Thiazole fused thiosemicarbazones: Microwave-assisted synthesis, biological evaluation and molecular docking study

Article abstract of DOI:10.1016/j.molstruc.2018.11.025

In the present study, series of novel compounds (E)-2-(1-(4-methyl-2-(substituted-phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothio-amide (5a-j) and (E)-N-cyclohexyl-2-(1-(4-methyl-2-(substituted-phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothio

Full text of DOI:10.1016/j.molstruc.2018.11.025

Accepted Manuscript
Thiazole fused thiosemicarbazones: Microwave-assisted synthesis, biological
evaluation and molecular docking study
Neelam P. Prajapati, Kinjal D. Patel, Rajesh H. Vekariya, Hitesh D. Patel, Dhanaji P.
Rajani
PII:
S0022-2860(18)31329-2
DOI:
https://doi.org/10.1016/j.molstruc.2018.11.025
MOLSTR 25854
Reference:
To appear in: Journal of Molecular Structure
Received Date: 13 October 2018
Revised Date: 7 November 2018
Accepted Date: 7 November 2018
Please cite this article as: N.P. Prajapati, K.D. Patel, R.H. Vekariya, H.D. Patel, D.P. Rajani, Thiazole
fused thiosemicarbazones: Microwave-assisted synthesis, biological evaluation and molecular docking
study, Journal of Molecular Structure (2018), doi: https://doi.org/10.1016/j.molstruc.2018.11.025.
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ACCEPTED MANUSCRIPT
Biological Evaluation
Molecular Docking
In-silico ADME Study

ACCEPTED MANUSCRIPT
Thiazole Fused Thiosemicarbazones: Microwave-Assisted Synthesis,
Biological Evaluation and Molecular Docking Study
Neelam P. Prajapatia, Kinjal D. Patela, Rajesh H. Vekariyaa, Hitesh D. Patel*a, Dhanaji P.
Rajanib
a Department of Chemistry, School of Sciences, Gujarat University, Navarangpura, Ahmedabad, Gujarat, India.
b Microcare laboratory and TRC, Surat, Gujarat, India.
•
Blue colour represents the changes made as per the reviewer’s suggestions.
Abstract:
In the present study, series of novel compounds (E)-2-(1-(4-methyl-2-(substituted-
phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothio-amide (5a-j) and (E)-N-cyclohexyl-
2-(1-(4-methyl-2-(substituted-phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothioamide
(6a-j) have been synthesized using microwave irradiation method in high yields and
characterized by IR, 1H-NMR, 13C-NMR and mass spectral analysis. Synthesized compounds
were evaluated for their in-vitro antimicrobial, antimalarial and anti-tuberculosis activity as
well as in-silico study. The obtained results indicate that compound 6b and 6g were found to
be the most potent against S. aureus bacterial strain. Further, the molecular docking study has
been performed for all the new compounds with the immune system of S. aureus (PDB ID:
5D1Q) as a target enzyme, and this study validated the experimental results.
Keywords: 5D1Q, Biological activity, Microwave chemistry, Thiazole, Thiosemicarbazone
1. Introduction
So far the heterocycles form the major divisions of organic chemistry due to their immense
industrial as well as biological use [1]. From the last few decades, we have seen that
researchers mainly focus in a heterocyclic compound containing sulfur and nitrogen, because

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compound that possesses sulfur and nitrogen atoms are essential for living organisms. Hence,
sulfur and nitrogen-containing small ring heterocyclic compounds have been under
investigation for a long time on account of their therapeutic relevance and their synthetic
diversity [2-6]. Among the wide range of heterocycles, thiazole occupies a vital role in
medicinal chemistry [7-10]. Thiazole ring is an essential core scaffold found in a various
natural compound such as thiamine (Vitamin B1), thiamine pyrophosphate and various
synthetic medicinally important compounds [11-14]. Thiazole derivatives are having wide
range of applications in various field such as agrochemicals, material science especially in the
preparation of liquid crystals, cosmetic industry, sensors and pharmacological activities such
as anticancer, antifungal, antiviral, antibacterial, anti-inflammatory etc. that can be represent
by the large number of drugs in the market [15-16]. Thiazole is also used in the synthesis and
applications of biomimicking and bioactive coordination compounds due to the versatile
coordination ability of nitrogen and sulfur atoms toward various transition metal ions [17].
Thiosemicarbazones are very important class of compounds due to its pharmacological
applications and are also belong to a large group of thiourea derivatives which show chemical
functionality in biologically active molecules [18]. Literature revealed that from last few
decades thiosemicarbazone derivatives had been evaluated in various biological activities
such as antiviral, anticancer, antibacterial, antimalarial, antiHIV etc. [19-23]. Triapine (1) and
Methisazone (2), synthetic analogs of thiosemicarbazone are easily available in the market.
Triapine is a potent ribonucleotide reductase inhibitor and also used in cancer treatment while
Methisazone is a good antiviral agent [18, 23].

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S
NH2
NH2
N
H
NH
O
N
N
NH2
N
S
N
1
2
Microwave-assisted organic synthesis (MAOS) is an excellent tool of green chemistry where
environment-friendly transformations have been carried out. In the last few decades,
microwave technology has been used in synthetic organic chemistry [24-26]. For commercial
use, the microwave oven has been designed especially for the organic synthesis which
increased the number of microwave-based research articles [27-31]. Microwave-assisted
organic synthesis is particularly crucial for industrial synthesis as it is cost-effective, efficient,
time saver; leads to improve yields and lower waste generation compare to traditional
synthetic protocols [32]. Five and six-membered heterocyclic compounds like thiazoles,
pyrroles, pyrazoles, etc. have been synthesized in improved yields under solvent-free
microwave as well as ultrasound assisted methods; because of it dramatic accelerations have
been observed as compared to their traditional procedure [33-35].
Keeping in view, the advantages of microwave-assisted organic synthesis; the present work
deals with the synthesis of an important class of organic compounds – Thiazole fused
__
thiosemicarbazones
under microwave irradiation. All the newly synthesized compounds
are well characterized and assessed for their in-vitro antimicrobial, antimalarial and anti-
tuberculosis activity, which revealed that compounds 6b and 6g are more potent against S.
aureus bacterial strain. So, molecular docking study has performed with S. aureus (PDB ID:
5D1Q) as a target enzyme, and the results lend weight to in-vitro biological study results. In-
silico pharmacophoric study is explained in ADME study.

