Discovery of Novel Thiazol-2-Amines and Their Analogues as Bioactive Molecules: Design, Synthesis, Docking and Biological Evaluation

Article abstract of DOI:10.1055/s-0043-120660

A simple and highly efficient procedure for the synthesis of novel thiazol-2-amines, via Mannich reaction with secondary amines, is described. The newly synthesized derivatives 8(a-e) and 9(a-e) were characterized by ¹ H NMR, ¹³ C NMR, IR, Mass spectroscopy and elemental analysis. All the derivatives were evaluated for their in-vitro anti-microbial activity against a panel of pathogenic strains of bacteria and fungi. The SAR showed that the secondary amines had a significant impact on the in-vitro antimicrobial activity of this class of agents. The most potent analogue N-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2(trifluoromethyl)phenyl)-4,5-dihydrothiazol-2-amine (8c) showed excellent inhibition with MIC (zoi) 6.25 (22.5), 25 (21.5) and 25 (18) μg/mL against E. coli, S. typhi and P. aeruginosa respectively as compared to the standard drug. Molecular docking results suggest that compound exhibited inhibitory activity by binding of the title compound within the active sites of the inhibiting Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase enzymes. The compound exhibited promising anti-microbial activity which can be further explored as potential lead for the development of cheaper, safe, effective and potent drugs against resistant microbial parasites.

Full text of DOI:10.1055/s-0043-120660

Thieme
Original Paper
Discovery of Novel Thiazol-2-Amines and Their Analogues as
Bioactive Molecules: Design, Synthesis, Docking and Biological
Evaluation
Authors
Anil Kumar Verma1, Abha Bishnoi1, Shaheen Fatma1, Huda Parveen1, Vineeta Singh2
Affiliations
Supporting Information for this article is available
1
Department of Chemistry, University of Lucknow,
Lucknow 226007, India
online at http://www.thieme-connect.de/products
2
Department of Biotechnology, IET Lucknow 226021,
India
ABStrAct
A simple and highly efficient procedure for the synthesis of
novel thiazol-2-amines, via Mannich reaction with secondary
amines, is described. The newly synthesized derivatives 8(a-e)
and 9(a-e) were characterized by 1H NMR, 13C NMR, IR, Mass
spectroscopy and elemental analysis. All the derivatives were
evaluated for their in-vitro anti-microbial activity against a
panel of pathogenic strains of bacteria and fungi. The SAR
showed that the secondary amines had a significant impact on
the in-vitro antimicrobial activity of this class of agents. The
most potent analogue N-((1H-benzo[d]imidazol-1-yl)methyl)-
N-(2(trifluoromethyl)phenyl)-4,5-dihydrothiazol-2-amine (8c)
showed excellent inhibition with MIC (zoi) 6.25 (22.5), 25 (21.5)
and 25 (18) µg/mL against E. coli, S. typhi and P. aeruginosa
respectively as compared to the standard drug. Molecular dock-
ing results suggest that compound exhibited inhibitory activ-
ity by binding of the title compound within the active sites of
the inhibiting Enoyl ACP reductase, Lipid A, Pyridoxal kinase
and type I DHQase enzymes. The compound exhibited promis-
ing anti-microbial activity which can be further explored as
potential lead for the development of cheaper, safe, effective
and potent drugs against resistant microbial parasites.
Key words
Benzimidazole moiety, Mannich reaction, Molecular Docking
received 22.02.2017
accepted 11.09.2017
Bibliography
DOI https://doi.org/10.1055/s-0043-120660
Published online: 2017 | Drug Res
© Georg Thieme Verlag KG Stuttgart · New York
ISSN 2194-9379
Correspondence
Dr. Abha Bishnoi, Professor
Department of Chemistry
University of Lucknow
Lucknow-226007
India
Tel.: + 91/941/5028 822, + 91/993/6953 444
abhabishnoi5@gmail.com
dr.abhabishnoi@gmail.com
anilfromlucknow@gmail.com
Introduction
without much inimical effect on the host [2–4]. Heterocycles, pre-
sent in a wide range of natural and synthetic compounds, are a ver-
satile group, found to exhibit a wide range of biological activities.
Among heterocycles, compounds possessing thiazole moiety have
been shown to play a vital role in pharmaceutical drug develop-
ment and are known to possess antimicrobial [5,6], anticancer [7],
anti-tumor [8], antiviral [9], antiphychotics [10] and antimalarial
[11] activities. They are also useful as anti-allergic [12], anthelmin-
tic [13] agents and as sedative hypnotics [14]. Several methods for
the synthesis of thiazole derivatives have been developed [15–17],
based on the above observations and as a part of our research in
the synthesis of novel heterocyclic systems [18, 19], a simple fac-
ile route has been described for the synthesis of new thiazol-
The effectiveness of antimicrobials, in the treatment of infections,
is because of their ability to kill an invading microorganism with no
harm to the cells of the host. The selective toxicity is relative rath-
er than absolute in most cases and it is important that the concen-
tration of the drug should carefully be controlled as to attack only
the microorganism, and is tolerated by the host [1]. With present
exploitative use of antibiotics, microorganisms are speedily devel-
oping resistance to the currently available drugs, and the develop-
ment of newer antimicrobials has become a necessity, for the treat-
ment of multi drug resistant organisms and for the treatment.
Newer antimicrobials are also needed for opportunistic infections
in immunocompromised hosts to tackle the invading organism
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Thieme
Original Paper
2-amine derivatives 8(a-e) and 9(a-e) via the widely used Mannich
reaction in ▶Fig. 1 (Scheme 1). The newly synthesized compounds
were screened for their antimicrobial activity against a panel of
bacterial strains, viz Staphylococcus aureus (Sa), Escherichia coli
(Ec), Salmonella typhi (St), Pseudomonas aeruginosa (Pa), and uni-
cellular and multicellular pathogenic fungi such as Candida albicans
(Ca) and Aspergillus niger (An).
