Synthesis, antimicrobial screening, and docking study of new 2-(2-ethylpyridin-4-yl)-4-methyl-N-phenylthiazole-5-carboxamide derivatives

Article abstract of DOI:10.1002/jccs.202000174

A series of new 2-(2-ethylpyridin-4-yl)-4-methyl-N-phenylthiazole-5-carboxamide derivatives (5a-l) were synthesized and evaluated for their in vitro antimicrobial activities. Among the screened compounds, 5b, 5d, 5e, 5f, and 5j have shown promising antimicrobial activities against both bacterial and fungal pathogens. A molecular docking study was conducted to know the probable mode of action of synthesized derivatives for antimicrobial activity. The active compounds have shown excellent binding affinity toward DNA gyrase and lumazine synthase enzymes. The physicochemical properties of the synthesized thiazole-carboxamide derivatives were calculated. It has displayed the potential to be a reasonable oral bioavailability drug as determined by Lipinski's rule.

Full text of DOI:10.1002/jccs.202000174

Received: 23 April 2020
Revised: 24 July 2020
Accepted: 25 August 2020
DOI: 10.1002/jccs.202000174
A R T I C L E
Synthesis, antimicrobial screening, and docking study of
new 2-(2-ethylpyridin-4-yl)-4-methyl-N-phenylthiazole-
5-carboxamide derivatives
Sanghratna L. Kasare1 | Pornima N. Gund1 | Bhaurao P. Sathe1
Pravin S. Patil1 | Naziya N. M. A. Rehman2 | Prashant P. Dixit2
Prafulla B. Choudhari3 | Kishan P. Haval1
|
|
1Department of Chemistry, Dr. Babasaheb
Abstract
Ambedkar Marathwada University
SubCampus, Osmanabad, Maharashtra,
India
2Department of Microbiology, Dr.
Babasaheb Ambedkar Marathwada
University SubCampus, Osmanabad,
Maharashtra, India
A series of new 2-(2-ethylpyridin-4-yl)-4-methyl-N-phenylthiazole-5-carbox-
amide derivatives (5a-l) were synthesized and evaluated for their in vitro anti-
microbial activities. Among the screened compounds, 5b, 5d, 5e, 5f, and 5j
have shown promising antimicrobial activities against both bacterial and fun-
gal pathogens. A molecular docking study was conducted to know the proba-
ble mode of action of synthesized derivatives for antimicrobial activity. The
active compounds have shown excellent binding affinity toward DNA gyrase
and lumazine synthase enzymes. The physicochemical properties of the synthe-
sized thiazole-carboxamide derivatives were calculated. It has displayed the
potential to be a reasonable oral bioavailability drug as determined by
Lipinski's rule.
3Department of Pharmaceutical
Chemistry, Bharati Vidyapeeth College of
Pharmacy, Kolhapur, Maharashtra, India
Correspondence
Kishan P. Haval, Department of
Chemistry, Dr. Babasaheb Ambedkar
Marathwada University SubCampus,
Osmanabad 413501, Maharashtra, India.
Email: havalkp@gmail.com
K E Y W O R D S
ADME prediction, antimicrobial activity, carboxamide, docking study, thiazole
Funding information
Dr. Babasaheb Ambedkar Marathwada
University Aurangabad, Grant/Award
Number: STAT/V1/RG/Dept/2019-20/323-
324
1 | INTRODUCTION
antibiotic, not finishing the complete course, overuse of
antibiotics,[4] and insanitary environment[5] have
Antimicrobial resistance has become the most challeng-
ing issue for worldwide researchers.[1] According to the
World Health Organization, every day, thousands of peo-
ples are dying due to microbial infections.[2] Hence, it has
become a serious problem for human health. There are
many reasons for antimicrobial resistance. Of the rea-
sons, mutation in genetic material, transfer of drug-resis-
tant genes from one microbe to another, replication and
spreading of survivor-resistant strains,[3] improper use of
antibiotics in viral infection, improper diagnosis referring
enhanced the increase in resistance.[6] The use of broad-
spectrum antibiotics can leads to undesirable distur-
bances to the microbiota, which has important roles in
various features of human biology.[7] The innovation of
antimicrobial agents with a unique model of action is
essential for the clinical management of bacterial
infections.[8]
Thiazoles are sulfur- and nitrogen-containing five-
membered heterocyclic compounds. Their derivatives
have played an important role in medicinal and pharma-
ceutical chemistry. They have potential biological
broad-spectrum antibiotic over
a
narrow-spectrum
J Chin Chem Soc. 2020;1–9.