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Reagents and conditions: (a) MWI 300 W (190 °C); (b) EtOH (5 mL), Gla. CH3COOH
(1.5 mL), MWI 300 W (190 °C)
Scheme 1. General reaction scheme
2. Results and Discussion
(E)-2-(1-(4-methyl-2-(substituted-phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5a-j) and (E)-N-cyclohexyl-2-(1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethylidene)
hydrazinecarbothioamide (6a-j) were prepared by condensation reaction of substituted 1-(4-
methyl-2-(phenylamino)thiazol-5-yl)ethanone (3a-j) with hydrazinecarbothioamide (4a) and
N-cyclohexylhydrazinecarbothioamide (4b), respectively via condensation reaction using
microwave irradiation (MWI) in presence of a catalytic amount of glacial acetic acid (Gla.
CH3COOH). Substituted 1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethanone (3a-j) were
prepared via Hantsch cyclization of substituted phenylthiourea (1a-j) and 3-chloropentane-
2,4-dione (2) (Scheme 1) using microwave irradiation. This reaction of phenylthiourea and 3-
chloropentane-2,4-dione proceeds well upon refluxing with ethanol for 2-4 h or with
ultrasound conditions at room temperature for 60 min., but here we adapted this to
microwave irradiation at 300W for 4-5 min without using any solvent. It resulted in good
yields and shorter reaction time compared to the reflux or ultrasound protocol.

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We initiated our screening by performing a model reaction of 1-(4-methyl-2-
(phenylamino)thiazol-5-yl)ethanone (3a) with hydrazinecarbothioamide (4a) using ethanol as
solvent at room temperature. The reaction was incomplete even after 24 h, as unreacted
starting materials were observed on TLC using (7:3) hexane: ethyl acetate (Table 1, Entry 1).
Even no significant change observed in the reaction yield after refluxing the reaction mixture
in ethanol for 12 h (Table 1, Entry 2). Generally, catalysts manifest themselves as asymmetric
catalytic reactions and green chemical processes for forming novel structural motifs. Thus, in
the model reaction, various catalysts were introduced, and their considerable effect on
product (5a) yield was observed. Firstly, p-toluenesulphonic acid (p-TSA) was applied as a
catalyst in the modal reaction under refluxing ethanol, which resulted in a 68% yield of
product 5a (Table 1, Entry 3). The reaction was also restrained using hydrochloric acid
(HCl), formic acid (HCOOH) which resulted, peripheral to p-TSA in terms of product yield
(Table 1 Entry 4, 5). Lewis acid catalyst like Cu(OAc)2 was tested in refluxing ethanol
which provided a trace amount of product (Table 1 Entry 6). It might have happened because
of complex formation with metal Cu. Further, the reaction was explored using an increasing
molar ratio of glacial acetic acid (5, 10, 15, 20 and 25 mol% gla. CH3COOH) as a catalyst in
refluxing ethanol for 5 h (Table 3, Entry 7-11). 20 mol% gla. CH3COOH has worked best for
this model reaction as the reaction was completed in 5 h with a 90% yield of product. We
have also carried out this reaction using various solvents like methanol, isopropanol, and
butanol with a fixed amount of gla. CH3COOH (20 mol%) which forms 75, 84 and 80% of
product yield, respectively (Table 1, Entry 12-14). However, ethanol was found as the best
solvent for this transformation in terms of the yield of the product and the time of reaction.
By seeing all the parameters, we found out that conventional method usually needs longer
heating time, whereas microwave-assisted organic synthesis is fast, efficient, economical and
environmentally friendly. Keeping this in mind, we performed this reaction under microwave

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irradiation (MWI) of 100 W using 20 mol% gla. CH3COOH as catalyst and ethanol as
solvent, and surprisingly we obtained 73% of product yield in just 4 min of time (Table 1,
Entry 16). Further, the reaction was conducted at a microwave irradiation power of 180 W
with the same conditions found 85% of product yield increased compared to 100 W of power
(Table 1, Entry 17). So, the reaction was carried out at increasing MWI of 300 W with same
reaction conditions resulted in the excellent product yield of 94% (Table 1, Entry 18). Further
increase in the MWI power did not affect the reaction. Also, we got good results in
isopropanol in convention heating in terms of reaction time and product yield; isopropanol
was also implemented in MWI of 300 W for 4 min., resulted in good yield (87%) of the
product (Table 1, Entry 15).
From the optimization of reaction conditions, it can be inferred that the reaction of 1-(4-
methyl-2-(phenylamino)thiazol-5-yl)ethanone (3a) with hydrazinecarbothioamide (4a) in
microwave irradiation at 300W using 20 mol% of gla. CH3COOH as catalyst and ethanol as
the solvent is optimum condition for this protocol of preparation of (E)-2-(1-(4-methyl-2-
(phenylamino)thiazol-5-yl)ethylidene)hydrazine carbothioamide (5a) (Scheme 1).
Subsequently, reactions of differently substituted 1-(4-methyl-2-(phenylamino)thiazol-5-
yl)ethanone (3a-j) (1 mmol) with hydrazinecarbothioamide (4a) (1 mmol) or N-
cyclohexylhydrazinecarbothioamide (4b) (1 mmol) in MWI (300 W) using 20 mol% gla.
CH3COOH and ethanol gave corresponding thiazole fused thiosemicarbazones (5a-j and 6a-
j) in good to high yields (Table 2). Moreover, highly pure products were obtained with no
need of column purification using this protocol.
Table 1. Optimization of reaction conditions for the synthesis of thiazole fused
thiosemicarbazones (5a-j and 6a-j).a

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Reaction
conditions/
Temperature
Yield
(%)b
Entry
Solvent
Catalyst
Time
1
2
3
4
5
6
R.T.
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
-
24h
12h
12h
12h
12h
12h
-
-
Reflux
Reflux
Reflux
Reflux
Reflux
-
p-TSA
HCl
68
54
47
-
HCOOH
Cu(OAc)2
Gla. CH3COOH
(5 mol%)
7
8
Reflux
Reflux
Reflux
Reflux
Ethanol
Ethanol
Ethanol
Ethanol
5h
5h
5h
5h
65
72
80
90
Gla. CH3COOH
(10 mol%)
Gla. CH3COOH
(15 mol%)
9
Gla. CH3COOH
(20 mol%)
10