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine] is outlined in
▶Fig. 1. The synthesis of compounds 8(a-e)/ 9(a-e) was carried
out by the Mannich reaction of compound N-(2-(trifluoromethyl)
phenyl)-4,5-dihydrothiazol-2-amine(6a)/N-(4-fluorophenyl)-4-(4-
methoxy-phenyl)thiazol-2-amine (7a) with different secondary
amines in presence of paraformaldehyde. The structures of the final
compounds were determined by spectroscopic techniques and
were in accordance with the proposed structures. The 2-(trifluoro-
methyl)aniline (1a)/4-fluoroaniline (1b), on reaction with benzoyl
isothiocyanate in dry benzene, resulted in the formation of
N((2(trifluoromethyl)phenyl)carbamothioyl)benzamide(2a)/
N((4fluorophenyl)carbamothioyl)benzamide (2b), which upon al-
kaline hydrolysis gave 1-(2-(trifluoromethyl)phenyl)thiourea
(3a)/1-(4-fluorophenyl)thiourea (3b).
Results and Discussion
Chemistry
The synthetic pathway followed in the preparation of 8(a-e) [N-
(substituted methyl)-N-(2-(trifluoromethyl)phenyl)-4,5-dihydro-
thiazol-2-amine] and 9(a-e) [N-(substituted methyl)-N-(4-
▶Fig. 1 Synthetic Pathway for the formation of Compounds 8(a-e) and 9(a-e).
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Condensation of the 3a with 2-bromoethylamine in presence
of hydrogen bromide afforded (6a), whereas 2-Bromo-4-methoxy-
acetophenone on reaction with 3b in the presence of THF resulted
in the formation of (7a). Finally, 6a and 7a on reaction with substi-
tuted secondary amines in ethanol in presence of paraformalde-
hyde gave the desired compounds 8(a-e) and 9(a-e).
against P. aeruginosa. From the above results, it can be concluded
that, compounds 8 (a,b,c,e) and 9 (a,b,c,e) were found to be ac-
tive, among them, compound 8c opens up entrance to optimize
this series for a new class of antibacterial agents.
In vitro antifungal activity
Sharp singlets for NH2 of thiourea at δ 8.92 ppm and δ 8.30 ppm
was observed respectively in the NMR spectra of compound 3a and
3b which were found to be absent in cyclized products 6a/7a. The
NH vibrations of secondary amine in the key intermediates (6a/7a)
are at the region 3422cm− 1 and 3430 cm− 1 were also found to be
absent in compounds, (8a-e)/(9a-e) and a sharp peak for C-N-C in
the region 1090–1341 cm− 1 were observed in (8a-e)/(9a-e), con-
firming the attachment of -CH2 group to the secondary amine in
6a/7a. Further, the 1H-NMR spectra of key intermediate compound
6a showed two triplets that belong to CH2 protons of the thiazolyl
groups in the region δ 3.71 and δ 3.83 ppm whereas a singlet at δ
7.03 ppm in 7a showed the presence of one protons belonging to
thiazole. Finally, the structures of (8a-e)/(9a-e) were confirmed by
their IR, NMR (1H and 13C) and mass spectrometry, which were
found in accordance to their structures.
The results of antifungal study (▶table 2) of derivatives (8a-e and
9a-e) revealed that all the compounds had poor activity against
both the fungal strains C. albicans (Ca) and A. niger (An).
Structure-activity relationship (SAR)
Structure Activity Relationships (SAR) are relations between the
molecular structure and biological or physicochemical activity of
chemicals [21]. Most of the compounds were found to have in-
creased antibacterial activity against S. typhi (8a-c and e, 9a-c and
e), except 8d and 9d bearing diphenyl amine ring in main scaffold
indicating that its presence is liable for discrepancy in activities.
Among all derivatives, compound 8c with benzimidazole moiety,
was found to be superior in exhibiting antibacterial activity against
three bacterial strains i. e. E. coli, S. typhi and P. aeruginosa.
Molecular docking
Biological assay
Molecular docking serves to verify binding integrity and interac-
tion poses of ligands within the binding pocket of target proteins
[22]. From experimental results, compound 8c showed excellent
activity against E. coli, S. typhi and P. aeruginosa. To validate and
specify the target for anti-bacterial activity, different target pro-
teins i. e., enoyl acyl carrier protein reductase of the E. coli (PDBID:
1C14), Lipid A (LpxH) (PDBID: 5B49) and Pyridoxal kinase (PDBID:
5B6A) from P. aeruginosa and 3-Dehydroquinase from Salmonella
typhi (PDB ID: 1GQN) for the docking studies were fetched from
Protein Data Bank (http://www.rscb.org/pdb).
All the molecular docking studies had been carried out using
Auto Dock version 4.2 [23, 24]. Before the docking operation, the
water molecules were removed from the structure, hydrogen
atoms and Kollman charges were added. The ligand was prepared
for docking by minimizing its energy at B3LYP/6-31G (d, p) level of
theory. The active site of the enzyme was defined to include resi-
dues of the active site within the grid size of 60Å × 60 Å × 60 Å. The
most popular algorithm, Lamarckian Genetic Algorithm (LGA) avail-
able in Auto dock was employed for docking. The obtained dock-
ing results are stated as correct when the RMSD value is smaller
than 2 Ǻ [25]. RMSD value is the root mean square deviation from
the determined structural conformation of the ligand. In other
words, it means that the deviation from the active site of the ligand
to interact and it is the most important criteria for the docking re-
sults. The binding energy is the criteria that looked after the RMSD
values. The reason of this priority is that the molecule may also give
lower binding energy with a place other than the active region.
Therefore, first looking at its proximity to the active site, and then
looking at its binding energy which is made in the active region.
The graphical representations of docked pose were performed
using UCSF Chimera 1.10.2 program. The ligand binds at the active
site of the protein by H-bonding.
All the newly synthesized compounds (8a-e and 9a-e) were
screened for their antimicrobial activities against Gram positive
[Staphylococcus aureus (Sa) MTCC 96], and Gram negative [Escher-
ichia coli (Ec) MTCC 64, Salmonella typhi (St) MTCC 581 and Pseu-
domonas aeruginosa (Pa) MTCC 424] bacterial strains and against
fungal species [Candida albicans (Ca) MTCC 183, Aspergillus niger
(An) MTCC 1344] and some of which were found to possess good
or moderate activities against the test microorganisms. All the
newly synthesized compounds were weighed and dissolved in
DMSO (dimethylsulphoxide) to prepare the stock solution of 10.00
microgram/millilitre (µg/mL).
The antimicrobial activity was evaluated by using Disc diffusion
method by measuring the zone of inhibition in mm [20]. The anti-
bacterial activity was compared with standard drug Erythromycin
(E) and antifungal activity was compared with Amphotericin B (Am).
