Synthesis and antimycobacterial evaluation of new 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives

Article abstract of DOI:10.1007/s00044-019-02310-y

A new series of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives, 6a?w have been synthesized by click reaction of substituted benzylazide, 5a?d with 5-ethynyl-4-methyl-2-substituted phenylthiazole, 4a?f. The starting compounds 4-ethy

Full text of DOI:10.1007/s00044-019-02310-y

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02310-y
ORIGINAL RESEARCH
Synthesis and antimycobacterial evaluation of new 5-(1-benzyl-1H-
1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives
Vikas Shinde1 Pramod Mahulikar1 Pravin C. Mhaske2 Shakti Chakraborty3 Amit Choudhari3 Siddharth Phalle4
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Prafulla Choudhari4 Dhiman Sarkar3
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Received: 11 October 2018 / Accepted: 6 February 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
A new series of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives, 6a−w have been synthesized by
click reaction of substituted benzylazide, 5a−d with 5-ethynyl-4-methyl-2-substituted phenylthiazole, 4a−f. The starting
compounds 4-ethynyl-2-substituted phenylthiazole (4a−f) were synthesized from the corresponding thiazole aldehyde by
using the Ohira−Bestmann reagent. The structure of the synthesized compounds was determined by spectral analysis. All
the synthesized compounds were screened for their preliminary antitubercular activity against Mycobacterium tuberculosis
H37Ra (MTB, ATCC 25177). Most of the synthesized compounds reported good activity against M. tuberculosis H37Ra
strain with IC50 range of 0.58−8.23 µg/mL. Compounds 6g and 6k reported good antitubercular activity with MIC90 values
of 4.71 and 2.22 µg/mL, respectively. Potential antimycobacterial activity suggested that these compounds could serve as
good lead compounds for further optimization and development of a newer antitubercular candidate.
Graphical Abstract
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Keywords Thiazole 1,2,3-Triazole Ohira−Bestmann reagent Antitubercular activity Molecular docking
Introduction
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02310-y) contains supplementary
material, which is available to authorized users.
Mycobacterium tuberculosis (MTB) is among the most
challenging bacterial infections declared by the World
Health Organization (WHO). In 2015, WHO estimated that
globally 10.4 million people were diagnosed with TB and it
was one of the top 10 causes of death worldwide (WHO
Tuberculosis Fact Sheet 2016). In addition, Mycobacterium
bovis BCG vaccination is also among the most commonly
administered vaccines worldwide (Wang et al. 2013). The
spontaneous mutations in genes of the pathogenic strains
increase the number of multi-drug-resistant and extensively
drug-resistant pathogens; therefore, a need for new classes
of antimicrobial agents is warranted. The increase in anti-
biotic resistance has encouraged the researchers to search
for new compounds, which are active against acute as well
as chronic forms of tuberculosis (Shenoi and Friedland
* Pramod Mahulikar
mahulikarpp@rediffmail.com
* Pravin C. Mhaske
mhaskepc18@gmail.com
1
School of Chemical Sciences, North Maharashtra University,
Jalgaon, Maharashtra, India
2
Post Graduate Department of Chemistry, S.P. Mandali’s Sir
Parashurambhau College, Savitribai Phule Pune University, Tilak
Road, Pune, Maharashtra 411030, India
3
CombiChemBio Resource Centre, CSIR-National Chemical
Laboratory, Pune, Maharashtra 411008, India
4
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth
College of Pharmacy, Kolhapur, Maharashtra 413016, India

Medicinal Chemistry Research
Fig. 1 Representative antitubercular active thiazolyl-triazole compounds and the new proposed analogs
2009, Ramesh et al. 2016, Jeankumar et al. 2016, Tantry
et al. 2017).
anti-inflammatory (Rostom et al. 2009, Shelke et al. 2012,
Kouatly et al. 2008, Giri et al. 2009), antiviral (Barradas
et al. 2011), CNS-active agents (Mishra et al. 2015), and
anticancer activities (Liu et al. 2009, Pandya et al. 2015).
Thiazole clubbed with triazole reported antitubercular
(Shiradkar et al. 2007, Shinde et al. 2018) and antimicrobial
(Güzeldemirci and Küçükbasmac 2010, Karale et al. 2014)
activities. Substituted 2-amino thiazole clubbed with 1,2,3-
triazole was reported as inhibitors of leukemia stem cells (Li
et al. 2018), glucokinase activators (Liu et al. 2011), and
antitubercular activities (Azzali et al. 2017). These reports
encouraged facilitating the structural diversity and biologi-
cal importance of 1,2,3-triazole and thiazoles nucleus in
medicinal chemistry, and have made them attractive targets
for synthesis.
Mycobacterial fatty acid biosynthesis is a vital process
for the growth of mycobacterium. Fatty acid biosynthesis
results in the mycolic acid-rich cell wall, a major reason
behind the generation of MDR and XDR types of tuber-
culosis. Fatty acid biosynthesis is an attractive target due to
its conserved nature and its contribution in mycobacterium
growth. Enoyl acyl carrier protein reductase (INHA) is a
key enzyme involved in the type II fatty acid biosynthesis
that regulates the reduction of 2-trans-enoyl-ACP (acyl
carrier protein) to generate a reduced enoyl thioester–ACP
substrate. This enoyl thioester–ACP substrate takes part in
the mycolic acid synthesis to generate mycolic acid. Inhi-
bition of enoyl acyl carrier protein reductase will lead to
inhibition of the growth and survival of the Mycobacterium
in the host (Martinelli et al. 2017, Shanthi and Ramanathan
2014, Patil et al. 2016).
The synthesis of a new hybrid architecture of two or
more bioactive scaffolds is one of the powerful tools used in
new drug discovery. The synthesis of triazole and thiazole
pharmacophore units has received much attention due to
their antitubercular activity (Fig. 1). 1,2,3-Triazole, 1,2,4-
triazole, and their derivatives are an important class of
bioactive molecules that exhibit significant pharmacological
activities, such as antitubercular (Ramesh et al. 2016,
Jeankumar et al. 2016, Patpi et al. 2012, Shaikh et al. 2015,
Shanmugavelan et al. 2011, Keri et al. 2015, Gonzaga et al.
2013, Krishna et al. 2014, Foks et al. 2005, Jadhav et al.
2009, Shiradkar et al. 2007), antimicrobial (Chen et al.
2000, Holla et al. 2005, Dongamanti et al. 2014, Wang et al.
2017), analgesic, anti-inflammatory and ulcerogenic (Hafez
et al. 2008), antineoplastic (Passannanti et al. 1998),
anticonvulsant (Guan et al. 2007), antiproliferative (Dmitry
et al. 2014), Alzheimer (Christian et al. 2008), antiviral
activity (Farghaly et al. 2006), anticancer (Jeong et al. 2015,
Reddy et al. 2015), antimalarial (Gujjar et al. 2009), β-
lactamase inhibitors (Weide et al. 2010), fungicidal and
antitubercular (Kathiravan et al. 2012, Shirude et al. 2013)
activities, and many more.
Thiazole and its derivatives are an important structure in
medicinal chemistry that could provide a rich spectrum of
biological activities, such as antitubercular (Abhale et al.
2015, 2016, 2017, Jeankumar et al. 2012, Samala et al.
2016, Tomasic et al. 2015), antimicrobial (Davyt et al.
2010, Kashyap et al. 2012, Oniga et al. 2012, 2015, Shiran
et al. 2013, Skedelj et al. 2013, Gaikwad et al. 2012a, b),

