayapin Helianthus annuus + + - 88 Azadirachtin Azadirachta indica + - - 89 Bebeerine Cissampelos pareira - - + 90 Benzaldehyde Carica papaya, Murraya koenigii, Zingiber

officinale + - -

91 Benzyl-isothiocyanate Allium cepa, Carica papaya + - + 92 Berberine Berberis aristata, Coptis teeta, Thalictrum

foliolosum + + -

93 Bergapten Citrus sinensis, Murraya koenigii + - - 94 Bergaptol Citrus sinensis + - -

189

95 Beta-cyperone Cyperus rotundus + - - 96 Beta-ionone Zingiber officinale + - - 97 Beta-rotunol Cyperus rotundus + - + 98 Bicyclomahanimbicine Murraya koenigii + - - 99 Bicyclomahanimbine Murraya koenigii + - + 100 Borneol-acetate Centella asiatica, Helianthus annuus,

Zingiber officinale - - +

101 Butanedione Carica papaya + - + 102 Cadalene Annona squamosa - - + 103 Calacone Acorus calamus + - - 104 Calamenene Piper nigrum, Zingiber officinale - - + 105 Carbazole Murraya koenigii + - + 106 Carvone Citrus sinensis, Piper nigrum + - - 107 Casticin Vitex negundo - + - 108 Catalpol Picrorhiza scrophulariaeflora, Plantago

major + + +

109 Chanoclavine Argyreia nervosa + - - 110 Chavibetol Ocimum tenuiflorum + - - 111 Chavicine Piper nigrum + + - 112 Chavicol Melia azedarach, Zingiber officinale + - - 113 Chebulagic-acid Terminalia chebula + + + 114 Chlorobutanol Xanthium strumarium - + - 115 Cineole Aegle marmelos, Centella asiatica,

Hedychium spicatum, Ocimum tenuiflorum, Zingiber officinale

- + -

116 Cis-jasmone Murraya koenigii + - - 117 Cissampareine Cissampelos pareira + - + 118 Citronellal Aegle marmelos, Citrus sinensis,

Cymbopogon citratus, Piper nigrum, Zingiber officinale

+ - -

119 Citropten Citrus medica + - - 120 Citrunobin Citrus sinensis + - - 121 Corilagin Terminalia chebula, Mangifera indica - + - 122 Corydine Annona squamosa - + + 123 Coumarin Ageratum conyzoides + - - 124 Crotonoside Croton tiglium + - - 125 Cryptone Piper nigrum + - + 126 Cubenol Melia azedarach - + - 127 Cuminaldehyde Aegle marmelos + - - 128 Cycleanine Cissampelos pareira - - + 129 Cyclocolorenone Magnolia grandiflora + - - 130 Cyclomahanimbine Murraya koenigii + - + 131 Decan-1-al Zingiber officinale + - - 132 Decanal Carica papaya, Citrus sinensis,

Cymbopogon citratus, Zingiber officinale, Ocimum tenuiflorum

+ - -

190

133 Dehydroshikimic-acid Terminalia chebula + - - 134 Diallyl-trisulfide Allium cepa - - + 135 Dimethyl-disulfide Allium cepa - - + 136 Dimethyltetrasulfide Allium cepa - - + 137 Di-o-methylgalactose Plantago major + - - 138 Dipropyltetrasulfide Allium cepa - - + 139 Dodecanal Citrus sinensis + - - 140 Ecdysterone Achyranthes aspera + - - 141 Echinatine Ageratum conyzoides + + - 142 Elemicin Acorus calamus + - - 143 Enicoflavine Swertia chirata + - + 144 Epistephamiersine Stephania japonica - + - 145 Epistephanine Stephania japonica - - + 146 Epoxyazadiradione Azadirachta indica + - - 147 Ergine Argyreia nervosa - - + 148 Esculetin Melia azedarach + - - 149 Ethyl-eugenol Ageratum conyzoides + - - 150 Ethyl-vanillin Ageratum conyzoides + - - 151 Eugenin Syzygium cuminii + - - 152 Eugenol Helianthus annuus, Melia azedarach,