http://www.jccs.wiley-vch.de
© 2020 The Chemical Society Located in Taipei & Wiley-VCH GmbH
1

2
KASARE ET AL.
(a)
(b)
(d)
(c)
SCHEME 1 Reaction Conditions: (a) EtOH, reflux, 5 hr (90%);
(b) LiOHꢀH2O, THF + MeOH, rt, 3 hr (95%); (c) Amines, EDCꢀHCl,
HOBt, DMF, 0-rt, 10–12 hr (82–90%)
FIGURE 1 Representative drugs containing thiazole and
carboxamide moiety
TABLE 1 Physical data of thiazole–carboxamide derivatives
(5a-l)
activities such as anticancer,[9] antitubercular,[10] α-gluco-
sidase inhibitor,[11] antioxidant,[12] antibacterial,[13] anti-
inflammatory,[14] anti-Candida activity[15] and photo pro-
tection[16] and antifungal[17] and antiviral activities.[18]
Thiamine is one of the most essential natural thiazole.
Many commercial drugs containing thiazole moiety have
several clinical uses, such as the nonsteroidal anti-inflam-
matory drugs fentiazac and meloxicam, the anticancer
drug tiazofurin, the anti-HIV drug ritonavir, and the
immune-regulating drug fanetizole.[19] Pyridine derivatives
are found to have many biological activities, such as anti-
oxidant, antimicrobial,[20] β-glucuronidase[21] and cytotox-
icity activities against several human cancer cell lines.[22]
Pyridine–thiazole clubbed conjugates are common struc-
tural designs with extensive applications in drug discov-
ery.[23] Representative drugs containing thiazole and
carboxamide moiety are shown in Figure 1.
Entry
5a
5b
5c
R
M.P. (ꢁC)
90–92
Yield (%)
2-Cl
86
90
85
88
82
88
84
86
85
88
85
87
4-OCH3
4-Br
128–130
145–147
110–112
150–152
135–137
140–142
108–110
86–90
5d
5e
5f
4-CH3
2-CH3, 4-NO2
2-OCH3
4-F
5g
5h
5i
2-F
H
5j
2-CH3, 4-CH3
3-Cl
111–113
120–122
116–118
5k
5l
4-Cl
Based on these findings,[24] the objective of this
study was to combine the pyridyl and thiazolyl group
with the carboxamide moiety to form a new skeleton
that has the potential to act as an antimicrobial agent.
In continuation of our efforts toward the synthesis of
antimicrobial agents[25] here, we have designed and
synthesized a series of new pyridyl and thiazolyl
clubbed with carboxamide derivatives. All the synthe-
sized compounds were evaluated for their in vitro anti-
microbial activity, and a molecular docking study was
performed to identify the possible mode of action of
synthesized derivatives.