Medicinal Chemistry Research
Keeping in mind the biological significance of 1,2,3-
triazole and thiazole derivatives, we report herein the
synthesis of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-
phenylthiazole, 6a−x as potential antimycobacterial
agents.
2-(4-chlorophenyl)-5-ethynyl-4-methylthiazole,
4c 1H
NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.6 Hz, 2H), 7.40
(d, J = 8.6 Hz, 2H), 3.59 (s, 1H), and 2.55 (s, 3H); LCMS
m/z: 234.01 (M+H)+.
5-ethynyl-2-(4-fluorophenyl)-4-methylthiazole,
4d 1H
NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 8.7, 5.3 Hz, 2H),
7.11 (t, J = 8.6 Hz, 2H), 3.58 (s, 1H), and 2.54 (s, 3H);
LCMS m/z: 218.04 (M+H)+.
Materials and methods
Chemistry
5-ethynyl-4-methyl-2-(p-tolyl)thiazole, 4e 1H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.0
Hz, 2H), 3.56 (s, 1H), 2.54 (s, 3H), and 2.38 (s, 3 H);
LCMS m/z: 214.07 (M+H)+.
All the reactions were monitored by thin-layer chromato-
graphy (TLC), performed on Merck 60 F-254 silica gel
plates with visualization by UV light. The melting points
were determined in capillary tubes in silicon oil bath using a
Veego melting point apparatus and are uncorrected. 1H
NMR (500-MHz) and 13C NMR (126-MHz) spectra were
recorded on BRUKER AVANCE II 500 NMR spectro-
meter. Chemical shifts are reported from an internal tetra-
methylsilane standard and are given in δ units. All the target
compounds were purified by column chromatography using
silica gel (100–200 mesh). The starting compounds 4-
methyl-2-arylthiazole-5-carbaldehyde (3a−f) were synthe-
sized from a known literature method (Shinde et al. 2018).
General procedure for the synthesis of 2-phenyl-4-((4-
phenyl-1H-1,2,3-triazol-1-yl)methyl)thiazole (6a)
A reaction mixture of 5-ethynyl-4-methyl-2-phenylthiazole,
4a (0.2 g, 1 mmole), benzylazide, 5a (0.14 g, 1 mmole),
copper sulfate (0.040 g, 0.25 mmole), and sodium ascorbate
(0.050 g, 0.22 mmole) in DMF:water (6 mL, 3:1) was stir-
red overnight. After completion of the reaction (TLC), the
reaction mixture was quenched in water and extracted by
ethyl acetate (3 × 15 mL). The organic layer was dried over
sodium sulfate and evaporated on a rotary evaporator. The
crude product was purified by column chromatography
(ethyl acetate:hexane) and furnished the target compound 2-
phenyl-4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)thiazole
(6a). Compounds 6b−w were synthesized by a similar
procedure.
General procedure for the synthesis of 5-ethynyl-4-methyl-
2-phenylthiazole (4a)
To an ice-cold solution of freshly prepared diethyl (1-diazo-
2-oxopropyl)phosphonate (13 mmol) and K2CO3 (20 mmol)
in dry methanol (20 mL), a solution of 4-methyl-2-phe-
nylthiazole-5-carbaldehyde (3a) (10 mmol) in methanol (20
mL) was added and the reaction mixture was stirred at room
temperature for 24 h. After completion of the reaction
(TLC), the solvent was distilled under vacuum and the
residue was dissolved in water (80 mL), and the reaction
mass was extracted by ethyl acetate (3 × 25 mL). The
organic layer was washed with brine, dried over sodium
sulfate, and evaporated on a rotary evaporator. The crude
product purified by column chromatography using ethyl
acetate:hexane (2:8) as an eluent gave 5-ethynyl-4-methyl-
2-phenylthiazole (4a), yield 0.95 g, 45%.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-phenylthiazole
(6a) 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 3H, Thiazole
−CH3), 5.60 (s, 2H, Ar−CH2−N), 7.32 (dd, J = 7.7, 1.7
Hz, 2H, Ar−H), 7.59 (s, 1H, Triazole−H), 7.38–7.44 (m,
6H, Ar−H), and 7.93 (dd, J = 7.9, 1.7 Hz, 2H, Ar−H); 13
C
NMR (126 MHz, CDCl3): δ 17.12 (CH3, Thiazole−CH3),
54.42 (CH2, Ar−CH2−N), 120.10 (CH, Triazole−C-5),
121.68 (C, Thiazole–C-5), 127.86 (C, C-4′′), 127.94 (CH,
C-2′′,-6′′), 128.15 (CH, C-3′′,-5′′), 129.42 (CH, C-3′,-5′),
129.52 (CH, C-2′,-6′), 130.14 (CH, C-4′), 130.96 (C, C-1′
′), 134.96 (C, C-1′), 140.97 (C, Triazole−C-4), 149.95 (C,
Thiazole−C-4), and 165.68 (C, Thiazole−C-2); Chemical
formula: C19H16N4S, Exact mass: 332.1096, HRMS:
333.1172 (M+H)+, 355.0991 (M+Na)+.
5-ethynyl-4-methyl-2-phenylthiazole, 4a 1H NMR (500
MHz, CDCl3) δ 7.94–7.90 (m, 2H), 7.60 (m, 2H), 7.45–
7.41 (m, 1H), 3.55 (s, 1H), 2.55 (s, 3H); d, J = 8.6 Hz, 2H),
7.40 (d, J = 8.6 Hz, 2H), 3.59 (s, 1H), and 2.55 (s, 3H);
LCMS m/z: 200.04 (M+H)+.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(4-bromophenyl)-4-
methylthiazole(6b) 1H NMR (500 MHz, CDCl3) δ 2.59 (s,
3H, Thiazole−CH3), 5.60 (s, 2H, Ar−CH2−N), 7.33 (d, J
= 7.8, 2H, Ar−H), 7.38–7.44 (m, 5H, Ar−H), 7.59 (s, 1H,
Triazole−H), 7.93 (d, J = 7.8, 2H, Ar−H); 13C NMR (126
MHz, CDCl3) δ 17.08 (CH3, Thiazole−CH3), 54.36 (CH2,
2-(4-bromophenyl)-5-ethynyl-4-methylthiazole,
4b 1H
NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 2H), 7.56
(d, J = 8.6 Hz, 2H), 3.58 (s, 1H), and 2.56 (s, 3H); LCMS
m/z: 278.01 (M+H)+.