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Gla. CH3COOH
Ethanol
11
12
13
14
15
16
17
18
Reflux
Reflux
5h
5h
89
75
84
80
87
73
85
(25 mol%)
Gla. CH3COOH
Methanol
(20 mol%)
Gla. CH3COOH
Isopropanol
Reflux
5h
(20 mol%)
Gla. CH3COOH
Butanol
Reflux
5h
(20 mol%)
Gla. CH3COOH
Isopropanol
MWI, 300 W
MWI, 100 W
MWI, 180 W
MWI, 300 W
4 min.
4 min.
4 min.
4 min.
(20 mol%)
Gla. CH3COOH
Ethanol
(20 mol%)
Gla. CH3COOH
Ethanol
(20 mol%)
Gla. CH3COOH
Ethanol
94
(20 mol%)
a
=
1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethanone
(3a;
1
mmol),
hydrazinecarbothioamide (4a; 1 mmol).
b = Yield of isolated product
The phenyl ring of 1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethanone (3) substituted with
electron donating groups like –CH3, -OH at para-position form high yield compared to those

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substituted with electron withdrawing –Cl, -F groups or unsubstituted. The scope of the
present protocol was extended by investigating reactions of substituted thiazole with
cyclohexylthiosemicarbazone under identical conditions. The cyclohexyl substituted
thiosemicarbazones (6a-j) gave low yield as compared to simple thiosemicarbazones (5a-j).
The higher yield obtained in the case of 5d was attributed due to the presence of strong
electron donating group like –OCH3 (Table 2).
Table 2. Prepared derivatives of thiazole fused thiosemicarbazone.a
H
N
N
S
S
HN
N
NH2
5c
5a
5b
(4 min.; 96%)
MP: 227-229 °C
(4 min.; 94%)
MP: 203-210 °C
(4 min.; 92%)
MP: 170-175 °C
5d
5e
5f
(4 min.; 97%)
MP: 193-197 °C
(4 min.; 90%)
MP: 188-192 °C
(4 min.; 88%)
MP: 172-176 °C
5g
5h
5i
(4 min.; 91%)
MP: 192-196 °C
(4 min.; 92%)
MP: 180-186 °C
(4 min.; 94%)
MP: 153-156 °C

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5j
6a
(4 min.; 90%)
MP: 204-207 °C
6b
(5 min.; 90%)
MP: 212-215 °C
(5 min.; 89%)
MP: 173-177 °C
H
N
N
S
S
HN
N
NH
6c
6d
6e
(5 min.; 93%)
MP: 235-238 °C
(5 min.; 92%)
MP: 175-179 °C
(5 min.; 87%)
MP: 204-208 °C
6h
6g
6f
(5 min.; 90%)
MP: 180-184 °C
(5 min.; 89%)
MP: 178-181 °C
(5 min.; 85%)
MP: 195-197 °C
6j
6i
(5 min.; 91%)
MP: 170-174 °C
(5 min.; 92%)
MP: 171-176 °C
a Reaction conditions: 1-(4-methyl-2-(substituted phenylamino)thiazole-5-yl)ethanone 3a-j (1
mmol), Thiosemicarbazide or N-cyclohexyl hydrazinecarbothioamide 4a-c (1 mmol), Gla.
CH3COOH (20 mol%), EtOH (5 mL), MWI (300W, 190 °C) for 4-5 min.

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The reaction mechanism shows that thiazole derivatives form via Hantzsch synthetic
approach, which involves cyclization and condensation of haloketones with thioamide. The
reaction initiates with a nucleophilic attack of sulphur atom of substituted phenyl thiourea on
the α-carbon atom of α-haloketone, which form α-thioketone intermediate. The dehydration
of α-thioketone intermediate generates the corresponding thiazoles (1-(4-thiazolyl)ethanone).
Now, in the second step the addition reaction between substituted isothiocyanates and
hydrazine hydrate produced substituted thiosemicarbazide in excellent yield. We proposed
that mechanistically a lone pair of electrons present on the primary amine of
thiosemicarbazide attacks on the carbocation of the acetyl group of 1-(4-thiazolyl)ethanone
due to the presence of acetic acid as the catalyst. Acetic acid pulls the electron from the
carbonyl group of 1-(4-thiazolyl)ethanone to form the reactive intermediate carbocation. At
that time proton transfer occurs from nitrogen atom to oxygen atom. In the next step, removal
of water molecule occurs from the proton of nitrogen atom and hydroxyl group at carbon
atom, situated at the adjacent position, to form the thiazole substituted thiosemicarbazone
derivatives.
3. Experimental
3.1 Chemistry
3.1.1 Materials and instruments
All chemicals and solvents were obtained from commercial sources and were used without
further purification. The progress of the reactions was monitored by thin layer
chromatography (TLC) on Macherey-Nagel (Germany) Alugram Sil G/UV254 TLC plates,
visualized under UV light. Melting points were determined on an Optimelt MPA 100 melting
point apparatus and are uncorrected. Yields refer to isolated compounds after crystallization

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1
in ethanol, estimated to be >95% pure as determined by H-NMR. FT-IR spectra were
recorded on a Perkin Elmer FT-IR 377spectrometer using KBr as reference. Mass spectra
were recorded on Water's SQD detector with single quardropole analyzer. 1H-NMR and 13C-
NMR spectra were recorded on a Bruker AV 400 MHz spectrometer using DMSO-d6 as
solvent and TMS as the internal reference. The chemical shifts were reported in ppm (δ)
relative to TMS and coupling constants (J) in Hertz (Hz), whereas s, d, t and m refer to
1
13
singlet, doublet, triplet and multiplet, respectively. All the H-NMR and C-NMR spectral
data are refined using Mnova.
3.1.2 General procedure for the synthesis of Thiazole derivatives (3a-j)
Substituted thiourea (1 mmol) and 3-chloropentane-2,4-dione (1 mmol) were placed in an
open vessel microwave (Discover CEM, 300 W and temperature control set at 190 °C
measured with an IR sensor) for 4-5 min. Reaction progress was checked by TLC using
hexane: ethyl acetate (7: 3) as mobile phase. After completion of the reaction, 10 mL of
ethanol was added to the reaction mixture and the resulting mixture was further added to ice
cold water to form desired product (3a-j). The precipitates were filtered and purified by
recrystallization from ethanol.
3.1.3 General procedure for the synthesis of Thiosemicarbazone derivatives (5a-j, 6a-j)
A mixture of 1-(4-methyl-2-(substituted phenylamino)thiazole-5-yl)ethanone (1 mmol),
thiosemicarbazide or N-cyclohexyl hydrazinecarbothioamide (1 mmol) and glacial acetic acid
(20 mol%) in ethanol (5 mL) was irradiated in an open vessel microwave (Discover CEM,
300 W and temperature control set at 190 °C measured with an IR sensor) for appropriate
time shown in Table 1. The reaction was monitored by TLC using hexane: ethyl acetate (7: 3)
as mobile phase, during the interval of 1 minute. After cooling the reaction mixture at
ambient temperature, ethanol was removed by rotary evaporator. The product was