Ocimum tenuiflorum, Piper nigrum, Zingiber officinale

+ - -

153 Eugenol-methyl-ether Ocimum tenuiflorum, Piper nigrum + - - 154 Fagarine Aegle marmelos + - + 155 Fangchinoline Stephania hernandifolia - - + 156 Furfural Centella asiatica, Cymbopogon citratus,

Murraya koenigii, Zingiber officinale + - +

157 Furfurol Mangifera indica - - + 158 Galanolactone Zingiber officinale + - - 159 Gallocatechin Mangifera indica - - + 160 Gamma-asarone Acorus calamus + - - 161 Gamma-l-glutamyl-

arginine Allium cepa - - +

162 Gamma-l-glutamyl-cysteine

Allium cepa - - +

163 Gedunin Azadirachta indica, Melia azaderach + - - 164 Gingerenone-C Zingiber officinale + - - 165 Girinimbine Murraya koenigii + - + 166 Glaucine Annona squamosa - + - 167 Glyoxal Zingiber officinale + - + 168 Gossypol Helianthus annuus + + - 169 Guineensine Piper longum, Piper nigrum + + 170 Hasubanonine Stephania japonica + - - 171 Hayatidine Cissampelos pareira - - + 172 Hayatine Cissampelos pareira - - + 173 Hayatinine Cissampelos pareira - - +

191

174 Hedychenone Hedychium spicatum + - - 175 Heliangin Helianthus annuus + - + 176 Heliotropin Piper nigrum + + - 177 Heptan-1-al Centella asiatica + - - 178 Heptanal Carica papaya, Citrus sinensis + - - 179 Hernandifoline Stephania hernandifolia - + + 180 Hernandoline Stephania japonica + - - 181 Hex-3-en-2-one Centella asiatica + - - 182 Hexahydrocurcumin Zingiber officinale + - - 183 Hexan-1-al Centella asiatica, Helianthus annuus,

Zingiber officinale + - +

184 Histamine Helianthus annuus - + - 185 Homomangiferin Mangifera indica - - + 186 Homostephanoline Stephania japonica + - - 187 Hyperin Melia azedarach - + - 188 Hyperoside Azadirachta indica, Piper nigrum - + - 189 Hypoepistephanine Stephania japonica - - + 190 Insularine Stephania japonica - - + 191 Isoajmaline Rauvolfia serpentina - + - 192 Isochondodendrine Cissampelos pareira, Stephania japonica - - + 193 Isocorydine Annona squamosa - + + 194 Isofebrifugine Dichroa febrifuga - - + 195 Isogingerenone-B Zingiber officinale + - - 196 Isoheraclenin Murraya koenigii + - 197 Isoimperatorin Murraya koenigii + - - 198 Isoliquiritigenin Helianthus annuus + - - 199 Isomahanimbine Murraya koenigii + - - 200 Isopimpinellin Murraya koenigii + - + 201 Isopiperine Piper nigrum + + 202 Isoquercitrin Allium cepa, Centella asiatica, Piper

nigrum - + -

203 Isorhamnetin Allium cepa - + + 204 Isosafrole Murraya koenigii - + - 205 Isoshyobunone Acorus calamus + - - 206 Isotrilobine Stephania japonica - - + 207 Isovaleraldehyde Cymbopogon citratus, Zingiber officinale + - - 208 Jatrorrhizine Coptis teeta, Thalictrum foliolosum + - - 209 Kaempferol-3-o-

glucoside Syzygium cuminii - - +

210 Koenigine Murraya koenigii + - + 211 Koenine Murraya koenigii + - + 212 Kutkoside Picorrhiza kurooa + + - 213 Lantadene-A Lantana camara + - - 214 Lanuginosine Annona squamosa + + - 215 Limettin Citrus medica + - -