Medicinal Chemistry Research
Ar−CH2−N), 120.10 (CH, Triazole−C-5), 121.70 (C,
Thiazole−C-5), 127.90 (C, C-4′′), 128.12 (CH, C-2′′,-6′′),
127.35 (C, C-4′), 129.20 (CH, C-3′′,-5′′), 129.88 (CH, C-
2′,-6′), 130.90 (CH, C-3′,-5′), 130.99 (C, C-1′′), 134.96 (C,
C-1′), 140.92 (C, Triazole−C-4), 149.80 (C, Thiazole−C-
4), 165.35 (C, Thiazole−C-2). Chemical formula:
C19H15BrN4S, Exact mass: 410.0201, HRMS: 411.0269 (M
+H)+, 413.0249 (M+2+H)+.
(C, C-1′), 138.77 (C, C-3′), 140.89 (C, Triazole−C-4),
149.81 (C, Thiazole−C-4), 165.87 (C, Thiazole−C-2),
Chemical formula: C20H18N4S, Exact mass: 346.1252,
HRMS: 347.1334 (M+H)+, 369.1153 (M+Na)+.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-(p-tolyl)thia-
zole(6f) 1H NMR (500 MHz, CDCl3): δ 2.38 (s, 3H, Ar
−CH3), 2.57 (s, 3H, Thiazole−CH3), 5.59 (s, 2H, Ar−CH2
−N), 7.23 (d, J = 8.0 Hz, 2H, Ar−H), 7.30–7.34 (m, 2H,
Ar−H), 7.37−7.41 (m, 3H, Ar−H), 7. 7.58 (s, 1H, Triazole
−H), 82 (d, J = 8.1 Hz, 2H, Ar−H); 13C NMR (126 MHz,
CDCl3) δ 17.06 (CH3, Thiazole−CH3), 21.24 (CH3, Ar
−CH3), 54.40 (CH2, Ar−CH2−N), 120.08 (CH, Triazole
−C-5), 121.61 (C, Thiazole−C-5), 126.85 (CH, C-4′′),
128.07 (CH, C-2′′,-6′′), 129.37 (CH, C-3′,-5′), 129.28 (CH,
C-3′′,-5′′), 129.68 (CH, C-2′,-6′), 130.88 (C, C-1′′), 134.96
(C, C-1′), 138.86 (C, C-4′), 141.08 (C, Triazole−C-4),
150.02 (C, Thiazole−C-4), 165.87 (C, Thiazole−C-2),
Chemical formula: C20H18N4S, Exact mass: 346.1252,
HRMS: 347.1334 (M+H)+, 369.1153 (M+Na)+.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(4-chlorophenyl)-4-
methylthiazole(6c) 1H NMR (500 MHz, CDCl3) δ 2.57 (s,
3H, Thiazole−CH3), 5.60 (s, 2H, Ar−CH2−N), 7.30–7.35
(m, 2H, Ar−H), 7.37–7.41 (m, 5H, Ar−H), 7.60 (s, 1H,
Triazole−H), 7.86 (d, J = 8.6 Hz, 2H, Ar−H); 13C NMR
(126 MHz, CDCl3): δ 17.21 (CH3, Thiazole−CH3), 54.38
(CH2, Ar−CH2−N), 120.10 (CH, Triazole−C-5), 122.03
(C, Thiazole−C-5), 127.82 (C, C-4′′), 127.86 (CH, C-2′
′,-6′′), 129.10 (CH, C-3′′,-5′′), 129.38 (CH, C-2′,-6′),
129.45 (CH, C-3′,-5′), 130.92 (C, C-1′′), 135.00 (C, C-4′),
135.93 (C, C-1′), 140.84 (C, Triazole−C-4), 149.88 (C,
Thiazole−C-4), 164.77 (C, Thiazole−C-2). Chemical for-
mula: C19H15ClN4S, Exact mass: 366.0706, HRMS:
367.0786 (M+H)+, 369.0758 (M+2+H)+, and 389.0603
(M+Na)+.
5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-phe-
nylthiazole (6g) 1H NMR (500 MHz, CDCl3) δ 2.60 (s,
3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N), 7.07–7.13
(m, 2H, Ar−H), 7.39–7.35 (m, 2H, Ar−H), 7.40–7.46 (m,
3H, Ar−H), 7.59 (s, 1H, Triazole−H), 7.90–7.97 (m, 2H,
Ar−H); 13C NMR (126 MHz, CDCl3) δ 17.03 (CH3, Thia-
zole−CH3), 53.65 (CH2,Ar−CH2−N), 116.30 (CH, C-3′
′,-5′′), 120.01 (CH, Triazole−C-5), 121.66 (C, Thiazole
−C-5), 126.40 (CH, C-3′, -5′), 128.98 (CH, C-2′, -6′),
129.98 (CH, C-2′′,-6′′), 130.08 (CH, C-4′), 130.24 (C, C-1′
′), 133.45 (C, C-1′), 141.00 (C, Triazole−C-4), 149.96 (C,
Thiazole−C-4), 162.97 (C, C-4′′), 165.70 (C, Thiazole−C-
2), Chemical formula: C19H15FN4S, Exact mass: 350.1001,
HRMS: 351.1078 (M+H)+, 373.0895 (M+Na)+.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(4-fluorophenyl)-4-
methylthiazole(6c) 1H NMR (500 MHz, CDCl3) δ 2.57 (s,
3H, Thiazole−CH3), 5.60 (s, 2H, Ar−CH2−N), 7.12 (t, J
= 8.7 Hz, 2H, Ar−H), 7.30–7.36 (m, 2H, Ar−H), 7.40 (t, J
= 4.9 Hz, 3H, Ar−H), 7.59 (s, 1H, Triazole−H), 7.89–7.95
(m, 2H, Ar−H); 13C NMR (126 MHz, CDCl3) δ 16.96
(CH3, Thiazole−CH3), 54.42 (CH2,Ar−CH2−N), 116.05
(CH, C-3′, -5′), 120.13 (CH, Triazole−C-5), 121.86 (C,
Thiazole−C-5), 128.08 (CH, C-3′′,-5′′), 128.30 (CH, C-2′,
-6′), 128.99 (CH, C-4′′), 129.27 (CH, C-2′′,-6′′), 130.91 (C,
C-1′′), 134.36 (C, C-1′), 140.77 (C, Triazole−C-4), 149.87
(C, Thiazole−C-4), 163.86 (C, C-4′), 164.39 (C, Thiazole
−C-2), Chemical formula: C19H15FN4S, Exact mass:
350.1001, HRMS: 351.1078 (M+H)+, 373.0895 (M+Na)+.
2-(4-bromophenyl)-5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-
yl)-4-methylthiazole(6h) 1H NMR (500 MHz, CDCl3) δ
2.58 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.10 (t, J = 8.6 Hz, 2H, Ar−H), 7.33 (dd, J = 8.7, 5.2 Hz,
2H, Ar−H), 7.40 (d, J = 8.6 Hz, 2H, Ar−), 7.59 (s, 1H,
Triazole−H), 7.86 (d, J = 8.6 Hz, 2H, Ar−H); 13C NMR
(126 MHz, CDCl3) δ 16.99 (CH3, Thiazole−CH3), 53.67
(CH2, Ar−CH2−N), 116.31 (CH, C-3′′,-5′′), 120.04 (CH,
Triazole−C-5), 122.08 (C, Thiazole−C-5), 127.56 (CH, C-
2′, -6′), 129.19 (CH, C-3′, -5′), 130.0 (CH, C-2′′,-6′′),
130.20 (C, C-1′′), 131.95 (C, C-4′), 135.97 (C, C-1′),
140.81 (C, Triazole−C-4), 150.07 (C, Thiazole−C-4),
162.98 (C, C-4′′), 164.24 (C, Thiazole−C-2), Chemical
formula: C19H14BrFN4S, Exact mass: 428.0107, HRMS:
429.0187 (M+H)+, 431.0168 (M+H)+, and 453.9986
(M+Na)+.
5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-(m-tolyl)thia-
zole(6e) 1H NMR (500 MHz, CDCl3) δ 2.40 (s, 3H, Ar
−CH3), 2.58 (s, 3H, Thiazole−CH3), 5.59 (s, 2H, Ar−CH2
−N), 7.22 (d, J = 7.5 Hz, 2H, Ar−H), 7.31 (d, J = 7.3 Hz,
3H, Ar−H), 7.36−7.40 (m, 3H, Ar−H), 7.59 (s, 1H,
Triazole−H), 7.70 (d, J = 7.0 Hz, 1H, Ar−H), 7.78 (s, 1H);
13C NMR (126 MHz, CDCl3) δ 17.02 (CH3, Thiazole
−CH3), 21.37 (CH3, Ar−CH3), 54.38 (CH2, Ar−CH2−N),
120.19 (CH, Triazole−C-5), 121.65 (C, Thiazole−C-5),
123.68 (CH, C-5′), 126.85 (CH, C-4′′), 128.07 (CH, C-2′
′,-6′′), 128.88 (CH, C-2′), 128.95 (CH, C-4′), 129.25 (CH,
C-3′′,-5′′), 130.88 (C, C-1′′), 133.36 (C, C-6′), 134.41