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precipitated out by addition of cold water. The product was collected by filtration and purified
by crystallization from ethanol. The representative procedure was followed for the synthesis
of all the thiazole fused thiosemicarbazones 5a-j, 6a-j.
3.1.4 Physical and Spectral data of representative compounds
(E)-2-(1-(4-Methyl-2-(phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbothioamide (5a)
13C-NMR (100 MHz, DMSO): δ (ppm) = 165.0, 159.0, 156.6, 152.7, 149.3, 140.0, 129.1,
118.1, 117.1, 18.4, 15.7; IR (KBr): ν (cm-1) = 3429, 3215, 3059, 2854, 1600, 1496, 1446,
1324, 1123; MS: m/z (%) = [M+1]+ = 306.4271
(E)-2-(1-(4-Methyl-2-(m-tolylamino)thiazol-5-yl)ethylidene)hydrazinecarbothioamide (5b)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.35 (1H, s, NH), 10.28 (2H, s, NH2), 8.26 (1H,
s, NH), 7.44-7.42 (1H, d, Ar, J = 8 Hz), 7.34 (1H, s, Ar), 7.22-7.18 (1H, t, Ar, J = 7.8 Hz),
13
6.801-6.79 (1H, d, Ar, J = 7.2 Hz), 2.43 (3H, s, CH3), 2.31 (6H, s, 2CH3); C-NMR (100
MHz, DMSO): δ (ppm) = 178.2, 161.6, 148.7, 145.6, 140.7, 138.4, 129.1, 122.4, 119.4,
117.8, 114.4, 21.4, 18.4, 16.7; IR (KBr): ν (cm-1) = 3407, 3259, 3064, 2953, 2805, 1598,
1490, 1347, 1283, 1118, 772, 697; MS: m/z (%) = [M+1]+ = 320.4575
(E)-2-(1-(4-Methyl-2-(p-tolylamino)thiazol-5-yl)ethylidene)hydrazinecarbothioamide (5c)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.52 (3H, s, NH & NH2), 8.33 (1H, s, NH),
7.44-7.41 (2H, d, Ar, J = 12.4 Hz), 7.06-7.04 (2H, d, Ar, J = 8.8 Hz), 2.45 (3H, s, CH3), 2.32
13
(6H, s, 2CH3); C-NMR (100 MHz, DMSO): δ (ppm) = 178.5, 165.2, 157.3, 143.7, 139.7,
130.7, 123.4, 118.4, 115.1, 24.4, 16.1, 15.1; IR (KBr): ν (cm-1) = 3413, 3303, 3266, 2963,
2806, 1597, 1511, 1444, 1289, 1116, 832; MS: m/z (%) = [M+1]+ = 320.4575
(E)-2-(1-(2-((4-Methoxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbo-
thioamide (5d)

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1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.49 (1H, s, NH), 9.99 (2H, s, NH2), 8.32 (1H,
s, NH), 7.44-7.42 (2H, d, Ar, J = 8.8 Hz), 7.04-7.02 (2H, d, Ar, J = 8.8 Hz), 3.78 (3H, s,
OCH3), 2.44 (3H, s, CH3), 2.31 (3H, s, CH3); 13C-NMR (100 MHz, DMSO): (δ ppm) =
178.2, 165.0, 157.0, 143.7, 140.8, 131.0, 123.0, 118.4, 114.8, 55.3, 16.1, 15.4; IR (KBr): ν
(cm-1) = 3450, 3311, 3181, 3059, 2972, 1716, 1632, 1550, 1379, 1288, 1120, 834; MS: m/z
(%) = [M+1]+ = 336.4576
(E)-2-(1-(2-((2-Hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbo-
thioamide (5e)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.35 (1H, s, NH), 9.94 (1H, s, NH2), 9.51 (1H,
s, NH2), 8.25 (1H, s, NH), 7.96-7.97 (1H, d, Ar, J = 7.6 Hz), 7.15 (1H, s, OH), 6.48-6.91 (3H,
m, Ar), 2.40 (3H, s, CH3), 2.28 (3H, s, CH3); 13C-NMR (100 MHz, DMSO): δ (ppm) = 177.9,
163.0, 148.3, 147.0, 145.6, 128.3, 123.4, 120.4, 119.4, 119.1, 115.4, 18.4, 17.1; IR (KBr): ν
(cm-1) = 3421, 3243, 3051, 2808, 1602, 1454, 1341, 1237, 1111, 760; MS: m/z (%) = [M+1]+
= 322.4270
(E)-2-(1-(2-((3-Hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5f)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.37 (1H, s, NH), 9.50 (2H, s, NH2), 8.27 (1H,
s, NH), 7.22 (1H, s, OH), 7.16-7.08 (2H, m, Ar), 6.96 (1H, s, Ar), 6.42-6.40 (1H, d, Ar, J = 8
13
Hz), 2.44 (3H, s, CH3), 2.31 (3H, s, CH3); C-NMR (100 MHz, DMSO): δ (ppm) = 178.1,
161.6, 158.0, 148.3, 145.3, 141.4, 129.7, 119.4, 109.1, 108.4, 104.7, 18.4, 16.7; IR (KBr): ν
(cm-1) = 3403, 3261, 3089, 2967, 1599, 1425, 1345, 1286, 1114, 843, 766; MS: m/z (%) =
[M+1]+ = 322.4270
(E)-2-(1-(2-((4-Hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5g)