The minimal inhibitory concentration (MICs) of all the active com-
pounds ,were determined by micro broth dilution method using 96
well plates according to the method described by Vipra et al. [20]
DMSO with dilution of 1:10 was used as solvent control. The results
of antimicrobial screening are summarized in ▶tables 1 and 2.
Graphical representation of some of the active compounds against
tested strains is shown in ▶Fig. 2.
In vitro antibacterial activity
Upon investigation, it was observed that majority of compounds
showed highest potency against S. typhi as compared to Erythro-
mycin (MIC = 200 µg/ml) (▶table 2). Compounds 8a, 9a and 9c
showed same potency with MIC value of 200µg/ml whereas com-
pounds 8b, 8e, 9b and 9e illustrated highest activity with MIC value
of 25, 50, 50 and 50µg/ml respectively as compared to Erythromy-
cin. In case of inhibiting gram negative bacterial strain compound
8c showed brilliant activity with MIC 6.25, 25 and 25µg/ml against
E. coli, S. typhi and P. aeruginosa respectively as compared to the
standard drug. Compounds 8e, 9d and 9e exhibited weak activity
Out of 10 conformations acquired by docking into the active site
of Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase
the best conformation was chosen depending on the RMSD value
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Thieme
Original Paper
▶table 1 Antibacterial and antifungal activities of synthesized compounds 8(a-e) and 9(a-e) against different strains (diameter of zone of inhibition).
compound
Bacteria
Fungi
Gram positive
Gram negative
S. aureus
13.5
13.5
21
E. coli
14.5
14.5
22.5
18.5
16
S. typhi
17.5
21
P. aeruginosa
c. albicans
A. niger
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
E
14.5
14
6
7
–
6
21.5
–
18
11
–
10
–
14.5
14.5
15
–
19.5
16.5
14
18
7
–
18
16.5
–
6
–
15
13.5
16
7
6
13.5
15
13
12.5
17
9
8
16.5
22.5
20
–
–
–
14.5
32
17.5
10
18.5
15
7
–
–
–
Am
–
–
–
–
25
–
(-) No activity observed.
▶table 2 In vitro antimicrobial activity (MIC, μg/mL) of compounds 8(a-e) and 9(a-e).
compound
Bacteria
Fungi
Gram positive
Gram negative
S. aureus
200
200
12.5
200
50
E. coli
200
200
3.12a
50
S. typhi
200b
25a
P. aeruginosa
200
c. albicans
A. niger
> 400
400
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
E
400
400
200
> 400
400
400
400
200
> 400
400
–
400
25a
25a
> 400
> 400
> 400
> 400
400
> 400
50a
> 400
100
200
50
200
200
200
50
200b
50a
200
200
100
100
50
> 400
400
200b
> 400
50a
> 400
> 400
> 400
–
100
50
100
0.19
–
6.25
–
200
50
Am
–
–
1.56
6.25
aEntries in bold font indicates excellent activity than reference drug Erythromycin (E).
bEntries in bold font indicates same potency as compared to reference drug Erythromycin (E).
and binding energy. The ligand-target interaction of compound 8c
to Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase
binding site is shown in ▶Fig. 3–ꢀ5. The hydrogen bond interac-
tions and binding energy of compound 8c to Enoyl ACP reductase,
Lipid A, Pyridoxal kinase and type I DHQase are given in ▶table 3.
Amongst the docked conformations, one which binds well at the
active site was analyzed for detailed interactions. The docking re-
sults implied that of compound 8c could compactly occupy the ac-
tive site of Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type
I DHQase with binding energy −4.71, −5.76, −6.69 and −4.97kcal/
mol respectively.
(2) Final Total Internal Energy
(3) Torsional Free Energy
(4) Unbound System's Energy
= − 0.70 kcal/mol
= + 1.37 kcal/mol
= + 0.00 kcal/mol
Estimated Free Energy of Binding for 8c with Lipid
A = -5.76kcal/mol [=(1)+(2)+(3)-(4)]
(1) Final Intermolecular Energy
= − 6.55 kcal/mol
vdW + Hbond + desolv Energy = − 6.59 kcal/mol
Electrostatic Energy
(2) Final Total Internal Energy
(3) Torsional Free Energy
(4) Unbound System's Energy
= + 0.05 kcal/mol
= − 0.58 kcal/mol
= + 1.37 kcal/mol
= + 0.00 kcal/mol
Estimated Free Energy of Binding for 8c with Enoyl AcP
reductase = −4.71kcal/mol [=(1)+(2)+(3)-(4)]
Estimated Free Energy of Binding for 8c with Pyridoxal
kinase = −6.69kcal/mol [=(1)+(2)+(3)-(4)]
(1) Final Intermolecular Energy
vdW + Hbond + desolv Energy = − 5.39 kcal/mol
Electrostatic Energy = − 0.00 kcal/mol
= − 5.39 kcal/mol
(1) Final Intermolecular Energy
vdW + Hbond + desolv Energy = − 7.32 kcal/mol
Electrostatic Energy = − 0.06 kcal/mol
= − 7.38 kcal/mol
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

(2) Final Total Internal Energy
(3) Torsional Free Energy
(4) Unbound System's Energy
= − 0.68 kcal/mol
= + 1.37 kcal/mol
= + 0.00 kcal/mol
400
350
300
250
200
150
100
50
Estimated Free Energy of Binding for 8c with type I
DHQase = −4.97kcal/mol[=(1)+(2)+(3)-(4)]
(1) Final Intermolecular Energy
= − 5.96 kcal/mol
E. coli
S. typhi
vdW + Hbond + desolv Energy = − 5.75 kcal/mol
Electrostatic Energy
(2) Final Total Internal Energy
(3) Torsional Free Energy
(4) Unbound System's Energy
P. aeruginosa
= − 0.20 kcal/mol
= − 0.38 kcal/mol
= + 1.37 kcal/mol
= + 0.00 kcal/mol
0
The best docked conformation of 8c shows-
8a
8b
8c
8e
9a
9c
9e
E
Compounds with Standard Drug
▪ Two hydrogen bond interactions with the residue ARG 1171
and ARG 171. The residue ARG 1171 and ARG 171 has
hydrogen bond interactions with the ligand atom N at a
distance of 2.829 and 2.781 Å respectively.