Medicinal Chemistry Research
2-(4-chlorophenyl)-5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-
yl)-4-methylthiazole(6i) 1H NMR (500 MHz, CDCl3) δ
2.59 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.09 (t, J = 8.6 Hz, 2H, Ar−H), 7.32 (dd, J = 8.7, 5.2 Hz,
2H, Ar−H), 7.43 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H, Triazole
−H), 7.93 (d, J = 8.0 Hz, 2H, Ar−H), 13C NMR (126 MHz,
CDCl3) δ 17.02 (CH3, Thiazole−CH3), 53.65 (CH2, Ar
−CH2−N), 116.30 (CH, C-3′′,-5′′), 120.02 (CH, Triazole
−C-5), 121.67 (C, Thiazole−C-5), 126.40 (CH, C-2′, -6′),
128.98 (CH, C-3′, -5′), 129.99 (CH, C-2′′,-6′′), 130.25 (C,
C-1′′), 132.15 (C, C-4′), 133.44 (C, C-1′), 140.99 (C,
Triazole−C-4), 149.96 (C, Thiazole−C-4), 162.98 (C, C-4′
′), 165.70 (C, Thiazole−C-2), Chemical formula:
C19H14ClFN4S, Exact mass: 384.0612, HRMS: 385.0683
(M+H)+, 387.0655 (M+2+H)+, and 407.0503 (M+Na)+.
7.57 (s, 1H, Triazole−H), 7.82 (d, J = 8.0 Hz, 2H, Ar−H);
13C NMR (126 MHz, CDCl3) δ 17.02 (CH3, Thiazole
−CH3), 21.45 (CH3, C4′−CH3), 53.64 (CH2, Ar−CH2−N),
116.29 (CH, C-3′′,-5′′), 119.94 (CH, Triazole−C-5),
121.10 (C, Thiazole−C-5), 126.32 (CH, C-2′,-6′), 129.66
(CH, C-3′,-5′), 129.98 (CH, C-2′′,-6′′), 130.26 (C, C-1′′),
130.81 (C, C-1′), 140.37 (C, C-4′), 141.09 (C, Triazole−C-
4), 149.81 (C, Thiazole−C-4), 162.97 (C, C-4′′), 165.93 (C,
Thiazole−C-2), Chemical formula: C20H17FN4S, Exact
mass: 364.1158, HRMS: 365.1238 (M+H)+, 387.1056 (M
+Na)+.
5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-phe-
nylthiazole(6m) 1H NMR (500 MHz, CDCl3) δ 2.60 (s,
3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N), 7.23–7.31
(m, 2H, Ar−H), 7.38 (d, J = 8.4 Hz, 2H, Ar−H), 7.41
−7.45 (m, 3H, Ar−H), 7.60 (s, 1H, Triazole−H), 7.94 (dd,
J = 7.6, 1.7 Hz, 2H, Ar−H); 13C NMR (126 MHz, CDCl3):
δ 17.04 (CH3, Thiazole−CH3), 53.65 (CH2, Ar−CH2−N),
120.06 (CH, Triazole−C-5), 121.61 (C, Thiazole−C-5),
126.41 (CH, C-2′′,-6′′), 128.98 (CH, C-3′′,-5′′), 129.39
(CH, C-3′,-5′), 129.49 (CH, C-2′,-6′), 130.08 (CH, C-4′),
132.87 (C, C-4′′), 133.45 (C, C-1′′), 135.06 (C, C-1′),
141.07 (C, Triazole−C-4), 150.01 (C, Thiazole−C-4),
5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(4-fluorophe-
nyl)-4-methylthiazole(6j) 1H NMR (500 MHz, CDCl3): δ
2.58 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.08−7.14 (m, 4 H, Ar−H), 7.33 (dd, J = 8.7, 5.2 Hz, 2H,
Ar−H), 7.59 (s, 1H, Triazole−H), 7.92 (dd, J = 8.9, 5.3 Hz,
2H, Ar−H), 13C NMR (126 MHz, CDCl3): δ 16.98 (CH3,
Thiazole−CH3), 53.67 (CH2, Ar−CH2−N), 116.06 (CH, C-
3′′,-5′′), 116.41 (CH, C-3′, -5′), 119.97 (CH, Triazole−C-
5), 121.72 (C, Thiazole−C-5), 128.31 (CH, C-2′′,-6′′),
129.83 (C, C-1′′), 129.99 (CH, C-2′, -6′), 130.21 (C, C-1′),
140.89 (C, Triazole−C-4), 149.94 (C, Thiazole−C-4),
162.98 (C, C-4′′), 163.88 (C, C-4′), 164.47 (C, Thiazole
−C-2), Chemical formula: C19H14F2N4S, Exact mass:
368.0907, HRMS: 369.0990 (M+H)+, 391.0809 (M+Na)+.
165.73
(C,
Thiazole−C-2).
Chemical
formula:
C19H15ClN4S, Exact mass: 366.0706, HRMS: 367.0786 (M
+H)+, 369.0758 (M+2+H)+, and 389.0603 (M+Na)+.
2-(4-bromophenyl)-5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-
yl)-4-methylthiazole(6n) 1H NMR (500 MHz, CDCl3) δ
2.59 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.25 (d, J = 8.4 Hz, 2H, Ar−H), 7.38 (d, J = 8.4 Hz, 2H, Ar
−H), 7.43 (d, J = 7.1 Hz, 2H, Ar−H), 7.60 (s, 1H, Triazole
−H), 7.93 (d, J = 7.1, 2H, Ar−H); 13C NMR (126 MHz,
CDCl3) δ 17.12 (CH3, Thiazole−CH3), 53.66 (CH2, Ar
−CH2−N), 120.08 (CH, Triazole−C-5), 121.76 (C, Thia-
zole−C-5), 127.12 (CH, C-2′′,-6′′), 127.39 (C, C-4′),
128.89 (CH, C-3′′,-5′′), 129.96 (CH, C-2′,-6′), 130.88 (CH,
C-3′,-5′), 132.84 (C, C-4′′), 133.39 (C, C-1′′), 135.06 (C,
C-1′), 141.01 (C, Triazole−C-4), 149.96 (C, Thiazole−C-
4), 165.78 (C, Thiazole−C-2). Chemical formula:
C19H14BrClN4S, Exact mass: 443.9811, HRMS: 444.9880
(M+H)+, 446.9855 (M+2+H)+, and 448.9848 (M+4+H)+
5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-(m-
tolyl)thiazole(6k) 1H NMR (500 MHz, CDCl3) δ 2.41 (s,
3H, C3′−CH3), 2.60 (s, 3H, Thiazole−CH3), 5.57 (s, 2H,
Ar−CH2−N), 7.10 (t, J = 8.6 Hz, 2H, Ar−H), 7.23 (d, J =
7.6 Hz, 1H, Ar−H), 7.35–7.30 (m, 3H, Ar−H), 7.58 (s, 1H,
Triazole−H), 7.71 (d, J = 7.7 Hz, 1H, Ar−H), 7.78 (s, 1H,
Ar−H); 13C NMR (126 MHz, CDCl3) δ 17.03 (CH3, Thia-
zole−CH3), 21.37 (CH3, C3′−CH3), 53.64 (CH2, Ar−CH2
−N), 116.30 (CH, C-3′′,-5′′), 120.00 (CH, Triazole−C-5),
121.49 (C, Thiazole−C-5), 123.69 (CH, C-6′), 126.86 (CH,
C-4′), 128.88 (CH, C-5′), 129.99 (CH, C-2′′,-6′′), 130.25
(C, C-1′′), 130.91 (CH, C-2′), 133.34 (C, C-1′), 138.79 (C,
C-3′), 141.04 (C, Triazole−C-4), 149.89 (C, Thiazole−C-
4), 162.98 (C, C-4′′), 165.97 (C, Thiazole−C-2), Chemical
formula: C20H17FN4S, Exact mass: 364.1158, HRMS:
365.1238 (M+H)+, 387.1056 (M+Na)+.
5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(4-chlorophe-
nyl)-4-methylthiazole(6o) 1H NMR (500 MHz, CDCl3) δ
2.58 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.26 (d, J = 8.0 Hz, 2H, Ar−H), 7.38 (d, J = 8.0 Hz, 2H, Ar
−H), 7.40 (d, J = 8.5 Hz, 2H, Ar−H), 7.60 (s, 1H, Triazole
−H), 7.86 (d, J = 8.5 Hz, 2H, Ar−H); 13C NMR (126 MHz,
CDCl3) δ 17.21 (CH3, Thiazole−CH3), 53.67 (CH2, Ar
−CH2−N), 120.10 (CH, Triazole−C-5), 122.03 (C, Thia-
zole−C-5), 127.56 (CH, C-2′′,-6′′), 129.20 (CH, C-3′′,-5′′),
5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-(p-
tolyl)thiazole(6l) 1H NMR (500 MHz, CDCl3) δ 2.39 (s,
3H, C3′−CH3), 2.58 (s, 3H, Thiazole−CH3), 5.57 (s, 2H,
Ar−CH2−N), 7.09 (t, J = 8.6 Hz, 2H, Ar−H), 7.24 (d, J =
8.0 Hz, 2H, Ar−H), 7.32 (dd, J = 8.6, 5.2 Hz, 2H, Ar−H),