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1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.31 (1H, s, NH), 9.99 (2H, s, NH2), 8.21 (1H,
s, NH), 7.35-7.33 (2H, d, Ar, J = 8.8 Hz), 7.16 (1H, s, OH), 6.75-6.73 (2H, d, Ar, J = 8.8
13
Hz), 2.40 (3H, s, CH3), 2.28 (3H, s, CH3); C-NMR (100 MHz, DMSO): δ (ppm) = 177.9,
163.0, 153.0, 149.0, 145.7, 132.4, 120.0, 118.4, 115.5, 18.4, 16.8; IR (KBr): ν (cm-1) = 3421,
3243, 3051, 2808, 2722, 1602, 1509, 1454, 1280, 1111, 848; MS: m/z (%) = [M+1]+ =
322.4270
(E)-2-(1-(2-((3-Chlorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5h)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.42 (1H, s, NH), 9.72 (2H, s, NH2), 8.30 (1H,
s, NH), 7.81 (1H, s, Ar), 7.50-7.48 (1H, d, Ar, J = 8 Hz), 7.40-7.35 (1H, t, Ar, J = 8.2 Hz),
13
7.09-7.07 (1H, d, Ar, J = 8 Hz), 2.46 (3H, s, CH3), 2.33 (3H, s, CH3); C-NMR (100 MHz,
DMSO): δ (ppm) = 178.3, 161.6, 146.6, 144.8, 141.4, 133.5, 130.7, 122.0, 120.4, 117.4,
116.5, 17.7, 16.6; IR (KBr): ν (cm-1) = 3435, 3261, 3129, 2959, 1634, 1558, 1431, 1260,
1105, 833, 777, 690; MS: m/z (%) = [M+1]+ = 340.7811, [M+3]+ = 342.1832
(E)-2-(1-(2-((4-Chlorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5i)
IR (KBr): ν (cm-1) = 3417, 3237, 2806, 1595, 1499, 1348, 1122, 764, 818; MS: m/z (%) =
[M+1]+ = 340.7811, [M+3]+ = 342.1832
(E)-2-(1-(2-((4-Fluorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)hydrazinecarbothio-
amide (5j)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.48 (1H, s, NH), 9.61 (2H, s, NH2), 8.33 (1H,
s, NH), 7.61-7.57 (2H, d, Ar, J = 14 Hz), 7.28-7.26 (2H, d, Ar, J = 6.8 Hz), 2.45 (3H, s, CH3),
2.32 (3H, s, CH3); 13C-NMR (100 MHz, DMSO): δ (ppm) = 178.2, 164.0, 160.0, 157.6,

ACCEPTED MANUSCRIPT
144.0, 135.4, 122.0, 119.4, 116.1, 16.3; IR (KBr): ν (cm-1) = 3451, 3317, 3187, 2950, 1650,
1504, 1233, 1125, 1033, 837; MS: m/z (%) = [M+1]+ = 324.4175
(E)-N-Cyclohexyl-2-(1-(4-methyl-2-(phenylamino)thiazol-5-yl)ethylidene)hydrazinecarbo-
thioamide (6a)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.48 (1H, s, NH), 7.74 (1H, s, NH), 7.60-7.58
(2H, d, Ar, J = 7.6 Hz), 7.38-7.34 (2H, t, Ar, J = 8 Hz), 7.07-7.04 (1H, t, Ar, J = 7.2 Hz), 4.15
13
(1H, s, NH), 2.44 (3H, s, CH3), 2.32 (3H, s, CH3), 1.91-1.31 (11H, m, Cy); C-NMR (100
MHz, DMSO): δ (ppm) = 176.2, 162.1, 146.3, 144.4, 139.9, 129.2, 122.9, 119.5, 118.3, 51.3,
31.8, 25.1, 24.2, 17.5, 16.6; IR (KBr): ν (cm-1) = 3339, 3191, 2928, 2850, 1619, 1495, 1441,
1309, 1127; MS: m/z (%) = [M+1]+ = 388.5771
(E)-N-Cyclohexyl-2-(1-(4-methyl-2-(m-tolylamino)thiazol-5-yl)ethylidene)hydrazinecarbo-
thioamide (6b)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.35 (1H, S, NH), 7.55-7.53 (1H, d, Ar, J = 8.4
Hz), 7.39-7.25 (3H, m, (1H) NH & (2H) Ar), 6.95-6.93 (1H, d, Ar, J = 7.6 Hz), 4.15 (1H, s,
NH), 2.44 (3H, s, CH3), 2.32 (6H, s, 2CH3), 1.90-1.22 (11H, m, Cy ); IR (KBr): ν (cm-1) =
3326, 3206, 2929, 2853, 1633, 1524, 1378, 1257, 1128, 785, 698; MS: m/z (%) = [M+1]+ =
402.5970
(E)-N-Cyclohexyl-2-(1-(4-methyl-2-(p-tolylamino)thiazol-5-yl)ethylidene)hydrazinecarbo-
thioamide (6c)
13C-NMR (100 MHz, DMSO): δ (ppm) = 176.4, 173.1, 143.0, 139.0, 132.2, 134.4, 129.9,
128.1, 118.3, 52.0, 31.7, 25.1, 24.2, 20.9, 17.2, 14.8; IR (KBr): ν (cm-1) = 3354, 3053, 2928,
2851, 1605, 1513, 1470, 1303, 1125, 822; MS: m/z (%) = [M+1]+ = 402.5970