192

216 Limonin Citrus medica, Citrus sinensis + - - 217 Liriodenine Annona squamosa, Michelia champaca + + + 218 L-rhamnose Cocos nucifera + - - 219 Luteolin Clerodendrum serratum, Cymbopogon

citratus, Ocimum tenuiflorum, Plantago major

- - +

220 Lycopsamine Ageratum conyzoides + + - 221 Magnoflorine Thalictrum foliolosum - + + 222 Mahanimbine Murraya koenigii + - - 223 Mahanimbinine Murraya koenigii + - + 224 Mangiferin Mangifera indica, Swertia chirata - - + 225 Marmelosin Aegle marmelos + - - 226 Marmesin Aegle marmelos + - + 227 Marmin Aegle marmelos + + - 228 Melampomagnolide A Magnolia grandiflora + - - 229 Melialactone Melia azaderach - - + 230 Melianone Melia azedarach + - - 231 Melicitrin Melia azedarach - + + 232 Metaphanine Stephania japonica - + - 233 Methyl-chavicol Ocimum tenuiflorum + - - 234 Methyl-cis-propenyl-

trisulfide Allium cepa - - +

235 Methyl-cyclohepta-2,4-dien-6-one

Piper nigrum + - -

236 Methyl-glyoxal Zingiber officinale + - + 237 Methyl-n-methyl-

anthranilate Citrus sinensis + - -

238 Methyl-propenyl-trisulfide

Allium cepa - - +

239 Methyl-propyl-tetrasulfide

Allium cepa - - +

240 Methyl-thiocyanate Carica papaya - - + 241 Methyl-trans-propenyl-

trisulfide Allium cepa - - +

242 Michelalbine Annona squamosa - + + 243 Mukonine Murraya koenigii + - - 244 Murrayacine Murraya koenigii + - + 245 Murrayanine Murraya koenigii + - - 246 Myricetin Azadirachta indica, Citrus sinensis,

Mangifera indica, Zingiber officinale - + +

247 Myristicin Piper nigrum + + - 248 Myrtenal Helianthus annuus, Piper nigrum, Zingiber

officinale + - -

249 Neosakuranin Prunus cerasoides + - - 250 Nimbaflavone Azadirachta indica + - - 251 Nimbin Azadirachta indica, Melia azaderach + - - 252 Nimbolide Azadirachta indica + - -

193

253 N-methyl-aniline Citrus sinensis + - - 254 N-n-dimethyl-3-methyl-

aniline Citrus sinensis + - -

255 N-n-dimethyl-aniline Citrus sinensis + - - 256 Nomilin Citrus sinensis + - - 257 Nonan-1-al Zingiber officinale + - - 258 Nonanal Carica papaya, Citrus sinensis, Zingiber

officinale + - -

259 Nootkatone Citrus sinensis + - - 260 Norcorydine Annona squamosa - + 261 Nordentatin Citrus medica, Citrus sinensis + - + 262 Norhyoscine Datura metel + - + 263 Norisocorydine Annona squamosa - + + 264 Norlaureline Annona squamosa - + + 265 Obacunone Citrus sinensis + - - 266 Obamegine Stephania japonica - - + 267 Octan-1-al Citrus sinensis, Zingiber officinale + - - 268 Octanal Carica papaya, Citrus sinensis + - - 269 Octopamine Citrus sinensis - - + 270 Orientin Ocimum tenuiflorum - - + 271 Ornithine Annona squamosa, Momordica charantia,

Murraya koenigii - - +

272 Osthol Citrus sinensis + - + 273 Oxostephamiersine Stephania japonica - + - 274 Oxostephanine Stephania japonica + + + 275 Oxypeucedanin Murraya koenigii + - - 276 Pachypodol Vitex peduncalaris - + - 277 Pantothenic-acid Allium cepa, Annona squamosa, Carica

papaya, Citrus sinensis, Mangifera indica, Zingiber officinale

- + -

278 Penniclavine Argyreia nervosa - - + 279 Perillaldehyde Citrus sinensis, Piper nigrum, Zingiber

officinale + - -

280 Phellandral Lantana camara + - - 281 Phenethyl isothiocyanate Nasturtium officinale + - + 282 Phenyl-acetaldehyde Helianthus annuus + - - 283 Phlorin Citrus sinensis + - - 284 Phorbol Croton tiglium + - - 285 Phorbol-12-tiglate-13-

decanoate Croton tiglium + - -

286 Phylloquinone Citrus sinensis, Cocos nucifera, Helianthus annuus

+ - -

287 Picroside I Picorrhiza kurooa + + - 288 Picroside-ii Picorrhiza kurooa + + - 289 Pimpinellin Toddalia asiatica + - + 290 Piperanine Piper nigrum + + +