Medicinal Chemistry Research
129.40 (CH, C-2′,-6′), 129.49 (CH, C-3′,-5′), 131.94 (C, C-
4′′), 132.82 (C, C-1′′), 135.08 (C, C-4′), 135.98 (C, C-1′),
140.87 (C, Triazole−C-4), 150.11 (C, Thiazole−C-4),
Triazole−C-4), 149.84 (C, Thiazole−C-4), 165.94 (C,
Thiazole−C-2); Chemical formula: C20H17ClN4S, Exact
mass: 380.0862, HRMS: 381.0935 (M+H)+, 383.00912 (M
+2+H)+.
164.27
(C,
Thiazole−C-2).
Chemical
formula:
C19H14Cl2N4S, Exact mass: 400.0316, HRMS: 401.0385 (M
+H)+, 403.0348 (M+2+H)+, and 405.0335 (M+4+H)+.
4-methyl-5-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)-2-phe-
nylthiazole(6s) 1H NMR (500 MHz, CDCl3) δ 2.36 (s, 3H,
C4′′−CH3), 2.58 (s, 3H, Thiazole−CH3), 5.54 (s, 2H, Ar
−CH2−N), 7.24–7.17 (m, 4H, Ar−H), 7.45–7.39 (m, 3H,
Ar−H), 7.57 (s, 1H, Triazole−H), 7.95–7.91 (m, 2H, Ar
−H); 13C NMR (126 MHz, CDCl3) δ 17.01 (CH3, Thiazole
−CH3), 21.21 (CH3, C4′′−CH3), 54.22 (CH2, Ar−CH2
−N), 120.07 (CH, Triazole−C-5), 121.88 (C, Thiazole−C-
5), 126.38 (CH, C-2′′,-6′′), 128.13 (CH, C-3′,-5′), 128.96
(CH, C-3′′,-5′′), 129.91 (CH, C-2′,-6′), 130.01 (CH, C-4′),
131.35 (C, C-1′′), 133.50 (C, C-1′), 138.93 (C, C-4′′),
140.78 (C, Triazole−C-4), 149.85 (C, Thiazole−C-4),
165.55 (C, Thiazole−C-2); Chemical formula: C20H18N4S,
Exact mass: 346.1252, HRMS: 347.1334 (M+H)+,
369.1153 (M+Na)+
5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(4-fluorophe-
nyl)-4-methylthiazole(6p) 1H NMR (500 MHz, CDCl3) δ
2.58 (s, 3H, Thiazole−CH3), 5.57 (s, 2H, Ar−CH2−N),
7.12 (t, J = 8.6 Hz, 2H, Ar−H), 7.26 (d, J = 8.4 Hz, 2H),
7.37 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H, Triazole H), 7.88–
7.95 (m, 2H, Ar−H);); 13C NMR (126 MHz, CDCl3) δ
17.10 (CH3, Thiazole−CH3), 53.59 (CH2, Ar−CH2−N),
116.32 (CH, C-3′, -5′), 120.16 (CH, Triazole−C-5), 121.94
(C, Thiazole−C-5), 127.56 (CH, C-2′′,-6′′), 129.20 (CH, C-
3′′,-5′′), 129.94 (CH, C-2′, -6′), 130.21 (C, C-1′), 131.94
(C, C-4′′), 132.82 (C, C-1′′), 140.42 (C, Triazole−C-4),
149.65 (C, Thiazole−C-4), 163.94 (C, C-4′), 164.44 (C,
Thiazole−C-2). Chemical formula: C19H14ClFN4S, Exact
mass: 384.0612, HRMS: 385.0683 (M+H)+, 407.0503 (M
+Na)+
2-(4-bromophenyl)-4-methyl-5-(1-(4-methylbenzyl)-1H-
1,2,3-triazol-4-yl)thiazole(6t) 1H NMR (500 MHz, CDCl3)
δ 2.36 (s, 3H, Ar−CH3), 2.57 (s, 3H, Thiazole−CH3), 5.55
(s, 2H, Ar−CH2−N), 7.24–7.18 (m, 4H, Ar−H), 7.43 (d, J
= 7.8, 2H, Ar−H), 7.56 (s, 1H, Triazole−H), 7.93 (d, J =
7.8, 2H, Ar−H); 13C NMR (126 MHz, CDCl3) δ 17.01
(CH3, Thiazole−CH3), 21.21 (CH3, C4′′−CH3), 54.22
(CH2, Ar−CH2−N), 120.07 (CH, Triazole−C-5), 121.88
(C, Thiazole−C-5), 126.36 (CH, C-2′′,-6′′), 128.94 (CH, C-
3′′,-5′′), 129.96 (CH, C-2′,-6′), 130.86 (CH, C-3′,-5′),
132.80 (CH, C-4′), 131.34 (C, C-1′′), 135.02 (C, C-1′),
138.92 (C, C-4′′), 140.80 (C, Triazole−C-4), 149.84 (C,
Thiazole−C-4), 165.49 (C, Thiazole−C-2); Chemical for-
mula: C20H17BrN4S, Exact mass: 424.0357, HRMS:
425.0419 (M+H)+, 425.0403 (M+2+H)+.
5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-(m-
tolyl)thiazole(6q) 1H NMR (500 MHz, CDCl3) δ 2.41 (s,
3H, C3′−CH3), 2.60 (s, 3H, Thiazole−CH3), 5.57 (s, 2H,
Ar−CH2−N), 7.21–7.28 (m, 3H, Ar−H), 7.32 (t, J = 7.6
Hz, 1H, Ar−H), 7.38 (d, J = 8.4 Hz, 2H, Ar−H), 7.59 (s,
1H, Triazole−H), 7.71 (d, J = 7.7 Hz, 1H, Ar−H), 7.78 (s,
1H, Ar−H); 13C NMR (126 MHz, CDCl3) δ 17.10 (CH3,
Thiazole−CH3), 21.38 (CH3, C3′−CH3), 53.59 (CH2, Ar
−CH2−N), 120.16 (CH, Triazole−C-5), 121.94 (C, Thia-
zole−C-5), 123.70 (CH, C-6′), 127.56 (CH, C-2′′,-6′′),
127.12 (CH, C-4′), 128.90 (CH, C-5′), 129.26 (CH, C-3′
′,-5′′), 130.91 (CH, C-2′), 131.90 (C, C-4′′), 132.85 (C, C-
1′′), 133.34 (C, C-1′), 138.79 (C, C-3′), 140.86 (C, Triazole
−C-4), 149.85 (C, Thiazole−C-4), 165.87 (C, Thiazole−C-
2); Chemical formula: C20H17ClN4S, Exact mass: 380.0862,
HRMS: 381.0935 (M+H)+, 383.00912 (M+2+H)+.
2-(4-chlorophenyl)-4-methyl-5-(1-(4-methylbenzyl)-1H-
1,2,3-triazol-4-yl)thiazole(6u) 1H NMR (500 MHz, CDCl3)
δ 2.36 (s, 3H, C4′′−CH3), 2.56 (s, 3H, Thiazole−CH3),
5.55 (s, 2H, Ar−CH2−N), 7.25–7.19 (m, 4H, Ar−H), 7.39
(d, J = 8.6 Hz, 2H, Ar−H), 7.57 (s, 1H, Triazole−H), 7.85
(d, J = 8.6 Hz, 2H, Ar−H); 13C NMR (126 MHz, CDCl3): δ
16.94 (CH3, Thiazole−CH3), 21.19 (CH3, C4′′−CH3),
54.22 (CH2, Ar−CH2−N), 120.07 (CH, Triazole−C-5),
122.27 (C, Thiazole−C-5), 127.52 (CH, C-2′′,-6′′), 128.12
(CH, C-2′,-6′), 129.15 (CH C-3′′,-5′′), 129.90 (CH, C-3′,-
5′), 131.27 (C, C-1′′), 131.98 (C, C-1′), 135.87 (C, C-4′),
138.95 (C, C-4′′), 140.58 (C, Triazole−C-4), 149.93 (C,
Thiazole−C-4), 164.07 (C, Thiazole−C-2); Chemical for-
mula: C20H17ClN4S, Exact mass: 380.0862, HRMS:
381.0936 (M+H)+, 383.00913 (M+2+H)+.
5-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methyl-2-(p-
tolyl)thiazole(6r) 1H NMR (500 MHz, CDCl3) δ 2.41 (s,
3H C4′−CH3), 2.60 (s, 3H Thiazole−CH3), 5.57 (s, 2H, Ar
−CH2−N), 7.24 (d, J = 7.6 Hz, 2H, Ar−H), 7.25 (d, J =
7.6 Hz, 2H, Ar−H), 7.37 (d, J = 7.6 Hz, 2H, Ar−H), 7.58
(s, 1H, Triazole−H), 7.83 (d, J = 7.6 Hz, 2H, Ar−H); 13C
NMR (126 MHz, CDCl3) δ 17.02 (CH3, Thiazole−CH3),
21.44 (CH3, C4′′−CH3), 53.61 (CH2, Ar−CH2−N), 119.98
(CH, Triazole−C-5), 121.04 (C, Thiazole−C-5), 126.31
(CH, C-2′′,-6′′), 129.37 (CH, C-3′,-5′), 129.46 (CH, C-3′
′,-5′′), 129.64 (CH, C-2′,-6′), 130.79 (C, C-1′′), 132.88 (C,
C-4′′), 135.02 (C, C-1′), 140.36 (C, C-4′), 141.13 (C,