step, 2-ethylpyridine-4-carbothioamide (1) and ethyl 2-
chloro-3-oxobutanoate (2) were refluxed in ethanol for
5 hr to furnish 2-(2-ethylpyridin-4-yl)-4-methylthiazole-5-
carboxylate (3) with 90% yield.[26] The base-catalyzed
hydrolysis of 2-(2-ethylpyridin-4-yl)-4-methylthiazole-5-
carboxylate (3) gave 2-(2-ethylpyridin-4-yl)-4-meth-
ylthiazole-5-carboxylic acid (4) with 95% yield.[27] The
target compounds (5a-l) were synthesized by the reaction
of 2-(2-ethylpyridin-4-yl)-4-methylthiazole-5-carboxylic
acid (4) and substituted amines in the presence of EDC-
HOBt in DMF.[28]
The synthesized compounds were purified by recrys-
tallization with ethanol. The physical data of these newly
synthesized thiazole–carboxamide derivatives are sum-
marized in Table 1. The structures of synthesized com-
pounds (5a-l) were assigned on the basis of their 1H
NMR, 13C NMR, and high-resolution mass spectra
(HRMS) spectral data analysis.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
The synthetic sequence followed for the synthesis of the
target compounds is as shown in Scheme 1. In the first

KASARE ET AL.
3
2.2 | Antimicrobial activity
for 24 hr at 37ꢁC. A clear zone around the well was
considered to demonstrate positive results. After com-
plete incubation, the antimicrobial activity of the synthe-
sized compounds was measured. The zones were
measured and recorded by using scale in millimeter (mm).
The five compounds have shown good antibacterial and
antifungal activities against almost all pathogens. It has
been observed that the compounds having electron-donat-
ing substituents, such as 5b (4-OCH3), 5d (4-CH3), 5e (2-
CH3), 5f (2-OCH3), and 5j (2, 4-CH3), displayed better
activities (Table 2).
The minimum inhibitory concentration (MIC) value
was determined for the five most potent antimicrobial
compounds 5b, 5d, 5e, 5f, and 5j. It was determined
against S. aureus ATCC6538, B. cereus ATCC14579, and
B. subtilis ATCC6633 by following the method and guide-
lines of the Clinical and Laboratory Standard Institute
(CLSI). All experiments were performed in triplicate. The
results were expressed as mean SD in μg/ml (Table 3).
The in vitro antimicrobial activity of newly synthe-
sized compounds (5a-l) was assessed by using the agar
well diffusion method.[29] The Gram-positive patho-
gens Staphylococcus aureus ATCC6538, Bacillus cereus
ATCC14579, and Bacillus subtilis ATCC6633 and the
Gram-negative pathogens Escherichia coli ATCC8739,
Salmonella
typhi
ATCC9207,
Shigella
boydii
ATCC12034, Enterobacter aerogenes ATCC13048, Pseu-
domonas aeruginosa ATCC9027, and Salmonella abony
NCTC6017 were used. The antifungal activity of syn-
thesized compounds was determined against Saccha-
romyces cerevisiae ATCC9763 and Candida albicans
ATCC10231 fungal pathogens. Tetracycline and flu-
conazole were used as antibacterial and antifungal
standard reference compounds, respectively. The syn-
thesized
compounds
were
dissolved
in
dimethylsulfoxide (DMSO) at a concentration of 1 mg/
ml. Each bacterium and fungus was inoculated into
sterile nutrient broth medium and stored at 37ꢁC for
24 hr to develop inoculum, and then, this broth was
used for the study. Using sterile saline, the bacterial
suspension was diluted to adjust the turbidity to the
0.5 McFarland standards. A total of 200 μl of diluted
suspension of each pathogen was inoculated on sterile
Mueller Hinton agar plates. Wells were punched in the
agar medium. Using a micropipette, 100 μl of each
compound solution was put in a separate well. A total
of 100 μl of DMSO solution without any compound
was also placed in a well to check its activity against
the pathogenic culture. All Petri dishes were incubated
2.3 | Molecular docking study
A molecular docking was performed to investigate the
probable mode of action of synthesized derivatives for
anti-infective potential. The structure of the S.aureus
DNA gyrase (PDB ID: 6QX1) was used for the docking
analysis.[30] The compound 5b has shown a hydrogen
bonding interaction with ARG630 and hydrophobic
interactions with GLU634, MET27, VAL31, ARG342,
and PRO343 (Figure 2). The compound 5d has shown
a hydrogen bond interaction with ARG630 and
TABLE 2 Results of antimicrobial activity of thiazole–carboxamide derivatives (5a-l)
Entry !