194

291 Piperine Piper longum, Piper nigrum + + - 292 Piperitone Piper nigrum + - - 293 Piperylin Piper nigrum + + 294 PL Lantana camara + - - 295 Prometaphanine Stephania japonica - + - 296 Prunetin Oroxylum indicum + - - 297 Prunetinoside Prunus cerasoides + - - 298 Psoralen Aegle marmelos + - - 299 Quercetagetin Citrus sinensis - + + 300 Quercetin Ageratum conyzoides, Allium cepa,

Azadirachta indica, Centella asiatica, Citrus sinensis, Cymbopogon citratus, Helianthus annuus, Holarrhena pubescens, Mangifera indica, Melia azedarach, Piper nigrum, Syzygium cuminii, Withania somnifera, Zingiber officinale

- + +

301 Quercetin-3,4'-diglucoside

Allium cepa - + -

302 Quercitrin Azadirachta indica, Melia azedarach, Piper nigrum

- + +

303 Quinoline Annona squamosa - - + 304 Raugalline Rauvolfia serpentina - + - 305 Rhamnetin Piper nigrum - + - 306 Rutin Acacia farnesiana, Aegle marmelos, Allium

cepa, Azadirachta indica, Citrus sinensis, Cymbopogon citratus, Melia azedarach, Piper nigrum, Withania somnifera

- + -

307 Safrole Piper nigrum + + - 308 Sarpagine Rauvolfia serpentina - - + 309 Scoparone Citrus medica, Citrus sinensis + - - 310 Scopolamine Datura metel, Justicia adhatoda + - - 311 Scopoletin Azadirachta indica, Citrus medica,

Helianthus annuus, Melia azedarach, Withania somnifera

+ - -

312 Scopolin Murraya koenigii + - - 313 Sennoside-A Terminalia chebula - - + 314 Sesamin Piper longum - + - 315 Seselin Citrus sinensis + - + 316 Skimmianine Aegle marmelos, Toddalia asiatica + - + 317 Spilanthol Spilanthes paniculata - - + 318 Spiraeoside Allium cepa - + - 319 Stebisimine Stephania japonica - - + 320 Stephanaberrine Stephania japonica - + - 321 Stephanine Stephania japonica - + + 322 Stephasunoline Stephania japonica - + - 323 Stepholine Stephania japonica - - + 324 Stigmast-4-en-3-one Melia azedarach + - -

195

325 Suberenol Citrus sinensis + - + 326 Suberosin Citrus sinensis + - + 327 Sugeonol Cyperus rotundus + - - 328 Swerchirin Swertia chirata - - + 329 Swertianin Swertia chirata - - + 330 Syringaldehyde Cocos nucifera + - - 331 Terchebin Terminalia chebula + - - 332 Terpin-1-en-4-ol Piper nigrum - + - 333 Tetradecanal Citrus sinensis + - - 334 Tetrandrine Cissampelos pareira - - + 335 Thebaine Rauvolfia serpentina + - - 336 Theviridoside Lantana camara - - + 337 Toddalolactone Toddalia asiatica + + - 338 Trans-2-hexenal Citrus sinensis + - + 339 Trans-6-shogaol Zingiber officinale + - 340 Trans-octen-2-al Zingiber officinale + - + 341 Trichostachine Piper nigrum + + - 342 Tropone Acorus calamus + - - 343 Ubiquinone Piper nigrum + - - 344 Umbelliferon Citrus medica, Clausena excavata + - - 345 Undecanal Citrus sinensis + - - 346 Vanillin Cocos nucifera, Helianthus annuus, Melia