Medicinal Chemistry Research
4-methyl-5-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)-2-(m-
tolyl)thiazole(6v) 1H NMR (500 MHz, CDCl3) δ 2.35 (s,
3H, C4′′−CH3), 2.40 (s, 3H, C3′−CH3), 2.56 (s, 3H,
Thiazole−CH3), 5.56 (s, 2H, Ar−CH2−N), 7.20–7.27 (m,
3H, Ar−H), 7.32 (t, J = 7.6 Hz, 1H, Ar−H), 7.38 (d, J =
8.4 Hz, 2H, Ar−H), 7.60 (s, 1H, Triazole−H), 7.71 (d, J =
7.7 Hz, 1 H, Ar−H), 7.78 (s, 1H, Ar−H); 13C NMR (126
MHz, CDCl3) δ 16.96 (CH3, Thiazole−CH3), 21.20 (CH3,
C4′′−CH3), 21.35 (CH3, C3′−CH3), 54.20 (CH2, Ar−CH2
−N), 120.10 (CH, Triazole−C-5), 121.94 (C, Thiazole−C-
5), 123.68 (CH, C-6′), 127.10 (CH, C-4′), 127.23 (CH, C-2′
′,-6′′), 128.88 (CH, C-5′), 129.02 (CH, C-3′′,-5′′), 130.90
(CH, C-2′), 132.90 (C, C-1′′), 135.02 (C, C-4′′), 133.32 (C,
C-1′), 138.78 (C, C-3′), 140.85 (C, Triazole−C-4), 149.86
(C, Thiazole−C-4), 165.88 (C, Thiazole−C-2); Chemical
formula: C21H20N4S, Exact mass: 360.1409, HRMS:
319.1021 (M+H)+, 341.0840 (M+Na)+.
of cells. Absorbance obtained from the cells treated with 1%
DMSO alone was considered as 100% cell growth. The %
inhibition in the presence of the test material is calculated by
using the formula, % inhibition = (average of control −
average of compound)/(average of control − average of
blank) × 100), where control is the culture medium with cells
and DMSO and blank is the culture medium without cells.
For all samples, each compound concentration was tested in
triplicate in a single experiment and the quantitative value
was expressed as the mean standard deviation (SD).
Cytotoxic activity
Cell lines were obtained from NCCS, Pune, India, and
maintained under standard cell culture conditions at 37 °C
and 5% CO2 in a humidified environment. The cytotoxic
effect of the synthesized compounds was checked on cervix
adenocarcinoma HeLa and human acute monocytic leuke-
mia cell line THP-1 cancer cell lines using the concentra-
tions ranging from 0.781 to 100 μg/mL to determine the
growth inhibition (Alley et al. 1988). The log-phase cells
were harvested using trypsin (0.05% trypsin and 0.02%
ethylene diamine tetra-acetic acid in PBS) from tissue cul-
ture flasks and the suspension was diluted with appropriate
culture medium to obtain a cell density of 105 cells/mL as
determined by hemocytometry. An aliquot of 100 µL of
each suspension was seeded in 96-well cell culture plates
and was incubated at 37 °C in an atmosphere of 5% CO2
and 95% relative humidity in a CO2 incubator. After 24 h,
synthesized compounds (1 µL/well) were added to the wells
containing cells. The plates were further incubated for 48 h,
then the solution containing the unattached cells was dis-
carded, and the wells were washed three times with 1 mL of
PBS followed by addition of 10 µL of MTT (5 mg/mL in
PBS) to adherent cells in growth medium. After 4 h at 37 °C
for MTT cleavage, the formazan product was solubilized by
addition of 100 µL of 0.04 N HCl in isopropanol. Absor-
bance was measured on a SpectraMax® PLUS 384 plate
reader (Molecular Devices, Sunnyvale, CA) at a wavelength
of 570 nm. Percentage cytotoxicity was calculated using the
formula: % cytotoxicity = (average of control − average of
compound) / (average of control − average of blank) × 100).
Each concentration was tested in triplicate in a single
experiment and the quantitative value was expressed as the
mean SD.
4-methyl-5-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)-2-(p-
tolyl)thiazol(6w) 1H NMR (500 MHz, CDCl3) δ 2.36 (s,
3H, C4′′−CH3), 2.38 (s, 3H, C4′−CH3), 2.57 (s, 3H,
Thiazole−CH3), 5.54 (s, 2H, Ar−CH2−N), 7.19−7.23 (m,
6H, Ar−H), 7.55 (s, 1H, Triazole H), 7.82 (d, J = 8.1 Hz,
2H, Ar−H); 13C NMR (126 MHz, CDCl3) δ 16.96 (CH3,
Thiazole−CH3), 21.20 (CH3, C4′′−CH3), 21.22 (CH3, C3′
−CH3), 54.20 (CH2, Ar−CH2−N), 120.08 (CH, Triazole
−C-5), 121.94 (C, Thiazole−C-5), 127.23 (CH, C-2′′,-6′′),
127.58 (CH, C-2′, C-6′), 129.02 (CH, C-3′′,-5′′), 129.58
(CH, C-3′, C-5′), 132.38 (C, C-1′), 132.90 (C, C-1′′),
134.03 (C, C-4′), 135.02 (C, C-4′′), 140.84 (C, Triazole−C-
4), 149.90 (C, Thiazole−C-4), 165.85 (C, Thiazole−C-2);
Chemical formula: C21H20N4S, Exact mass: 360.1409,
HRMS: 319.1021 (M+H)+, 341.0840 (M+Na)+.
Biological activity
Antitubercular activity
In vitro antimycobacterial activity against M. tuberculosis
H37Ra (dormant) was performed using the XTT reduction
menadione assay (XRMA) (Khan and Sarkar 2008, Singh
et al. 2015, Sarkar and Sarkar 2012). A compound solution
(2.5 μL) was added in a total volume of 250 μL of Myco-
bacterium pheli medium consisting of the M. tuberculosis
H37Ra, sealed with plate sealers and allowed to incubate for
12 days at 37 °C. The XRMA was then carried out to esti-
mate viable cells present in different wells of the assay plate.
To all wells, 200 μM XTT was added and incubated at 37 °C
for another 20 min, followed by the addition of 60 μMme-
nadione, and incubated at 37 °C for a further 40 min. The
optical density was measured using a microplate reader
(SpectraMaxPlus 384 plate reader, Molecular Devices Inc.)
at a 470-nm filter against a blank prepared from a well free
Docking analysis
Virtual docking analysis was performed on the biopredicta
module of V life MDS 4.3. Docking simulations are utilized
to predict the drug target interactions using the molecular
structure of proteins or enzymes. Docking simulations were
performed on Enoyl acyl carrier protein reductase.

Medicinal Chemistry Research
Docking analysis was accrued out using the crystal structure
of Enoyl acyl carrier protein reductase (PDB ID: 4tzk)
downloaded from free protein database www.rcsb.org. Prior
to docking simulations, the crystal structure of Enoyl acyl
carrier protein reductase was cleaned for reducing experi-
mental errors. All the ligand structures were first drawn in a
molecular builder in V life MDS 4.3 and converted into 3D
geometry via a 3D converter; these 3D structures of ligands
were optimized via MMFF. These optimized ligands were
utilized for grip-based docking analysis (Patil et al. 2016,
Patravale et al. 2016, Bansode et al. 2016).
5a−d furnished target compounds 4-(1-substituted benzyl-
1H-1,2,3-triazol-4-yl)-2-arylthiazole, 6a−w (Table 1).
The structure of the title compounds, 6a−w was con-
firmed by NMR and HRMS. As a representative analysis of
compound
4-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(4-fluor-
ophenyl)thiazole, (6d), the 1H NMR spectrum that dis-
played two singlets in the aliphatic region at δ 2.57 and 5.59
corresponds to thiazole−CH3 and thiazole−CH2–triazole,
respectively. A triplet at δ 7.12 and a multiplate at δ 7.89–
7.95 were attributed to protons of a fluoro-substituted
phenyl ring, while a multiplate at δ 7.30−7.36 and a triplet
at δ 7.40 corresponds to protons of the phenyl ring. Triazole
proton was resonated as a singlet at δ 7.59. The 13C NMR
spectrum of compound 6d showed two signals of thiazole
−CH3 at δ 16.96 and phenyl−CH2−N carbon at δ 54.33.
Aromatic carbons of fluoro-substituted phenyl reported
typical fluoro-coupling (C1-F δ 164.86, 162.86 (1J = 252
Hz), C2-F δ 116.14, 115.96 (2J = 21.42 Hz), and C3-F δ
128.33, 128.26 (3J = 8.82 Hz)). The structure of compound
6d was further confirmed by HRMS, m/z 337.0930 (M+H)+,
359.0748 (M+Na)+. The structure of all the derivatives was
ascertained similarly.
Results and discussion
Chemistry
A series of 4-(1-substituted benzyl-1H-1,2,3-triazol-4-yl)-2-
arylthiazole derivatives, 6a−w were synthesized according
to Scheme 1. Ethyl 4-methyl-2-arylthiazole-5-carboxylate
1a−f on reduction with lithium aluminum hydride in die-
thyl ether gave (4-methyl-2-arylthiazol-5-yl)methanol, 2a
−f. Alcohol 2a−f on selective oxidation with iodox-
ybenzoic acid (IBX) furnished 4-methyl-2-arylthiazole-5-
carbaldehyde, 3a−f. Aldehyde 3a−f on reaction with die-
thyl (1-diazo-2-oxopropyl)phosphonate and K2CO3 in
methanol gave 5-ethynyl-4-methyl-2-phenylthiazole, 4a−f.
Alkyne 4a−f on click reaction with substituted benzylazide,
Antitubercular activity evaluation: primary
screening
The antitubercular activity for each synthesized compound
was determined by measuring the inhibition of growth
CH3
CH3
CH3
OH
OEt
N
N
IBX,
LiAlH4
H
O
N
S
S
R1
S
DMSO, rt
O
R1
Et2O,
R1
0 oC - rt
2a-f
3a-f
1a-f
N3
O
O
P
OEt
CH3
R2
CH3
N
N
5a-d
Me
OEt
N
N
N
R2
Na-ascorbate, CuSO4
DMF:H2O (3:1) rt
N2
S
R1
S
R1
K2CO3, MeOH, rt
6a-w
Comp. R1
4a-f
Comp. R1
Comp. R1
R2
H
H
H
H
H
H
R2
F
F
F
F
F
F
Comp. R1
R2
Cl
Cl
Cl
Cl
R2
6a
6b
6c
6d
6e
6f
6g
6h
6i
6m
6n
6o
6p
6q
6r
6s
6t
H
H
H
H
CH3
CH3
CH3
CH3
CH3
4-Br
4-Cl
4-F
3-CH3
4-CH3
4-Br
4-Cl
4-F
4-Br
4-Cl
4-F
3-CH3 Cl
4-CH3 Cl
4-Br
4-Cl
3-CH3
4-CH3
6u
6v
6w
6j
6k
6l
3-CH3
4-CH3
Scheme 1 Synthetic route of 4-(1-substituted benzyl-1H-1,2,3-triazol-4-yl)-2-arylthiazole derivatives, 6a−w