Pathogens #
5a
13
—
—
—
—
—
—
—
—
—
14
5b
11
11
09
5c
11
12
—
—
—
—
—
—
09
—
10
5d
14
14
16
07
10
12
—
09
09
06
10
5e
10
11
15
09
11
13
14
—
09
—
13
5f
5g
22
14
10
10
07
06
—
06
06
—
—
5h
20
10
—
—
—
—
—
—
—
—
14
5i
5j
5k
20
11
14
—
—
—
—
10
—
—
—
5l
Standarda
Staphylococcus aureus ATCC6538
Bacillus cereus ATCC14579
Bacillus subtilis ATCC6633
Escherichia coli ATCC8739
Salmonella typhi ATCC9207
Shigella boydii ATCC12034
Enterobacter aerogenes ATCC13048
Pseudomonas aeruginosa ATCC9027
Salmonella abony NCTC6017
Saccharomyces cerevisiae ATCC9763
Candida albicans ATCC10231
12
11
18
10
09
13
06
06
—
08
11
—
08
—
07
—
—
—
03
—
—
—
12
06
11
07
10
—
06
11
08
12
07
—
08
11
—
06
07
—
—
10
—
08
29
33
32
29
33
34
33
32
32
30
30
08
13
07
06
10
08
—
Note: “—” denotes inactive.
aTetracycline and fluconazole were used as antibacterial and antifungal standard reference compounds, respectively.

4
KASARE ET AL.
TABLE 3 MIC determinations of
most potent antimicrobial compounds
Entry !
Pathogens #
5b
5d
5e
5f
5j
Tetracycline
Staphylococcus aureus
120
270
280
200
150
220
150
170
210
170
200
130
210
250
230
30
30
25
Bacillus cereus
Bacillus subtilis
FIGURE 2 Docking interactions of 5b with DNA gyrase
FIGURE 4 Docking interactions of 5e with DNA gyrase
FIGURE 3 Docking interactions of 5d with DNA gyrase
FIGURE 5 Docking interactions of 5f with DNA gyrase
hydrophobic interactions with ILE633, GLU634,
ALA637, MET27, and LYS344 (Figure 3). The com-
pound 5e was found to interact with DNA gyrase via
the formation of a hydrogen bond interaction with
ARG630 and a hydrophobic interaction with LYS344
(Figure 4). The compound 5f has shown a hydrogen
bond interaction with ARG630 and hydrophobic inter-
actions with GLU634, MET27, VAL31, ARG342, and
LYS344 (Figure 5). The compound 5J has displayed a
hydrogen bond interaction with ARG630 and hydropho-
bic interactions with ILE633, GLU634, ALA637,
ARG342, PRO343, and LYS344 (Figure 6).
The lumazine synthase is an enzyme involved in the
vitamin regulations is and nonhomologous to the mam-
malian system.[31] The structure of the lumazine synthase

KASARE ET AL.
5
FIGURE 8 Docking interactions of 5j with lumazine synthase
FIGURE 6 Docking interactions of 5j with DNA gyrase
carried out using the online portal www.swiss.adme.ch.
All the synthesized molecules have shown desired ADME
properties, which indicates their suitability as drug-like
candidates (Table 4).
3 | EXPERIMENTAL
3.1 | General
All the chemicals were obtained from commercial sup-
pliers and used without further purification. The melting
points were determined in open capillary tubes and are
uncorrected. The IR spectra were recorded on Bruker FT-
1
IR spectrometer. H NMR and 13C NMR spectra were
recorded on a Bruker DRX-400 MHz NMR spectrometer
using tetramethylsilane (TMS) as an internal standard.