▶Fig. 2 Pictorial representation of Antibacterial Activity of MIC
values of active compounds against various bacterial strains.
▪ Three hydrogen bond interactions one with the residues GLN
222 and other two with the water molecules of the active site.
The residue GLN 222 has hydrogen bond interaction with the
N at a distance of 3.378 Å.
▪ One hydrogen bond interactions with the residues GLN 48.
The residue GLN 48 has hydrogen bond interaction with the S
at a distance of 3.737 Å.
▪ Two hydrogen bond interactions with the residues ARG 213
and ARG 48. The residue ARG 213 and ARG 48 has hydrogen
bond interaction with the N at a distance of 3.416 and
2.990 Å.
It is a well known fact that, more the number of interactions in
the docked complex, more enriched will be the bioactivity of the
compound. The noteworthy part of the observation is that the two
hydrogen bond interactions were obtained in 8c- Enoyl ACP reduc-
tase complex and 8c- type I DHQase complex and one hydrogen
bond interactions was obtained in 8c- Lipid A/Pyridoxal kinase com-
plex. As a result, the 8c may be deemed as a capable inhibitor of
Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase.
The 8c will be considered as a competent drug for treating infec-
tion caused by E. coli, S. typhi and P. aeruginosa strains on the basis
of experimental results, molecular docking studies and binding in-
teractions.
Synthesis of 1-(2-(trifluoromethyl)phenyl)thiourea
(3a) or 1-(4-fluorophenyl)thiourea (3b).
1-(2-(trifluoromethyl)phenyl)thiourea (3a)/1-(4-fluorophenyl)thi-
ourea (3b) were obtained by the alkaline hydrolysis of N-((2-
(trifluoromethyl)phenyl)carbamothioyl)benzamide (2a) or N-((4-
fluorophenyl)carbamothioyl)benzamide(2b), synthesized by the
reaction of 2-(trifluoromethyl)aniline (1a) or 4-fluoroaniline (1b)
with benzoyl isothiocyanate in dry benzene according to the liter-
ature method [26, 27].
1-(2-(trifluoromethyl)phenyl) thiourea (3a): Yield: 86%; mp:
170 °C; 1H NMR (CDCl3): δ 7.73-7.53 (m, 4H), 8.05 (d, J = 7.02 Hz,
2H), 8.92 (s, NH); IR (KBr): 763, 928, 1216, 1536, 1621, 1689, 2366,
3428; MS (ESI + ): m/z = 221 [M + H]+ .
1-(4-fluorophenyl) thiourea (3b): Yield: 95 %; mp: 93 °C 1H
NMR (CDCl3): δ 6.17 (bs, 2H), 7.13-7.65 (m, 3H), 8.13(d, J = 7.2
Hz, 1H), 8.30 (s, NH); IR (KBr): 707, 812, 1212, 1536, 1625, 1689,
2363, 3437; MS (ESI + ): m/z = 171 [M + H]+ .
Synthesis of compounds 6a and 7a-
Procedure for the synthesis of N-(2-(trifluoromethyl)phenyl)-4,
5-dihydrothiazol-2-amine (6a): To a solution of 2-bromoethyl-
amine hydrobromide 4 (2.05 g, 0.01 mol) in 5.0 mL of water was
added 3a (1.70 g, 0.01 mol) in ethanol (40 mL), and the reaction
mixture was refluxed under stirring overnight. Ethanol was distilled
off under reduced pressure and the reaction mixture was basified
with dilute aqueous ammonia solution. The product 6a was filtered,
washed with water, dried and recrystalized with methanol. Yield
63 %; mp: 130 °C; IR (KBr): 3422, 3021, 1640, 1216, 767; 1H NMR
(400 MHz, CDCl3) δ: 3.71 (t, 2H,-CH2-CH2-), 3.83 (t, 2H, -CH2-
CH2-), 7.03-7.57 (m, 4H); MS (ESI + ): m/z 247 [M + H]+ .
Procedure for the synthesis of N-(4-fluorophenyl)-4-(4-
methoxyphenyl)thiazol-2-amine (7a): The mixture of the equi-
molar (0.01 mol) amounts of the 1-(4-fluorophenyl) thiourea (3b,
1.71 g) and 2-Bromo-4-methoxyacetophenone 5 (2.29 g) in THF
on stirring at room temperature for 30min, resulted in the forma-
tion of a suspension, which was filtered and dried to yield the key
intermediate 7a. Yield 93%; mp: 100°C; IR (KBr cm− 1): 3430, 3021,
2401, 1620, 1509, 1409, 1216, 1030, 760; 1H NMR (400 MHz,
Experimental Section
Materials and methods
All chemicals were purchased from Merck, Sdfine and Qualigens.
Solvents and reagents were used without further purification, un-
less otherwise specified. Melting points were determined in open
capillaries in an electrically heated block and are uncorrected. The
progresses of the reactions were monitored by TLC, using TLC grade
silica gel (G) and developed by exposure to an atmosphere of iodine
vapors. IR spectra were recorded on Perkin-Elmer 1430 spectro-
photometer using KBr pellets and 1H and 13C NMR spectra were ob-
tained on Bruker 300MHz NMR spectrometer in deuterated CHCl3,
MeOH and DMSO using TMS as an internal standard (chemical shifts
in δ, ppm). The DART mass spectra of compounds were recorded
on JMS-T100LC, Accu TOF mass spectrometer. Elemental analyses
were determined using EuroVector E 3000 elemental analyser.
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Thieme
Original Paper
▶Fig. 3 Schematic representation for the docked conformation at active site of the bacterial enzyme: Enoyl acyl carrier protein reductase of the E.
coli (PDBID: 1C14) with 8c.
▶Fig. 4 Schematic representation for the docked conformation at active site of the bacterial enzyme: Lipid A (LpxH) (PDBID: 5B49) and Pyridoxal
kinase (PDBID: 5B6A) from P. aeruginosa with 8c.
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

▶Fig. 5 Schematic representation for the docked conformation at active site of the bacterial enzyme: Dehydroquinase from S. typhi (PDB ID:
1GQN) with 8c.