Medicinal Chemistry Research
Table 1 Structure and physical properties of compounds 6a−w
Comp. Structure
m.p. Yield Comp. Structure
°C
m.p Yield
%
. °C
%
CH3
168- 84
170
158 88
6a
6m
CH3
N
N
-
N
N
N
N
N
N
Cl
Cl
160
S
S
CH3
CH3
149- 80
150
128 85
6b
6n
N
N
N
N
-
N
N
N
N
129
S
S
S
Br
Cl
Br
Cl
CH3
CH3
176- 75
178
140 84
6c
6d
6e
6o
6p
6q
N
S
N
N
N
N
N
-
N
N
N
N
Cl
Cl
Cl
141
CH3
CH3
168- 80
170
142 84
N
N
-
N
N
N
N
143
S
N
S
F
F
CH3
CH3
136- 88
137
136 90
N
N
N
-
N
N
N
N
H3C
H3C
S
138
S
S
CH3
CH3
139- 86
140
156 88
6f
6r
N
N
N
-
N
N
N
N
N
S
157
Cl
H3C
H3C
CH3
CH3
136- 72
138
170 85
6g
6h
6s
6t
N
N
N
N
-
N
N
N
N
F
CH3
CH3
172
S
S
CH3
CH3
160- 78
161
134 80
N
N
N
N
N
N
N
-
N
N
N
F
F
F
F
S
N
S
S
135
Br
Br
Cl
F
CH3
CH3
166- 72
168
136 84
6i
6v
6v
6w
N
N
N
-
N
N
N
N
CH3
CH3
138
S
Cl
CH3
CH3
138- 76
139
160 78
6j
6k
6l
N
N
N
-
N
N
N
N
H3C
S
162
S
CH3
CH3
130- 78
131
150 84
N
N
-
N
N
N
N
N
H3C
S
152
S
CH3
H3C
CH3
168- 82
170
N
N
N
N
S
F
H3C

Medicinal Chemistry Research
Table 2 Antitubercular activity in % inhibition at 30, 10, 3, and 1 µg/
mL concentration of compounds 6a−p against M. tuberculosis H37Ra
Table 3 Antitubercular activity (IC50 and MIC90) in µg/mL of
compounds 6a−w against M. tuberculosis H37Ra and cytotoxicity
activity (IC50) of compounds 6g and 6k in µg/mL
Comp. % inhibition
Comp.
R1
R2
IC50 (µM) MIC90
(µM)
Hela
IC50
THP-1
IC50
30 µg/mL
10 µg/mL
3 µg/mL
1 µg/mL
6a
6b
6c
6d
6e
6f
81.56 8.23 86.71 0.08 70.91 2.08 49.85 2.79
88.89 3.60 88.35 0.16 76.00 5.10 58.60 2.37
44.10 5.62 39.91 5.84 38.55 1.09 35.41 6.66
44.75 5.13 44.74 0.90 45.40 4.22 42.90 8.82
85.41 0.85 87.24 2.58 85.67 5.12 72.88 6.93
81.44 0.94 81.78 0.15 67.63 4.76 59.17 13.72
90.38 4.09 90.46 3.33 91.08 0.68 80.74 3.47
43.01 6.07 62.75 1.84 71.00 2.52 72.43 6.77
83.30 2.84 79.54 0.42 73.43 8.65 75.70 5.22
69.87 3.67 64.31 3.09 71.51 11.00 71.58 5.22
92.40 0.04 91.90 0.94 91.47 0.44 91.22 1.35
81.33 0.02 84.04 5.72 85.36 3.18 84.27 5.05
84.11 5.04 86.36 0.95 86.06 5.36 83.65 5.80
63.32 8.81 81.07 0.65 85.67 1.58 79.52 6.56
65.64 6.09 67.65 9.79 59.81 0.67 49.57 6.17
19.43 3.06 23.40 10.79 37.63 12.71 0.09 8.15
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
F
1.28 (3.85) >30
1.09 (2.65) >30
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>80
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>80
4-Br
4-Cl
4-F
>30
>30
>30
>30
3-CH3
4-CH3
0.84 (2.42) >30
1.06 (3.05) >30
0.69 (1.96) 4.71
6g
6h
6i
6g
(13.44)
6h
6i
4-Br
4-Cl
4-F
F
F
F
F
0.83 (1.93) >30
0.77 (2.00) >30
0.75 (2.03) >30
0.58 (1.59) 2.22
n.d.
n.d.
n.d.
>80
n.d.
n.d.
n.d.
>80
6j
6k
6l
6j
6k
3-CH3
(6.09)
6m
6n
6o
6p
6q
6r
6s
6l
4-CH3
F
0.68 (1.86) >30
n.d.
n.d.
n.d.
6m
Cl
0.71 (1.93) n.d.
>30
6n
6o
6p
6q
6r
6s
4-Br
4-Cl
4-F
Cl
Cl
Cl
0.74 (1.66) >30
1.65 (4.11) >30
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
17.99 2.27 27.90 10.31 27.62 2.46
9.85 6.93
64.33 4.41 71.02 2.88 70.32 3.83 61.30 11.49
56.22 9.17 49.59 9.68 29.08 10.86 24.53 7.79
62.07 11.18 57.32 12.48 43.81 4.54 47.04 2.30
>30
>30
>30
>30
3-CH3 Cl
4-CH3 Cl
6t
1.07 (2.80) >30
CH3 >30 >30
6u
6v
6w
37.38 10.49 31.53 4.70 23.72 4.00
7.93 5.68
H
53.23 2.96 57.64 7.09 38.49 7.06 29.18 12.00
57.32 2.24 68.25 4.98 57.74 3.58 48.77 1.07
6t
4-Br
4-Cl
CH3 6.3 (14.81) >30
6u
6v
CH3 >30
>30
>30
3-CH3 CH3 8.23
(22.83)
4-CH3 CH3 1.74 (4.82) >30
against the avirulent strain of M. tuberculosis H37Ra
(MTB, ATCC 25177) in liquid medium. In vitro activity
studies against MTB were performed using the XRMA
(Khan and Sarkar 2008, Singh et al. 2015, Sarkar and
Sarkar 2012). In a preliminary screening, the anti-
mycobacterial activity of these compounds was assessed at
30, 10, and 3 μg/mL concentration; the results of % inhi-
bition are shown in Table 2. All the compounds were fur-
ther screened for minimum inhibition concentration
(MIC90). The results of antitubercular activity are reported
in Table 3. The first-line antitubercular drug rifampicin was
used as the reference standard.
6w
n.d.
>80
n.d.
Rifampicin
0.002
0.75
>80
(0.0024)
(0.91)
n.d. not determined
The active compounds are presented in the bold values
R1
A
S
N
B
N
R2
N
N
Fig. 2 Compounds 6a−w
The result of the antitubercular activity against M.
tuberculosis H37Ra revealed that most of the compounds
exhibited good activity. The preliminary structure−activity
relationship study revealed that substitution of the hydrogen
atom of phenyl rings A and B (Fig. 2) by substituent groups
like Br, Cl, F, and CH3 affects the antitubercular activity.
The analysis of antitubercular activity revealed that, among
the compounds 6a−f with an unsubstituted phenyl ring A and
a substituted phenyl ring B, compounds 6a (R1 = H), 6b (R1
= Br), 6e (R1 = H), and 6f (R1 = H) showed good activity
against M. tuberculosis H37Ra with IC50 values of 0.84
−1.28 µg/mL. Compounds 6c (R1 = Cl) and 6d (R1 = F)
were found less active. Among the compounds 6g−l with a
substituted phenyl ring A and 4-fluro-substituted phenyl ring
B, all these compounds showed excellent activity with IC50
values of 0.58−0.83 µg/mL. Among the compounds 6g−l,