HRMS were obtained using the XEVO G2-XS QTOF
(TOF MS ES+) instrument.
FIGURE 7 Docking interactions of 5f with lumazine synthase
3.2 | General procedure for the synthesis
of 2-(2-ethylpyridin-4-yl)-4-methyl-N-
phenylthiazole-5-carboxamide derivatives
(5a-l)
(PDB ID 2JFB) was downloaded from the free protein data-
base www.rscb.org. The compound 5f has shown a hydro-
gen bond interaction with LYS12 and hydrophobic
interactions with LYS12, LYS93, LEU129, and THR130 (Fig-
ure 7). The compound 5j has displayed an aromatic interac-
tion with PHE46 and hydrophobic interactions with LYS12,
ASP14, LYS93, GLY94, SER95, and MET97 (Figure 8).
A mixture of 2-(2-ethylpyridin-4-yl)-4-methylthiazole-5-
carboxylic acid (4) (1 mol), DIPEA (2 mol), and HOBt
(1 mol) in DMF was cooled to 0ꢁC. To this reaction mix-
ture, various amines (1 mol) were added followed by
EDCꢀHCl (1 mol) at 0ꢁC and stirred overnight at room
temperature. After completion of reactions, cold water
was added to the reaction mixture. The solids obtained
were filtered, washed with water, and crystallized with
ethanol to furnish the corresponding 2-(2-ethylpyridin-4-
2.4 | ADME prediction
The absorption, distribution, metabolism and excretion
(ADME) predictions of synthesized molecules were

6
KASARE ET AL.
TABLE 4 ADME predictions of thiazole–carboxamide derivatives (5a-l)
Entry
5a
5b
5c
Mol. Wt.
357.86
353.44
402.31
337.44
382.44
353.44
341.40
341.40
323.41
351.47
357.86
357.86
Rotatable bonds
H-bond acceptors
H-bond donors
LOGP
3.64
3.55
3.54
3.49
3.19
3.63
3.28
3.48
3.22
3.74
3.47
3.62
Bioavailability score
5
6
5
5
6
6
5
5
5
5
5
5
3
4
3
3
5
4
4
4
3
3
3
3
1
1
1
1
1
1
1
1
1
1
1
1
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
5d
5e
5f
5g
5h
5i
5j
5k
5l
yl)-4-methyl-N-phenylthiazole-5-carboxamide derivatives
(5a-l) with 82–90% yields.
150.12, 156.92, 157.04, 159.60, 164.79, 164.89; HRMS
(ESI)+ calcd. for C19H19N3O2S [M + H]+: 354.1232 and
found 354.1274.
3.3 | N-(2-Chlorophenyl)-2-(2-
ethylpyridin-4-yl)-4-methylthiazole-5-
carboxamide (5a)
3.5 | N-(4-Bromophenyl)-2-(2-
ethylpyridin-4-yl)-4-methylthiazole-5-
carboxamide (5c)
1
Yield: 86%; M.P.: 90–92ꢁC; H NMR (400 MHz, CDCl3)
δ = 1.38 (t, J = 7.6 Hz, 3H, CH3), 2.90 (s, 3H, Thiazolyl-
CH3), 2.92 (q, J = 7.6 Hz, 2H, CH2), 7.11–7.7.15 (m, 1H,
Ar-H), 7.33–7.37 (m, 1H, Ar-H), 7.44 (dd, J = 1.6 and
8 Hz, 1H, Ar-H), 7.63 (dd, J = 1.6 and 5.2 Hz, 1H, Ar-H),
7.73 (s, 1H, Ar-H), 8.20 (s, 1H, N-H), 8.49 (dd, J = 1.6 and
8.4 Hz, 1H, Ar-H), 8.66 (d, J = 5.2 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CDCl3) δ = 13.83, 17.84, 31.46, 117.88,
118.71, 121.52, 122.87, 125.25, 127.99, 128.28, 129.15,
134.26, 139.75, 150.27, 156.76, 159.26, 164.99, 165.81;
HRMS (ESI)+ calcd. for C18H16ClN3OS [M + H]+:
358.0736 and found 358.0784.