▶table 3 Hydrogen bond interactions of 8c with target Enoyl acyl carrier protein reductase of the E. coli (PDBID: 1C14), Lipid A (LpxH) (PDBID: 5B49) and
Pyridoxal kinase (PDBID: 5B6A) from P. aeruginosa and 3-Dehydroquinase from S. typhi (PDB ID: 1GQN).
Compound→
8c
Macromolecular
Target ↓
Bonded residue …….
No. of Hydrogen
Bonds
Bond Distance
Inhibition
Constant (μM)
Binding Energy
Ligand atom
(Å)
Kcal/mol
1C14
5b49
ARG 1171.B NH2……………0 N
ARG 171.A NH1 ……………0 N
GLN 222.B NE2 ………….0 N
HOH 553.B O …………….0 N
HOH 608.A O………..0 N
GLN 48.A NE2………..0 S
ARG 213.A NH1……..0 N
ARG 48.A NH1………0 N
2
2.829
2.781
3.378
0.706
2.777
3.737
3.416
2.990
350.99
60.01
− 4.71
− 5.76
3
5b6a
1
2
12.55
− 6.69
− 4.97
1gqn
227.38
N-(morpholinomethyl)-N-(2-(trifluoromethyl)phenyl)-4,5-
dihydrothiazol-2-amine (8a)
CDCl3) δ: 3.85 (s, 3H, CH3), 6.6 (s, NH), 6.99-7.02 (m, 2H, ArH),
7.03 (s, 1H, -CH of thiazole), 7.09-7.11 (m, 2H, ArH), 7.32 (dd, 2H),
7.47 (m, 2H); MS (ESI + ): m/z 301 [M + H]+ .
The compound was synthesized by the reaction of N-(2-
(trifluoromethyl)phenyl)-4, 5-dihydrothiazol-2-amine (6a) and
morpholine as secondary amine following the above general pro-
cedure. Brown liquid; Yield: ~72 %; m.p.: low; Rf: 0.75; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3201 (=C-H), 3059 (-C-H),
2424, 1656 (C = N), 1302 (C-N), 1020 (C-F), 699 (C-S); 1H NMR δ:
2.44-2.50 (m, 4H, morpholine), 3.59-3.64 (m, 4H, morpholine),
3.71 (t, J = 5.86 Hz, 2H, -CH2-CH2-), 3.83 (t, J = 6.01 Hz, 2H, -CH2-
CH2-), 4.33 (s, 2H, -CH2), 7.06 (t, J = 7.22 Hz, 1H, ArH), 7.12 (t,
J = 6.42 Hz, 1H, ArH), 7.18 - 7.23 (m, 1H, ArH), 7.57 (ddd, J = 7.47,
5.57, 1.61 Hz, 1H, ArH); 13C NMR δ: 34.05, 50.79, 61.40, 66.63,
68.76, 116.81, 117.39, 124.28, 126.06, 128.33, 131.76, 141.66,
160.40; MS, m/z: 346 M + 1; Anal. calcd for c15H18F3N3OS: C,
52.16; H, 5.25; N, 12.17; Found: C, 52.19; H, 5.12; N, 12.07.
General procedure for the synthesis of compounds
N-(substituted methyl)-N-(2-(trifluoromethyl)phenyl)-4,5-
dihydrothiazol-2-amine (8a-e) and N-(substituted methyl)-
N-(4-fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine
(9a-e)
The solution of an appropriate secondary amine (0.01mol) in eth-
anol (20ml) was cooled in an ice-bath (0–5°C) for 15min and conc.
HCl (0.014 mol) was added dropwise with stirring. After 20 min,
the solution was allowed to attain room temperature and para-
formaldehyde was added in portions (1/5th of the required
0.15 mol) and the reaction mixture was heated at 100–110°C for
30min. Finally, after addition of intermediate 6a/7a (0.01mol), the
reaction mixture was refluxed for 1–2h at 100–110°C. On comple-
tion of the reaction, the reaction mixture was concentrated and
kept overnight at room temperature to obtain the products 8 (a-e)
and 9 (a-e).
N-(piperidin-1-ylmethyl)-N-(2-(trifluoromethyl)
phenyl)-4,5-dihydrothiazol-2-amine (8b)
The compound was synthesized by the reaction of N-(2-
(trifluoromethyl)phenyl)-4, 5-dihydrothiazol-2-amine (6a) and pi-
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Thieme
Original Paper
peridine as secondary amine following the above general proce-
dure. Brown liquid; Yield: ~56 %; m.p.: low; Rf: 0.62; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3210 (=C-H), 2929 (-C-H),
2445, 1642 (C = N), 1316 (C-N), 1116, 1043 (C-F), 707 (C-S); 1H
NMR δ: 1.44-1.54 (m, 2H, piperidine), 1.67-1.78 (m, 4H, piperi-
dine), 2.48-2.57 (m, 4H, piperidine), 3.71 (t, 2H, -CH2-CH2-), 3.83
(t, 2H, -CH2-CH2-), 4.29 (s, 2H, -CH2), 7.07 (t, J=7.44Hz, 1H, ArH),
7.12 (t, J = 6.34 Hz, 1H, ArH), 7.18-7.23 (m, 1H, ArH), 7.57 (ddd,
J = 7.47, 5.57, 1.61 Hz, 1H, ArH); 13C NMR δ: 24.10, 25.99, 34.05,
53.09, 61.40, 68.76, 116.81, 117.39, 124.28, 126.06, 128.33,
131.76, 141.66, 160.40; MS, m/z: 344 M + 1; Anal. calcd for
c16H20F3N3S: C, 55.96; H, 5.87; N, 12.24; Found: C, 55.19; H, 5.72;
N, 12.27.
2H, -CH2-CH2-), 3.80-3.85 (m, 2H, -CH2-CH2-), 5.16 (s, 2H, -CH2),
5.96 (d, J = 9.67 Hz, 1H, acridone), 6.36 (d, J = 2.05 Hz, 1H, acrid-
one), 7.04-7.66 (m, 9H, ArH), 7.87 (ddd, J=8.64, 4.25, 1.46Hz, 1H,
acridone); 13C NMR δ: 34.05, 61.40, 68.76, 109.08, 116.81,
117.39, 120.59, 121.78, 124.28, 126.06, 126.80, 128.33, 128.80,
130.92, 131.40, 131.76, 140.24, 141.66, 156.25, 160.40, 184.93;
MS, m/z: 454 M + 1; Anal. calcd for c24H18F3N3OS: C, 63.57; H,
4.00; N, 9.27; Found: C, 63.82; H, 4.03; N, 9.29.