azedarach, Zingiber officinale + - -

347 Vasicolinone Justicia adhatoda + - - 348 Verbenone Helianthus annuus + - - 349 Vicine Momordica charantia - - + 350 Violaxanthin Carica papaya, Citrus sinensis, Helianthus

annuus + - -

351 Vitexin Vitex peduncalaris - - + 352 Vomalidine Rauvolfia serpentina - + - 353 Withaferin A Withania somnifera + - - 354 Withametelin Datura metel + - - 355 Withasomnine Withania somnifera - - + 356 Xanthanol Xanthium strumarium - - + 357 Xanthoxyletin Citrus sinensis + - + 358 Xanthyletin Citrus medica, Citrus sinensis + - + 359 Zeatin Momordica charantia - + + 360 Zerumbodienone Zingiber officinale + - -

196

Out of the 1347 chemicals screened, compounds with slightly toxic and

practically non-toxic are comparatively less than toxic compounds including moderate

types. In the present study, moderately toxic compounds are highest with 798,

followed by slightly toxic with 224. Very toxic compounds are 194 and practically

non-toxic compounds are 62. Relative distribution of different compound categories

is represented in the Figure 42.

Figure 42 : Percentage of the toxicity observed in the compound dataset

In these test, 2 compounds and 31 compounds are predicted as Super Toxic

and Extremely Toxic respectively. These compounds are listed in the Table 39.

Table 39 : List of the compound included in the Super Toxic, Extremely Toxic and Very Toxic categories in the Oral Rat LD 50 test

Sl No.

Chemical name Plant Name Predicted Value mg/kg

Super Toxic 1 Salannin Azadirachta indica 2.12 2 Withaferin A Withania somnifera 4.92 Extremely toxic 1 14-deoxy-11-

oxoandrographolide Andrographis paniculata 40.62

2 Antheraxanthin Carica papaya, Citrus sinensis 13.24

ExtremelyToxic2%

ModeratelyToxic61%

Practicallynon Toxic

5%

Slightly Toxic17%

Super Toxic0%

Very Toxic15%

197

3 Arvenin-iii Picorrhiza kurooa 6.99 4 Azadirachtin Azadirachta indica 27.18 5 Beta-carotene-5,6-

epoxide Carica papaya 36.61

6 Cycloeucalenol Allium cepa, Melia azedarach 38.31 7 Deoxyandrographolide Andrographis paniculata 35.31 8 Epoxyazadiradione Azadirachta indica 14.72 9 Flavoxanthin Citrus sinensis 39.64 10 Gedunin Azadirachta indica, Melia azaderach 13.02 11 Glaucine Annona squamosa 15.46 12 Heliangin Helianthus annuus 24.53 13 Ingenol-3,20-dibenzoate Croton tiglium 8.65 14 Isocorydine Annona squamosa 23.86 15 Limonin Citrus medica, Citrus sinensis 5.46 16 Lutein Allium cepa, Citrus sinensis, Helianthus annuus,

Momordica charantia 40.39

17 Magnoflorine Thalictrum foliolosum 22.84 18 Mutatoxanthin Citrus sinensis 8.86 19 Neoandrographolide Andrographis paniculata 24.7 20 Nimbolide Azadirachta indica 17.75 21 Nomilin Citrus sinensis 22.78 22 Norisocorydine Annona squamosa 34.14 23 Obacunone Citrus sinensis 10.5 24 Phorbol Croton tiglium 11.73 25 Phorbol-12-tiglate-13-

decanoate Croton tiglium 15.91

26 Picroside-i Picorrhiza kurooa 38.15 27 Protostephanine Stephania japonica 14.15 28 Stephanine Stephania japonica 22.64 29 Violaxanthin Carica papaya, Citrus sinensis, Helianthus annuus 39.76 30 Withametelin Datura metel 37.88 31 Xanthophyll Mangifera indica 40.39