Yield: 85%; M.P.: 145–147ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.33 (t, J = 7.6 Hz, 3H, CH3), 2.76 (s, 3H, Thiazolyl-
CH3), 2.88 (q, J = 7.6 Hz, 2H, CH2), 7.44 (d, J = 8 Hz, 2H,
Ar-H), 7.54 (d, J = 8 Hz, 2H, Ar-H), 7.57 (s, 1H, Ar-H),
7.67 (s, 1H, Ar-H), 8.60 (d, J = 4.8 Hz, 1H, Ar-H), 8.72 (s,
1H, N-H); 13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ = 13.80, 17.46, 31.36, 117.37, 117.81, 118.62, 122.15,
127.36, 131.90, 136.99, 139.90, 150.13, 157.39, 159.92,
164.88 (2-carbons merged); HRMS (ESI)+ calcd. for
C18H16BrN3OS [M + H]+: 404.0211 and found 404.0259.
3.4 | 2-(2-Ethylpyridin-4-yl)-N-(4-
methoxyphenyl)-4-methylthiazole-5-
carboxamide (5b)
3.6 | 2-(2-Ethylpyridin-4-yl)-4-methyl-N-
(p-tolyl)thiazole-5-carboxamide (5d)
Yield: 88%; M.P.: 110–112ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.33 (t, J = 7.6 Hz, 3H, CH3), 2.32 (s, 3H, Ar-CH3),
2.76 (s, 3H, Thiazolyl-CH3), 2.87 (q, J = 7.6 Hz, 2H, CH2),
7.14 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 (d, J = 8.4 Hz, 2H,
Ar-H), 7.51 (d, J = 4 Hz, 1H, Ar-H), 7.64 (s, 1H, Ar-H),
7.89 (s, 1H, N-H), 8.57 (d, J = 5.2 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CDCl3) δ = 13.81, 17.45, 20.94, 31.35,
117.84, 118.65, 120.57, 127.63, 129.66, 134.69, 134.93,
139.88, 150.06, 156.86, 159.62, 164.79, 164.85.
Yield: 90%; M.P.: 128–130ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.35 (t, J = 7.6 Hz, 3H, CH3), 2.80 (s, 3H, Thiazolyl-
CH3), 2.90 (q, J = 7.6 Hz, 2H, CH2), 3.80 (s, 3H, OCH3),
6.90 (d, J = 6.8 Hz, 2H, Ar-H), 7.48 (d, J = 8.8 Hz, 2H,
Ar-H), 7.56 (dd, J = 1.6 and 5.2 Hz, 1H, Ar-H), 7.68 (s,
2H, Ar-H and N-H), 8.61 (d, J = 5.2 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CDCl3) δ = 13.80, 17.48, 31.38, 55.49,
114.29, 117.84, 118.65, 122.46, 127.47, 130.20, 139.88,

KASARE ET AL.
7
3.7 | 2-(2-Ethylpyridin-4-yl)-4-methyl-N-
(2-methyl-4-nitrophenyl)thiazole-5-
carboxamide (5e)
3.10 | 2-(2-Ethylpyridin-4-yl)-N-(2-
fluorophenyl)-4-methylthiazole-5-
carboxamide (5h)
Yield: 82%; M.P.: 150–152ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.36 (t, J = 7.6 Hz, 3H, CH3), 2.44 (s, 3H, Ar-CH3)
2.85 (s, 3H, Thiazolyl-CH3), 2.91 (q, J = 7.6 Hz, 2H, CH2),
7.39 (d, J = 8.4 Hz, 1H, Ar-H), 7.59 (dd, J = 1.6 and
5.2 Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.70 (s, 1H, N-H),
7.97 (dd, J = 2.4 and 8.4 Hz, 1H, Ar-H), 8.61 (d,
J = 5.2 Hz, 1H, Ar-H), 8.86 (d, J = 2.4 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CDCl3) δ = 13.81, 17.75, 18.25, 31.41,
117.76, 117.88, 118.72, 120.23, 126.71, 131.19, 136.08,
136.17, 139.62, 146.84, 150.23, 157.89, 159.60, 165.02,
165.62.