N-(4-fluorophenyl)-4-(4-methoxyphenyl)-N-
(morpholinomethyl)thiazol-2-amine (9a)
The compound was synthesized by the reaction of N-(4-
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine (7a) and mor-
pholine as secondary amine following the above general procedure.
Violet solid; Yield: ~69 %; m.p.: 252–254 °C; Rf: 0.49; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3040 (=C-H), 2931 (-C-H),
1564 (C = N), 1443, 1220 (C-N), 1104 (C-F), 726 (C-S); 1H NMR δ:
2.44-2.50 (m, 4H, morpholine), 3.59-3.64 (m, 4H, morpholine),
3.85 (s, 3H, -OCH3), 4.56 (s, 2H, -CH2), 6.99-7.02 (m, 2H, ArH),
7.04 (s, 1H, -CH of thiazole), 7.39-7.46 (m, 5H, ArH); 13C NMR δ:
50.79, 55.46, 66.63, 68.76, 102.19, 114.24, 116.11,126.23,
129.06, 131.40, 144.74, 148.50, 160.44, 160.47, 164.57; MS, m/z:
400 M + 1; Anal. calcd for c21H22FN3O2S: C, 63.14; H, 5.55; N,
10.52 Found: C, 63.29; H, 5.47; N, 10.55.
N-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2-
(trifluoromethyl)phenyl)-4,5-dihydrothiazol-2-amine (8c)
The compound was synthesized by the reaction of N-(2-
(trifluoromethyl)phenyl)-4, 5-dihydrothiazol-2-amine (6a) and
benzimidazole as secondary amine following the above general
procedure. Reddish brown semi-solid; Yield: ~61%; m.p.: low; Rf:
0.62; (20 % Chloroform:Methanol); Ir (KBr cm− 1): 3218 ( = C-H),
2838 (-C-H), 2445, 1577 (C=N), 1341 (C-N), 1120, 1043 (C-F), 790
1
(C-S); H NMR δ: 3.71 (t, J = 6.01 Hz, 2H, -CH2-CH2-), 3.83 (t,
J = 6.01 Hz, 2H, -CH2-CH2-), 5.27 (s, 2H, -CH2), 6.94-7.14 (m, 4H,
benzimidazole), 7.18-7.23 (m, 1H, ArH), 7.57 (ddd, J= 7.47,5.57,
1.61 Hz, 1 H), 7.67-7.75 (m, 2H), 8.01-8.04 (m, 1H, benzimida-
zole); 13C NMR δ: 34.05, 61.40, 68.76, 110.19, 116.81, 117.39,
119.95, 122.54, 123.04, 124.28, 126.06, 128.33, 131.76, 132.69,
141.66, 143.40, 144.00, 160.40; MS, m/z: 377 M + 1; Anal. calcd
for c18H15F3N4S: C, 57.44; H, 4.02; N, 14.88; Found: C, 57.49; H,
4.12; N, 14.37.
N-(4-fluorophenyl)-4-(4-methoxyphenyl)-N-(piperidin-
1-ylmethyl)thiazol-2-amine (9b)
The compound was synthesized by the reaction of N-(4-
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine (7a) and pi-
peridine as secondary amine following the above general proce-
dure. Green solid; Yield: ~49 %; m.p.: 280–282 °C; Rf: 0.37; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 2931 (=C-H), 2847 (-C-H),
1569 (C = N), 1506, 1306 (C-N), 1219 (C-F), 726 (C-S); 1H NMR δ:
1.44-1.54 (m, 2H, piperidine), 1.67-1.78 (m, 4H, piperidine), 2.48-
2.57 (m, 4H, piperidine), 3.85 (s, 3H, -OCH3), 4.53 (s, 2H, -CH2),
6.99-7.02 (m, 2H, ArH), 7.04 (s, 1H, -CH of thiazole), 7.39-7.46 (m,
6H, ArH); 13C NMR δ: 24.10, 25.99, 53.09, 55.46, 68.76, 102.19,
114.24, 116.11, 126.23, 129.06, 131.40, 144.74, 148.50, 160.44,
160.47, 164.57; MS, m/z: 398 M + 1; Anal. Calcd for C22H24FN3OS:
C, 66.47; H, 6.09; N, 10.57; Found: C, 66.19; H, 6.10; N, 10.65.
N-(4,5-dihydrothiazol-2-yl)-N,N-diphenyl-N-(2-
(trifluoromethyl)phenyl) methanediamine (8d)
The compound was synthesized by the reaction of N-(2-
(trifluoromethyl)phenyl)-4, 5-dihydrothiazol-2-amine (6a) and di-
phenylamine as secondary amine following the above general pro-
cedure. Brown solid; Yield: ~87 %; m.p.: > 300 °C; Rf: 0.41; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3100 (=C-H), 1642 (C=N),
1240 (C-N), 1090 (C-F), 727 (C-S); 1H NMR δ: 3.67-3.71 (m, 2H,
-CH2-CH2-), 3.81-3.85 (m, 2H, -CH2-CH2-), 4.78 (s, 2H, -CH2), 6.94
(t, J = 7.97 Hz, 2H, diphenyl amine), 7.04-7.25 (m, 11H, ArH), 7.57
(ddd, J=7.47, 5.71, 1.46Hz, 1 H); 13C NMR δ: 34.05, 61.40, 68.76,
116.81, 117.39, 122.12, 124.28, 124.72, 126.06, 128.33, 129.25,
131.76, 141.66, 144.74, 160.40; MS, m/z: M + 1 428; Anal. calcd
for c23H20F3N3S: C, 64.62; H, 4.72; N, 9.83; Found: C, 64.56; H,
4.60; N, 9.39.