ACCEPTED MANUSCRIPT
(E)-N-Cyclohexyl-2-(1-(2-((4-methoxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)-
hydrazinecarbothioamide (6d)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.54 (1H,s, NH), 7.57 (1H, s, NH), 7.49-7.47
(2H, d, Ar, J = 7.2 Hz), 6.99-6.97 (2H, d, Ar, J = 8.8 Hz), 4.16 (1H, s, NH), 3.76 (3H, s,
13
OCH3), 2.44 (3H, s, CH3), 2.30 (3H, s, CH3), 1.92-1.23 (11H, m, Cy); C-NMR (100 MHz,
DMSO): δ (ppm) = 176.4, 172.2, 164.0, 156.4, 143.6, 132.3, 122.0, 118.9, 114.6, 55.3, 51.2,
31.5, 25.0, 23.9, 21.1, 16.3; IR (KBr): ν (cm-1) = 3338, 3221, 2928, 2849, 1618, 1520, 1385,
1251, 1115, 828; MS: m/z (%) = [M+1]+ = 418.5972
(E)-N-Cyclohexyl-2-(1-(2-((2-hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)-
hydrazinecarbothioamide (6e)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.59 (1H, s, NH), 9.23 (1H, s, NH), 7.87-7.85
(2H, d, Ar, , J = 7.2 Hz), 7.47-7.37 (2H, dd, Ar, J = 8 Hz), 5.75 (1H, s, OH), 4.17 (1H, s,
NH), 2.37 (3H, s, CH3), 2.17 (3H, s, CH3), 1.92-1.24 (11H, m, Cy); 13C-NMR (100 MHz,
DMSO): δ (ppm) = 176.4, 173.1, 167.3, 143.3, 139.0, 136.3, 134.4, 131.7, 129.8, 128.1,
118.5, 51.9, 31.8, 24.2, 20.9, 17.2, 14.7; IR (KBr): ν (cm-1) = 3438, 3255, 3023, 2801, 1615,
1478, 1335, 1218, 1108, 771; MS: m/z (%) = [M+1]+ = 404.5672
(E)-N-Cyclohexyl-2-(1-(2-((3-hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)-
hydrazinecarbothioamide (6f)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.49 (1H, s, NH), 7.91 (1H, s, NH), 7.55-7.53
(1H, d, Ar, J = 8.4 Hz), 7.16-7.12 (1H, t, Ar, J = 8.2 Hz), 7.05 (1H, s, Ar), 6.96-6.94 (1H, d,
Ar, J = 9.2 Hz), 6.51 (1H, s, OH), 4.16 (1H, s, NH), 2.44 (3H, s, CH3), 2.32 (3H, s, CH3),
1.90-1.32 (11H, m, Cy); 13C-NMR (100 MHz, DMSO): δ (ppm) = 176.2, 162.5, 158.2, 144.2,
140.6, 129.9, 119.5, 110.7, 109.4, 105.8, 5.3, 31.8, 25.1, 24.2, 17.2, 16.6; IR (KBr): ν (cm-1)

ACCEPTED MANUSCRIPT
= 3333, 3190, 2929, 2851, 1581, 1524, 1308, 1201, 1129, 862, 782; MS: m/z (%) = [M+1]+ =
404.5672
(E)-N-Cyclohexyl-2-(1-(2-((4-hydroxyphenyl)amino)-4-methylthiazol-5-yl)ethylidene)-
hydrazinecarbothioamide (6g)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.59 (1H, s, NH), 7.55-7.53 (2H, d, Ar, J = 8
Hz), 7.29 (2H, s, OH, NH), 6.85-6.82 (2H, d, Ar, J = 8.8 Hz), 4.14 (1H, s, NH), 2.42 (3H, s,
13
CH3), 2.30 (3H, s, CH3), 1.83-1.23 (11H, m, Cy); C-NMR (100 MHz, DMSO): δ (ppm) =
176.4, 165.1, 155.7, 143.2, 129.8, 123.5, 11.3, 116.1, 52.9, 31.4, 25.1, 23.8, 15.9, 15.3; IR
(KBr): ν (cm-1) = 3443, 3354, 3196, 2938, 2853, 1595, 1522, 1451, 1266, 1126, 834; MS: m/z
(%) = [M+1]+ = 404.5672
(E)-2-(1-(2-((3-Chlorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)-N-cyclohexyl-
hydrazinecarbothioamide (6h)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.47 (1H, s, NH),7.86 (1H, s, Ar), 7.54-7.52
(2H, d, (1H) NH & 1H (Ar), J = 8.4 Hz), 7.34-7.32 (1H, d, Ar, J = 8 Hz), 7.04-7.02 (1H, d,
Ar, J = 8 Hz), 4.15 (1H, s, NH), 2.46 (3H, s, CH3), 2.32 (3H, s, CH3), 1.93-1.23 (11H, m,
Cy); 13C-NMR (100 MHz, DMSO): δ (ppm) = 176.2, 160.9, 147.5, 144.4, 141.8, 133.2,
130.5, 121.3, 120.7, 116.8, 115.9, 51.3, 31.8, 25.1, 24.2, 18.1, 16.6; IR (KBr): ν (cm-1) =
3330, 3179, 2931, 2852, 1633, 1571, 1449, 1202, 1124, 892, 783, 671; MS: m/z (%) = =
[M+1]+ = 423.1123, [M+3]+= 425.6321
(E)-2-(1-(2-((4-Chlorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)-N-cyclohexyl-
hydrazinecarbothioamide (6i)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.49 (1H, s, NH), 9.03 (1H, s, NH), 7.66-7.64
(2H, d, Ar, J = 8.8 Hz), 7.41-7.39 (2H, d, Ar, J = 8.8 Hz), 4.14 (1H, s, NH), 2.45 (3H, s,
13
CH3), 2.32 (3H, s, CH3), 1.91-1.31 (11H, m, Cy); C-NMR (100 MHz, DMSO): δ (ppm) =

ACCEPTED MANUSCRIPT
176.2, 161.9, 146.3, 144.2, 139.0, 129.0, 125.9, 120.1, 51.3, 31.8, 25.1, 24.1, 17.5, 16.6; IR
(KBr): ν (cm-1) = 3339, 3191, 2928, 2850, 1619, 1583, 1525, 1495, 1200, 1127, 774, 615;
MS: m/z (%) = [M+1]+ = 423.1123, [M+3]+= 425.6321
(E)-N-Cyclohexyl-2-(1-(2-((4-fluorophenyl)amino)-4-methylthiazol-5-yl)ethylidene)-
hydrazinecarbothioamide (6j)
1H-NMR (400 MHz, DMSO-d6): δ (ppm) = 10.53 (1H, s, NH), 7.64-7.61 (3H, d, (1H) NH &
(2H) Ar, J = 9.2 Hz), 7.27-7.25 (2H, d, Ar, J = 8.4 Hz), 4.15 (1H, s, NH), 2.44 (3H, s, CH3),
13
2.32 (3H, s, CH3), 1.88-1.23 (11H, m, Cy); C-NMR (100 MHz, DMSO): δ (ppm) = 176.2,
163.1, 159.4, 157.3, 143.9, 135.6, 121.3, 119.5, 116.1, 51.3, 31.5, 25.0, 23.9, 16.8, 16.3; IR
(KBr): ν (cm-1) = 3348, 3193, 2929, 2853, 1587, 1521, 1314, 1207, 1123, 1041, 845; MS: m/z
(%) = [M+1]+ = 406.5673
3.2 Biological assay
This work has been done in Microcare Laboratory and TRC, Surat, India as per the reported
method. (Hawkey and Lewis, 2003)
4. Biological Evaluation
All newly prepared thiazole hybrid thiosemicarbazone derivatives were inspected for
antimicrobial activity against two Gram-positive bacterial strains, two Gram-negative
bacterial strains and three fungal strains using the agar dilution method [36]. Ampicillin,
Chloramphenicol, Ciprofloxacin, Gentamycin and Norfloxacin were used as standard control
drugs for antibacterial activity, whereas Griseofulvin and Nystatin were used as standard
control drugs for antifungal activity.
The in-vitro antimalarial activity was carried out in 96 well microtiter plates according to the
microassay protocol of Reickmann and co-workers [37] with minor modifications.
Chloroquine and Quinine were used as standard control drugs for antimalarial activity as well