Medicinal Chemistry Research
compounds 6g (R1 = H) and 6k (R1 = 3-CH3) were found
most active with MIC90 values of 4.71 and 2.22 µg/mL. It is
worth mentioning that, as compared to the standard drug
Rifampicin, compounds 6g and 6k were found sixfold and
threefold less potent, respectively.
binding interaction with TYR158, PHE149, and PHE97
and hydrophobic interactions with GLY96, PHE97, and
MET199 and van der Waals interactions with amino acid
residues like GLY96, PHE97, MET98, MET103,
PHE149, MET155, PRO156, and TYR158 (Fig. S2). 5-(1-
benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-(m-tolyl)thia-
zole (6e) is another active derivative that showed binding
interaction via the formation of hydrophobic bonds with
amino acid residues like ALA206, ALA201, ALA198,
MET161, PHE97, and GLY96. Compound 6e also
showed van der Waals interactions with amino acid resi-
dues like GLY96, PHE97, MET103, TYR158, MET161,
ALA198, ALA201, ILE202, ALA206, and LEU207
(Fig. S3). Derivative 6f showed hydrophobic interactions
with LEU207, ALA206, GLY205, ILE202, ALA201,
ALA198, and PHE97 and van der Waals interactions with
amino acid residues like GLY96, PHE97, MET161,
ALA198, ALA201, ILE202, and GLY204 (Fig. S4).
Compound 6g showed aromatic binding interaction with
TYR158 and PHE149 and hydrophobic interaction with
PHE149, MET161, LYS165, PRO193, MET199, and
LEU218 and van der Waals interactions with GLY96,
PHE97, MET98, MET103, PHE149, MET155, PRO156,
TYR158, MET161, MET199, GLN214, and LEU218
(Fig. 3). Compound 6h interacted with Enoyl acyl carrier
protein reductase via the formation of hydrogen bond
interaction with ALA198, TYR158, and MET98 and
aromatic interaction with TYR158 and van der Waals
interactions with GLY96, PHE97, MET98, MET103,
PHE149, MET155, PRO156, TYR158, MET161, and
MET199 (Fig. S5). Compound 6i showed interactions
with MET199 via the formation of a hydrogen bond and
TYR158 via the formation of an aromatic bond; it also
showed hydrophobic interaction with PHE97, ALA198,
and MET199 and van der Waals interactions with GLY96,
PHE97, MET98, MET103, and PHE149 (Fig. S6). Com-
pound 6j is another active molecule found to show
hydrogen bond interactions with TYR158 and hydro-
phobic interactions with ALA201 and ALA206 and van
der Waals interactions with GLY96, PHE97, MET103,
TYR158, MET161, and ALA201 (Fig. S7). Compound 6k
showed hydrogen bond interaction with MET103 and
aromatic interactions with PHE149 and TYR158 and
hydrophobic interaction with LEU218, ILE215, ILE202,
MET199, PRO193, and TYR158 and van der Waals
interactions with GLY96, PHE97, MET103, TYR158,
and MET161 (Fig. 4). Compound 6l showed hydrogen
bond interactions with TYR158, hydrophobic interaction
with PHE97, LEU197, ALA198, ALA201, and GLY205,
and van der Waals interactions with GLY96, PHE97,
MET98, MET103, PHE149, MET155, and PRO156 (Fig.
S8). Compound 6n is also an active derivative that
showed hydrogen bond interaction with TYR158 and
Among the compounds 6m−k with a substituted phenyl
ring A and 4-chloro-substituted phenyl ring B, compounds
6m (R1 = H), 6n (R1 = 4-Br), 6o (R1 = 4-Cl), and 6r (R1 = 4-
CH3) reported good activity with IC50 values of 0.71−1.65
µg/mL, whereas compounds 6p (R1 = 3-CH3) and 6q (R1 =
3-CH3) were found less active. Among the compounds 6a−w
with a substituted phenyl ring A and 4-methyl-substituted
phenyl ring B, compound 6w (R1 = 3-CH3) exhibited good
activity with an IC50 value of 1.74 µg/mL, compounds 6t (R1
= 3-CH3) and 6v (R1 = 3-CH3) reported moderate activity
with IC50 values of 6.3 and 8.23 µg/mL, respectively. Com-
pounds 6s (R1 = H) and 6u (R1 = 4-Cl) were found less
active. It was notable that 4-fluoro-substituted benzyl (ring B)
on 1,2,3-triazole and a substituted phenyl (ring A) at 2-
position of thiazole, all the compounds reported good-to-
excellent activity. Also, 4-bromo- or 4-methyl-substituted
phenyl (ring A) at 2-position of thiazole and an unsubstituted,
4-fluoro-, 4-chloro-, or 4-methyl-substituted benzyl ring (ring
B) at 1,2,3-triazole showed good antitubercular activity
against M. tuberculosis H37Ra.
Cytotoxicity activity
Active thiazolyl-triazole 6g and 6k were further evaluated
against two human cancer cell lines (HeLa and THP-1) to
check the toxicity of these compounds (Table 4). The IC50
values of compounds 6g and 6k against both cell lines are
>80 μg/mL, indicating that these compounds are potent and
specific inhibitors against MTB. Compounds 6g and 6k
were relatively nontoxic against HeLa and THP-1 cell lines.
Docking analysis
Docking analysis was performed to evaluate the possible
mode of action of synthesized derivatives for anti-
mycobacterial potential. Enoyl acyl carrier protein
reductase is a key enzyme involved in the metabolic and
many conservative processes in mycobacterium. Docking
analysis was performed using the crystal structure of
Enoyl acyl carrier protein reductase (PDB ID: 4TZK)
downloaded from the free protein database www.rcsb.org.
Derivative 6a showed aromatic interaction with amino
acids like PHE149 and TYR158 and hydrophobic inter-
actions with PHE97, MET98, MET103, and MET161 and
van der Waals interactions with amino acid residues like
PHE97, MET98, GLN100, MET103, PHE149, and
TYR158 (Fig. S1). 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-
(4-bromophenyl)-4-methylthiazole (6b) showed aromatic

Medicinal Chemistry Research
Table 4 ADME prediction of compounds 6a−w
Comp. MW
#Rotatable
bonds
#H-bond
acceptors
#H-bond
donors
MR
TPSA M LogP GI absorption BBB
permeate
Bioavailability
score
6a
6b
6c
6d
6e
6f
332.42
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
3
3
4
3
3
4
4
4
5
4
4
4
3
3
4
3
3
3
3
3
4
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
97.28 71.84 3.02
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
411.32
366.87
350.41
346.45
346.45
350.41
429.31
384.86
368.4
104.98 71.84 3.63
102.29 71.84 3.52
97.24 71.84 3.4
102.25 71.84 3.25
102.25 71.84 3.25
97.24 71.84 3.4
6g
6h
6i
104.94 71.84 4.01
102.25 71.84 3.9
97.2 71.84 3.78
102.2 71.84 3.63
102.2 71.84 3.63
102.2 71.84 3.63
109.99 71.84 4.12
107.3 71.84 4.01
102.25 71.84 3.9
107.26 71.84 3.74
107.26 71.84 3.74
102.25 71.84 3.25
109.95 71.84 3.85
107.26 71.84 3.74
102.2 71.84 3.63
107.21 71.84 3.47
6j
6k
6l
364.44
364.44
364.44
445.76
401.31
384.86
380.89
380.89
346.45
425.34
380.89
364.44
360.48
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
MW molecular weight; MR molar refraction; TPSA total polar surface area; M LogP logarithm of participation coefficient; GI absorption
gastrointestinal tract absorption; BBB blood–brain barrier
Fig. 3 Docking image of compound 6g (5-(1-(4-fluorobenzyl)-1H-
1,2,3-triazol-4-yl)-4-methyl-2-phenylthiazole)
Fig. 4 Docking interactions of 5-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-
4-yl)-4-methyl-2-(m-tolyl)thiazole (6k) (most active)
aromatic interaction with TYR158 and PHE149, and
hydrophobic interactions with GLY96, PHE97, MET161,
and MET199 and van der Waals interactions with GLY96,
PHE97, MET98, MET103, PHE149, MET155, and
PRO156 (Fig. S9).
ADME prediction
ADME of all the synthesized molecules was predicted using
the online free portal www.swissadme.ch to check the

Medicinal Chemistry Research
possible violation of any drug-like properties (SwissADME
2017, iLOGP 2014). The synthesized derivatives are found
to have good drug-like properties for oral use. All the
molecules showed good GI absorption and nonpermeation
in the BBB, which is an ideal property; they also showed a
good bioavailability score of 0.55 (Table 4).
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DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988)
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In the present study, we have detailed the synthesis and
biological screening of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-
4-methyl-2-phenylthiazole derivatives, 6a−w. It can be
concluded that most of the synthesized compounds showed
good-to-excellent antitubercular activity against M. tuber-
culosis H37Ra. It is worth mentioning that 4-fluoro-
substituted benzyl on 1-position of 1,2,3-triazole and a
substituted phenyl at 2-position of thiazole reported good-
to-excellent activity. Also, 4-bromo- or 4-methyl-
substituted phenyl (ring A) at 2-position of thiazole and
an unsubstituted or a substituted benzyl ring at 1,2,3-tria-
zole showed good antitubercular activity. Among the syn-
thesized compounds, compounds 5-(1-(4-fluorobenzyl)-1H-
1,2,3-triazol-4-yl)-4-methyl-2-phenylthiazole (6g) and 5-(1-
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Acknowledgements The authors would like to thank CSIR-NCL,
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Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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