N-((1H-benzo[d]imidazol-1-yl)methyl)-N-(4-fluorophenyl)-
4-(4-methoxyphenyl)thiazol-2-amine (9c)
The compound was synthesized by the reaction of N-(4-
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine (7a) and ben-
zimidazole as secondary amine following the above general proce-
dure. Bluish green solid; Yield: ~67%; m.p.: 262–264°C; Rf: 0.25;
(20 % Chloroform:Methanol); Ir (KBr cm− 1): 3062 ( = C-H), 1590
(C = N), 1341 (C-N), 1120 (C-F), 758, 701 (C-S); 1H NMR δ: 3.85 (s,
3H, -OCH3), 5.43 (s, 2H, -CH2), 6.94-7.02 (m, 5H), 7.04 (s, 1H, -CH
of thiazole), 7.40-7.48 (m, 4H, ArH), 7.67-7.75 (m, 3H, ArH), 8.01
(dd, J=3.66, 2.20Hz, 1H, benzimidazole); 13C NMR δ: 55.46, 68.76,
102.19, 110.19, 114.24, 116.11, 119.95, 122.54, 123.04, 126.23,
129.06, 131.40, 132.69, 143.40, 144.00, 144.74, 148.50, 160.44,
160.47, 164.57; MS, m/z: 431 M+1; Anal. calcd for c24H19FN4OS:
C, 66.96; H, 4.45; N, 13.01; Found: C, 66.71; H, 4.22; N, 13.37.
10-(((4,5-dihydrothiazol-2-yl)(2-(trifluoromethyl)phenyl)
amino)methyl)acridin-1(10H)-one (8e)
The compound was synthesized by the reaction of N-(2-
(trifluoromethyl)phenyl)-4, 5-dihydrothiazol-2-amine (6a) and
acridone as secondary amine following the above general proce-
dure. Light green solid; Yield: ~92 %; m.p.: > 300 °C; Rf: 0.92; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3252 (=C-H), 3110 (-C-H),
1622 (C=N), 1474, 1163 (C-F), 757 (C-S); 1H NMR δ: 3.67-3.71 (m,
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

N-(4-fluorophenyl)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-
N,N-diphenylmethanediamine (9d)
(CDRI), Lucknow, India for providing spectral, elemental and bio-
logical activity data. Authors are also thankful to UGC (Grant No.-
F1-17.1/2012-13/RGNF-2012-13-SC-UTT-14495) for providing fi-
nancial support.
The compound was synthesized by the reaction of N-(4-
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine (7a) and di-
phenylamine as secondary amine following the above general pro-
cedure. Dirty green solid; Yield: ~78%; m.p.: >300°C; Rf: 0.28; (20%
Chloroform:Methanol); Ir (KBr cm− 1): 3062 (=C-H), 2522, 1612
(C=N), 1304 (C-N), 1240, 1160 (C-F), 798 (C-S); 1H NMR δ: 3.85 (s,
3H, -OCH3), 4.87 (s, 2H, -CH2), 6.91-7.02 (m, 6H), 7.04 (s, 1H, -CH
of thiazole), 7.10-7.25 (m, 8H, diphenyl amine), 7.40-7.48 (m, 4H,
ArH); 13C NMR δ: 55.46, 68.76, 102.19, 114.24, 116.11, 122.12,
124.72, 126.23, 129.06, 129.25, 131.40, 144.74, 148.50, 160.44,
160.47, 164.57; MS, m/z: 482 M+1; Anal. calcd for c29H24FN3OS:
C, 72.33; H, 5.02; N, 8.73; Found: C, 72.21; H, 5.10; N, 8.79.
Conflict of Interest
The authors declare no conflict of interest.
References
[1] Rang HP, Dale MM, Ritter JM et al. Analgesic drugs, rang and dale’s
pharmacology. Churchill Livingstone, International addition; 2003: 5th
Ed. 562
10-(((4-fluorophenyl)(4-(4-methoxyphenyl)thiazol-2-yl)
amino)methyl)acridin-1(10H)-one (9e)
[2] Ulusoy N, Kiraz M, Kucukbasmaci O. New 6-(4-Bromophenyl)-
imidazo[2,1-b] thiazole Derivatives: Synthesis and Antimicrobial
ActivityMonatshefte fur chemie 2002; 133: 1305–1315
The compound was synthesized by the reaction of N-(4-
fluorophenyl)-4-(4-methoxyphenyl)thiazol-2-amine (7a) and acri-
done as secondary amine following the above general procedure.
Light green solid; Yield: ~83 %; m.p.: 272–274 °C; Rf: 0.57; (20 %
Chloroform:Methanol); Ir (KBr cm− 1): 3033 (=C-H), 2923 (-C-H),
1656 (C = N), 1301 (C-N), 1174 (C-F), 830, 698 (C-S); 1H NMR δ:
3.85 (s, 3H, -OCH3), 5.11 (s, 2H, -CH2), 5.96 (d, J=9.38Hz, 1H, acri-
done), 6.36 (d, J= 2.05 Hz, 1H, acridone), 6.99-7.02 (m, 3H), 7.04
(s, 1H, -CH of thiazole), 7.16 (t, J=7.69Hz, 1H, acridone), 7.37-7.55
(m, 8H, ArH), 7.66 (ddd, J=8.06, 4.25, 1.46Hz, 1H, acridone), 7.87
(ddd, J = 8.57, 4.18, 1.32 Hz, 1H, acridone); 13C NMR δ: 55.46,
68.76, 102.19, 109.08, 114.24, 116.11, 117.39, 120.59, 121.78,
126.23, 126.80, 128.80, 129.06, 130.92, 131.40, 131.76, 140.24,
141.66, 144.74, 148.50, 156.25, 160.44, 160.47, 164.57, 184.93;
MS, m/z: 508 M + 1; Anal. calcd for c30H22FN3O2S: C, 70.99; H,
4.37; N, 8.28; Found: C, 70.89; H, 4.23; N, 8.29.