ACCEPTED MANUSCRIPT
as Isoniazid and Rifampicin were used as standard control drugs for the anti-tuberculosis
activity. The zone of inhibition and minimum inhibitory concentrations (MIC) were noted
(Table 3).

ACCEPTED MANUSCRIPT
Table 3. In-vitro antibacterial, antifungal, antimalarial and anti-tuberculosis activities of compounds 5a-j and 6a-j.
In-vitro Antibacterial
activity
In-vitro Antifungal
activity
In-vitro Antimalarial
In-vitro Anti-tuberculosis
activity
IC50c (µg/mL)
PFk
activity
Entry
Compound code
MICa (µg/mL)
MFCb (µg/mL)
MICa (µg/mL)
ECd SAe PAf SPg CAh
ANi
250
250
500
ACj
250
H37Rvl
500
50
1
2
5a
5b
5c
5d
5e
5f
500
250
125
100
500
125 250 1000
200 125
0.82
100
125
250
200
100
500
250
0.97
3
500
1.04
1000
25
500
4
250 200 1000 1000
1000
1000
0.86
5
250 500 200 500
1000
0.90
100
500
62.5
500
500
250
500
6
200
250
250
>1000 >1000
1.06
100
200
100 250
7
5g
5h
5i
250 250
500
500
1.11
500
8
125 200 1000 1000
1000
0.84
100 200
9
200
125
200 200 1000 >1000 >1000
125 200 1000 1000
1.02
200
200
10
5j
0.99
500

ACCEPTED MANUSCRIPT
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
6a
250 250
62.5 100 100 500
500
500
500
1000
250
500
500
250
250
500
-
500
1000
>1000
1000
250
500
>1000
250
250
1000
-
1.70
2.18
2.57
1.15
0.73
0.65
0.32
0.84
0.82
1.40
-
500
500
500
250
1000
1000
250
250
500
250
-
100 250
250
6b
125
6c
1000
500
100 250 100 50
125 500 125 250
6d
6e
250
125
250
250
125
250 250
100
500
6f
6g
125 1000
100 125
12.5 100 100 250
6h
500
125
125
125
100
100 250
1000
100 500
6i
62.5
6j
100 125
Ampicillinm
Chloramphenicolm
Ciprofloxacinm
Gentamycinm
Norfloxacinm
Griseofulvinm
100 250 100 100
-
50
25
50
50
50
25
1
50
50
0.5
10
-
-
-
-
-
-
-
-
-
-
-
-
0.05 0.25
-
-
-
-
10
-
10
-
10
-
-
-
-
-
-
500
100
100
-
-

ACCEPTED MANUSCRIPT
27
28
29
30
31
Nystatinm
Chloroquinem
Quininem
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
100
100
100
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.020
0.268
-
Isoniazidm
-
-
0.20
0.25
Rifampicinm
a MIC= Minimum Inhibitory Concentration
b MFC= Minimum Fungicidal Concentation
c IC50= Half maximal inhibitory concentration
d
e
f
EC= Escherichia coli (E. coli) MTCC 443, SA= Staphylococcus aureus (S. aureus) MTCC 96, PA= Pseudomonas aeruginosa (P.
g
h
i
aeruginosa) MTCC 1688, SP= Streptococcus pyogenes (S. pyogenes) MTCC 442, CA= Candida albicans (C. albicans) MTCC 227, AN=
j
k
Aspergillus niger (A. niger) MTCC 282, AC= Aspergillus clavatus (A. clavatus) MTCC 1323, PF= Plasmodium falciparum 3D7 (P.
falciparum), l H37Rv= Mycobacterium tuberculosis strain
m
=
Standard
control
drug

ACCEPTED MANUSCRIPT
4.1. In-vitro antibacterial activity
The in-vitro antibacterial activities of compounds 5a–j and 6a-j were evaluated against
Gram-positive and Gram-negative bacteria using the cultures of four different standard
microorganisms: Escherichia coli (E. coli) MTCC 443 and Pseudomonas aeruginosa (P.
aeruginosa) MTCC 1688 as Gram-negative models, and Staphylococcus aureus (S. aureus)
MTCC 96 and Streptococcus pyogenes (S. pyogenes) MTCC 442 as a Gram-positive model.
The results of this study are given in Table 3.
Bioassay results of series of 5a-j and 6a-j compounds revealed that almost all derivatives
(5b-d, 5f-j, 6a-c, 6e-j) were found to exhibit excellent activity against specific S. aureus
microbial strain compared to standard control drug Ampicillin. Compound 5a having
unsubstituted phenyl ring was found to be equally effective with 100 µg/mL MIC value
against E. coli and P. aeruginosa bacteria compared to Ampicillin. Compound 5h with chloro
group on meta-position of the phenyl ring showed equal potency with 100 µg/mL MIC value
against E. coli compared to Ampicillin. Compound 5f having electron donating hydroxyl
group on the meta-position of the phenyl ring found 100 µg/mL MIC value against S.
pyogenes equivalent to Ampicillin. Compound 6a, 6c and 6j showed MIC values of 100
µg/mL and are equally active as compared to Ampicillin against E. coli microorganism.
Compound 6b, 6c and 6g (MIC 100 µg/mL) are equally potent against P. aeruginosa strain
whereas compound 6b, 6g, 6h and 6j (MIC 100 µg/mL) are equally potent against S.
pyogenes strain. Compound 6b having methyl group on meta-position of phenyl ring has
presented excellent activity (MIC 62.5 µg/mL) against S. aureus compared to Ampicillin
whereas compound 6g having hydroxyl group on para-position of phenyl ring exhibited
excellent activity against the same microorganism compared to standard drugs Ampicillin,
Chloramphenicol and Ciprofloxacin with MIC value 12.5 µg/mL. Compound 6c having a