Yield: 86%; M.P.: 108–110ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.36 (t, J = 7.6 Hz, 3H, CH3), 2.84 (s, 3H, Thiazolyl-
CH3), 2.91 (q, J = 7.6 Hz, 2H, CH2), 7.08–7.20 (m, 3H,
Ar-H), 7.60 (dd, J = 2 and 5.2 Hz, 1H, Ar-H), 7.69 (s, 1H,
Ar-H), 7.84 (s, 1H, N-H), 8.35 (td, J = 8.4 and 1.2 Hz, 1H,
Ar-H), 8.63 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR
(100 MHz, CDCl3) δ = 13.82, 17.60, 31.42, 114.88, 115.07,
117.86, 118.70, 121.85, 125.82, 125.92, 127.76, 139.75,
150.21, 153.80, 156.96, 159.29, 164.95, 165.59; HRMS
(ESI)+ calcd. for C18H16FN3OS [M + H]+: 342.1032 and
found 342.1086.
3.11 | 2-(2-Ethylpyridin-4-yl)-4-methyl-N-
phenylthiazole-5-carboxamide (5i)
3.8 | 2-(2-Ethylpyridin-4-yl)-N-(2-
methoxyphenyl)-4-methylthiazole-5-
carboxamide (5f)
1
Yield: 85%; M.P.: 86–90ꢁC; H NMR (400 MHz, CDCl3)
δ = 1.36 (t, J = 7.6 Hz, 3H, CH3), 2.82 (s, 3H, Thiazolyl-
CH3), 2.91 (q, J = 7.6 Hz, 2H, CH2), 7.08 (t, J = 8 Hz, 2H,
Ar-H), 7.53–7.59 (m, 5H, Ar-H), 7.69 (s, 1H, Ar-H), 8.64
(d, J = 5.2 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3)
δ = 13.81, 17.58, 31.43, 115.20, 116.11, 117.40, 118.52,
121.60, 125.27, 126.79, 127.14, 139.75, 150.17, 159.43,
164.68, 165.12.
Yield: 88%; M.P.: 135–137ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.37 (t, J = 7.6 Hz, 3H, CH3), 2.85 (s, 3H, Thiazolyl-
CH3), 2.91 (q, J = 7.6 Hz, 2H, CH2), 3.94 (s, 3H, OCH3),
6.93 (dd, J = 1.2 and 8.4 Hz, 1H, Ar-H), 7.02 (td, J = 8
and 1.2 Hz, 1H, Ar-H), 7.11 (td, J = 7.6 and 1.6 Hz, 1H,
Ar-H), 7.61 (dd, J = 1.6 and 5.2 Hz, 1H, Ar-H), 7.71 (s,
1H, Ar-H), 8.34 (s, 1H, N-H), 8.43 (dd, J = 1.6 and 8 Hz,
1H, Ar-H), 8.63 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR
(100 MHz, CDCl3) δ = 13.84, 17.55, 31.45, 55.93, 109.98,
117.86, 118.66, 119.84, 121.28, 124.43, 127.19, 129.21,
139.94, 147.93, 150.20, 155.79, 159.07, 164.90, 165.31;
HRMS (ESI)+ calcd. for C19H19N3O2S [M + H]+:
354.1232 and found 354.1274.