[3] Kaplancikli ZA, Zitouni GT, Revial G et al. Synthesis and study of
antibacterial and antifungal activities of Novel 2-[[(benzoxazole/
benzimidazole-2-yl)sulfanyl] acetylamino] thiazoles Arch pharm Res
2004; 27: 1081–1085
[4] Al-Saddi MS, Faidallah HM, Rostom SAF. Synthesis and biological
evaluation of some 2,4,5-trisubstituted thiazole derivatives as
potential antimicrobial and anticancer agents Arch Pharm Che Life Sci
2008; 341: 424–434
[5] Desai NC, Bhatt NB, Somani HC et al. Synthesis and antimicrobial
activity of some thiazole and 1,3,4-oxadiazole hybrid heterocycles
Indian J Chem 2016; 55B: 94–101
[6] Pawar CD, Sarkate AP, Karnik KS et al. Synthesis and antimicrobial
evaluation of novel ethyl 2-(2-(4-substituted)acetamido)-4-subtituted-
thiazole-5-carboxylate derivatives Bioorg Med Chem Lett 2016; 26:
3525–3528
[7] Tay F, Erkan C, Sariozlu NY et al. Synthesis, antimicrobial and
anticancer activities of some naphthylthiazolylamine derivatives Bio
Med Res 2017; 28: 2696–2703
[8] Abdel-Sattar NEA, El-Naggar AM, Abdel-Mottaleb MSA. Novel Thiazole
Derivatives of Medicinal Potential: Synthesis and Modeling Journal of
Chem 2017; 2017: 1–11
Conclusion
In the present study, authors have reported the simple and highly
efficient procedure for the synthesis, spectral studies and biologi-
cal screening of novel thiazol-2-amines 8(a-e) and 9(a-e). The com-
pounds were tested for their in vitro antimicrobial activity. The
compound 8c exhibited excellent antimicrobial potency against
the E. coli, S. typhi and P. aeruginosa strains. From the docking stud-
ies, it is observed that most active compound 8c binds at the ac-
tive sites of the targets by hydrogen bond interactions. The docked
ligand forms a stable complex with all the enzymes and greater
binding interaction of compound with enzymes suggests that the
compound 8c might exhibit inhibitory activity by inhibiting Enoyl
ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase enzyme
which was further confirmed by experimental biological data. This
work contributes to authenticate the design of the thiazol-2-amines
motifs as a template useful as new antimicrobial compounds.
[9] Abdel-Aziz M, El-Din A, Abuo-Rahma G et al. Synthesis of novel
pyrazole derivatives and evaluation of their antidepressant and
anticonvulsant activities Eur J Med Chem 2009; 44: 3480–3487
[10] Pattan SF, Dighe NS, Nirmal SA et al. Synthesis and Biological Evaluation
of Some Substituted Amino Thiazole Derivatives Asian J Res Chem 2009;
9: 196–201
[11] Karade HN, Acharya BN, Sathe M et al. Design, synthesis, and
antimalarial evaluation of thiazole-derived amino acids Med Chem Res
2008; 17: 19–29
[12] Musser JH, Brown RE, Loev B et al. Synthesis of 2-(2,3-dihydro-2-oxo-
1,3,4-oxadiazol-5-yl) benzo heterocycles- A novel series of orally active
antiallergic agents J Med Chem 1984; 27: 121–125
[13] Amnerkar ND, Bhongade BA, Bhusari KP. Synthesis and biological
evaluation of some 4-(6-substituted-1, 3-benzothiazol-2-yl) amino-1,
3-thiazole-2-amines and their Schiff bases Arab J Chem 2015; 8:
545–552
[14] Reddy GJ, Manjula D, Rao KS et al. A Direct single step synthesis of
1,3-diaryl-4-cyanopyrazoles and their conversion to 1,3-diaryl-4-(4,6-
diamino 1,3,5-triazin-2-yl)pyrazoles Indian J Chem 2005; 44:
2412–2415
Acknowledgement
The authors are thankful to the Head, Department of Chemistry,
University of Lucknow, Lucknow, for providing necessary Labora-
tory facilities and to the Director, Central Drug Research Institute
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res

Thieme
Original Paper
[15] Karabasanagouda T, Adhikari AV, Ramgopal D et al. Synthesis of some
new 2-(4-alkylthiophenoxy)-4- substituted-1,3-thiazoles as possible
anti-inflammatory and antimicrobial agents Ind J Chem 2008; 47:
144–152
[22] Tanoli SA, Tanoli NU, Usmani S. The exploration of interaction studies
of smaller size, mostly ignored yet intrinsically inestimable molecules
towards BSA; An example of STD and DOSY NMR Cent Eur J Chem
2014; 12: 332–340
[16] Amir M, Kumar H, Khan SA. Synthesis and pharmacological evaluation
of pyrazoline derivatives as new anti-inflammatory and analgesic
agents Bioorg Med Chem Lett 2008; 18: 918–922
[23] Huey R, Morris GM, Olson AJ et al. A semiempirical free energy force
field with charge-based desolvation J Comp Chem 2007; 28:
1145–1152
[17] Nassar E. Synthesis, (in vitro) antitumer and antimicrobial activity of
some pyrazoline, pyridine and pyrimidine derivatives linked to indoles
moiety J Am Sci 2010; 6: 463–471
[24] Trott O, Olson A. AutoDock Vina: improving the speed and accuracy of
docking with a new scoring function, efficient optimization and
multithreading J Comp Chem 2010; 31: 455–461
[18] Bishnoi A, Tiwari AK, Singh S et al. Synthesis, characterization, and
biological evaluation of novel thiazole and pyrazole derivatives of
quinoline-4-carboxylic acid as potential antimicrobial agents Med Chem
Res 2013; 22: 3527–3535
[25] Kramer B, Rarey M, Lengauer T. Evaluation of the FLEXX incremental
construction algorithm for protein–ligand docking Proteins: Structure,
Function, and Bioinform 1999; 37: 228–241
[26] Rasmassen R, Villani FJ, Weaner LE et al. Improved procedures for the
preparation of cycloalkyl-, arylalkyl- and arylthioureas Synthesis 1988;
6: 456–459
[19] Bishnoi A, Singh S, Tiwari AK et al. Design, synthesis and antimicrobial
properties of novel 3,3a,4,5,6,7- hexahydroindazole and arylthi-
azolylpyrazoline derivatives Med Chem 2013; 9: 45–52
[27] Varshney K, Gupta S, Rahuja N et al. Synthesis, structure-activity
relationship and docking studies of substituted aryl thiazolyl phenylsul-
fonamides as potential protein tyrosine phosphatase 1B inhibitors
ChemMedChem 2012; 7: 1185–1190
[20] Vipra A, Desai SN, Junjappa RP et al. Determining the Minimum
Inhibitory Concentration of Bacteriophages: Potential Advantages
Advances in Microbiology 2013; 3: 181–190
[21] Hulzebos EM, Janssen PAH, Maslankiewicz L et al. The application of
structure-activity relationships in human hazard assessment: a first
approach, RIVM Report No 601516008, 2001
Verma AK et al. Thiazol-2-amines as Bioactive Molecules… Drug Res