ACCEPTED MANUSCRIPT
methyl group on para-position of the phenyl ring is equally potent (MIC 50 µg/mL) against
S. pyogenes compared to Chloramphenicol and Ciprofloxacin, however 50% more active
(MIC 50 µg/mL) against the same microorganism compared to Ampicillin. Compound 6i
having chloro group on para-position of the phenyl ring has shown excellent activity (MIC
62.5 µg/mL) against the same microorganism compared to Ampicillin.
4.2. In-vitro antifungal activity
The in-vitro antifungal activity of compound 5a-j and 6a-j were evaluated against the
cultures of three different standard fungal strains: Candida albicans (C. albicans) MTCC
227, Aspergillus niger (A. niger) MTCC 282 and Aspergillus clavatus (A. clavatus) MTCC
1323. The results of this study are given in Table 3.
The antifungal activities of thiazole fused thiosemicarbazone derivatives (5a-j and 6a-j)
indicate that, thirteen out of twenty novel compounds (5a, 5c, 5e, 5f, 5g, 5j, 6a, 6b, 6d, 6e,
6g, 6h and 6j) tested in the present study were found to have good to excellent activity
against the C. albicans microorganism compared to standard control drug Griseofulvin,
whereas none of them found active against A. niger and A. clavatus fungal strains compared
to both the standard control drugs Griseofulvin and Nystatin. The best results were
encountered with compounds 5f, 6a, 6g and 6h with the MIC value of 250 µg/mL against C.
albicans compared to Griseofulvin. Results of the remaining five compounds 5a, 5c, 5e, 5g,
5j, 6b, 6d, 6e and 6j showed MIC values 500 µg/mL, and were equally effective as compared
to Griseofulvin against C. albicans microorganisms.

ACCEPTED MANUSCRIPT
Figure 1. Graphical presentation of biological assay
4.3 In-vitro antimalarial and anti-tuberculosis activity
All the newly synthesized compounds (5a-j and 6a-j) were also screened for their in-vitro
antimalarial activity against Plasmodium falciparum 3D7 (P. falciparum) strain by measuring
the mean Half Maximal Inhibitory Concentration (IC50 µg/mL) values. All experiments were
performed in duplicate. As shown in Table 3, neither of the compounds had shown
satisfactory results against P. falciparum as good as standard control drug Chloroquine and
Quinine.
The in-vitro anti-tuberculosis activity of series of compounds (5a-j and 6a-j) was performed
against Mycobacterium tuberculosis H37Rv microorganism compared to standard drugs
Isoniazid and Rifampicin. None of the synthesized compounds match up to the MIC (µg/mL)
values of the standard control drugs Isoniazid (0.20 µg/mL) and Rifampicin (0.25 µg/mL)
against the H37Rv strain of tuberculosis.
5. ADME Study

ACCEPTED MANUSCRIPT
ADME properties were used to evaluate in-silico pharmacophoric properties leading to drug-
likeness (Schrodinger, LLC, New York, NY, 2015). ADME properties of the title molecules
were analyzed using QikProp incorporated in Maestro 11. Jorgensen’s method was utilized to
compute pharmacophoric properties and descriptors in QikProp tool [38].
Pharmacophoric properties of the title molecules were described in table 4 with their
acceptable limits. Most of the compounds have polar surface area in the acceptable range of
limit assures good impact on bioavailability of the molecule (Lu et al., 2004). Caco-2 cell
permeability (QPPCaco) for the predicted molecules shows excellent intestinal absorption.
Water solubility parameter (QPlogS) of all the tested molecules except 5e shows results out
of the permissible range. Further, octanol/water partition coefficient (QPlogPo/w) of all the
tested molecules except 6h and 6i; and percentage human oral absorption (PHOA) of all the
compounds showed outcome in the acceptable range. Moreover, the results vary in the
permissible range for blood/brain partition coefficient (QPPlogBB). We consider that this
survey may help in broadening the scope for further evaluation of deserving molecules.
Table 4. ADME results.
PHOAf
QPPCacob
(<25 poor,
>500 great)
(<25%
poor,
>80%
high)
91.62
100
Comp.
Code
PSAa
QPlogBBc
QPlogPo/wd
(<5)
QPlogSe
(>-4)
(70-200 Ao)
(-1.5 to -3.0)
1
2
3
4
5
79.61
76.378
79.637
84.589
99.977
723.086
1004.546
723.667
1003.703
301.96
-0.705
-0.543
-0.739
-0.6
2.306
2.813
2.627
2.649
1.711
-4.155
-4.76
-4.671
-4.527
-3.845
93.508
96.178
81.348
-1.173

ACCEPTED MANUSCRIPT
6
102.201
98.904
79.632
79.625
79.617
64.441
64.469
64.456
72.751
85.749
87.009
86.968
64.422
64.434
64.446
219.469
305.069
722.245
723.509
722.948
2408.535
2382.896
2400.401
2378.109
873.86
-1.455
-1.133
-0.557
-0.555
-0.601
-0.341
-0.367
-0.361
-0.413
-0.934
-1.029
-1.026
-0.181
-0.182
-0.234
1.76
1.735
2.816
2.814
2.569
4.694
4.992
4.991
4.76
-4.422
-3.987
-4.849
-4.844
-4.5
79.158
81.571
94.599
94.602
93.16
100
7
8
9
10
11
12
13
14
15
16
17
18
19
20
-6.733
-7.281
-7.278
-6.783
-6.378
-6.391
-6.386
-7.453
-7.456
-7.081
100
100
100
3.98
100
729.378
731.825
2406.793
2401.204
2399.984
3.919
3.918
5.18
100
100
100
5.178
4.921
100
100
a PSA= Polar Surface Area
b QPPCaco= Caco-2 cell permeability
c QPLogBB= Blood/brain partition co-efficient
d QPLogPo/w= Patition co-efficient
e QPLogS= Water Solubitity
f PHOA= Percentage Human Oral Absorption
6. Molecular Docking Study
Molecular Docking was performed using Glide tool in maestro 11. Protein (PDB id: 5D1Q)
was downloaded from the protein data bank (RCSB PDB) and prepared with the help of a
protein preparation wizard by using default parameters and saved. All the ligands were