3.12 | N-(2,4-Dimethylphenyl)-2-(2-
ethylpyridin-4-yl)-4-methylthiazole-5-
carboxamide (5j)
Yield: 88%; M.P.: 111–113ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.35 (t, J = 7.6 Hz, 3H, CH3), 2.27 (s, 3H, Ar-CH3),
2.30 (s, 3H, Ar-CH3), 2.80 (s, 3H, Thiazolyl-CH3), 2.91 (q,
J = 7.6 Hz, 2H, CH2), 7.02 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-
H), 7.52 (s, 1H, Ar-H), 7.57 (dd, J = 1.6 and 5.2 Hz, 1H,
Ar-H), 7.61 (d, J = 8 Hz, 1H, Ar-H), 7.68 (s, 1H, N-H),
8.60 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR (100 MHz,
CDCl3) δ = 13.83, 17.58, 17.91, 20.94, 31.37, 117.86,
118.67, 123.78, 127.46, 128.42, 130.06, 131.36, 132.51,
135.88, 139.92, 150.11, 156.77, 159.59, 164.86, 164.92
3.9 | 2-(2-Ethylpyridin-4-yl)-N-(4-
fluorophenyl)-4-methylthiazole-5-
carboxamide (5g)
Yield: 84%; M.P.: 140–142ꢁC; 1H NMR (400 MHz,
CDCl3) δ = 1.37 (t, J = 7.6 Hz, 3H, CH3), 2.83 (s, 3H,
Thiazolyl-CH3), 2.92 (q, J = 7.6 Hz, 2H, CH2), 7.10 (d,
J = 8 Hz, 2H, Ar-H), 7.54–7.70 (m, 4H, Ar-H), 7.71 (s,
1H, N-H), 8.64 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR
(100 MHz, CDCl3) δ = 13.80, 17.55, 31.41, 115.84,
116.07, 117.86, 118.70, 122.37, 126.99, 133.15, 139.78,
150.21, 157.42, 159.59, 164.97, 165.08; HRMS (ESI)+
calcd. for C18H16FN3OS [M + H]+: 342.1032 and found
342.1086.
3.13 | N-(3-Chlorophenyl)-2-(2-
ethylpyridin-4-yl)-4-methylthiazole-5-
carboxamide (5k)
Yield: 85%; M.P.: 120–122ꢁC; 1H NMR (400 MHz, CDCl3)
δ = 1.37 (t, J = 7.6 Hz, 3H, CH3), 2.86 (s, 3H, Thiazolyl-

8
KASARE ET AL.
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3.14 | N-(4-Chlorophenyl)-2-(2-
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1
Yield: 87%; M.P.: 116–118ꢁC; H NMR (400 MHz, CDCl3)
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δ = 1.37 (t, J = 7.6 Hz, 3H, CH3), 2.82 (s, 3H, Thiazolyl-
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4 | CONCLUSIONS
In conclusion, a series of new pyridyl–thiazolyl clubbed
carboxamide derivatives (5a-l) were synthesized starting
from the clinically used antitubercular drug ethionamide.
The synthesized compounds were characterized with the
1
help of H NMR, 13C NMR, and HRMS spectral analysis.
The in vitro antimicrobial activity of all the synthesized
carboxamide derivatives were evaluated by using the dif-
fusion method. Among the series, compounds 5b, 5d, 5e,
5f, and 5j were found to possess encouraging antimicro-
bial activities. A molecular docking study was performed
to identify the possible mode of action of synthesized
derivatives. The compounds have shown excellent bind-
ing affinity toward DNA gyrase and lumazine synthase
enzymes. We believe that these newly synthesized thia-
zole–carboxamide derivatives with antimicrobial proper-
ties will be helpful for identification of new potential
antimicrobial agents
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Kasare SL, Gund PN,
Sathe BP, et al. Synthesis, antimicrobial screening,
and docking study of new 2-(2-ethylpyridin-4-yl)-4-
methyl-N-phenylthiazole-5-carboxamide
derivatives. J Chin Chem Soc. 2020;1–9. https://doi.
org/10.1002/jccs.202000174
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