Synthesis and biological evaluation of novel 4-(6-substituted quinolin-4-yl)-N-aryl thiazol-2-amine derivatives as potential antimicrobial agents

Article abstract of DOI:10.1002/jhet.4317

Cyclocondensation reaction of 4-(2-bromoacetyl)quinolin-1-ium bromide (4a–d) with substituted arylthiourea, (5a–g) afforded 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine (6a-ab). These newly synthesized derivatives were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388) (Gram-negative strains), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178) (Gram-positive strains) and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Compounds 6a, 6b, 6d, 6f, 6k, and 6l showed moderate to good antibacterial activity against S. albus. Ten derivatives 6c, 6q, 6r, 6s, 6t, 6v, 6w, 6x, 6y, and 6aa, showed moderate to good activity against A. niger. N-[4-(Quinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine presented comparable activity against A. niger with respect to standard drug Rouconazole.

Full text of DOI:10.1002/jhet.4317

Synthesis and biological evaluation of novel 4-(6-substituted quinolin-4-yl)-N-
arylthiazol-2-amine derivatives as potential antimicrobial agents
Prashant Thakare,a Abhijit Shinde,a Sagar Dhakane,b Abhijit Chavan,a Vivek Bobade,c Pravin C.
Mhaskea*
aPost-Graduate Department of Chemistry, S. P. Mandali’s Sir Parashurambhau College, Tilak
Road, Pune, India 411 030, (Affiliated to Savitribai Phule Pune University).
Fax: 91-020-24332479; Tel: 91-020-24331978; E-mail: mhaskepc18@gmail.com
bDepartment of Chemistry, Abasaheb Garware College, Pune, India, (Affiliated to Savitribai
Phule Pune University).
cPost-Graduate Department of Chemistry, H. P. T. Arts and R. Y. K. Science College, Nashik
India 422005 (Affiliated to Savitribai Phule Pune University).
Abstract
Cyclocondensation reaction of 4-(2-bromoacetyl)quinolin-1-ium bromide (4a-d) with substituted
arylthiourea, (5a-g) afforded 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine (6a-
ab). These newly synthesized derivatives were evaluated for in vitro antibacterial activity against
Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388) (Gram negative strains) Bacillus
subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178) (Gram positive strains) and in vitro
antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100).
Compounds 6a, 6b, 6d, 6f, 6k and 6l showed moderate to good antibacterial activity against S.
albus. Ten derivatives 6c, 6q, 6r, 6s, 6t, 6v, 6w, 6x, 6y and 6aa, showed moderate to good
activity against A. niger. N-[4-(Quinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine presented
comparable activity against A. niger with respect to standard drug Rouconazole.
Keywords: Quinoline, 2-Amino Thiazole, Antibacterial activity, Antifungal activity
1 | INTRODUCTION
WHO has warned the misuse of antibiotics during the COVID-19 pandemic that could
increase the antimicrobial drug resistance[1] which may become future public health emergencies.
This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/jhet.4317
This article is protected by copyright. All rights reserved.

Accordingly, the prevention and treatment of infections will become more challenging.[2,3] Two
or more bioactive pharmacophore tethered scaffolds plays a vital role in the search of new lead
compounds.[4] Nitrogen and sulphur containing pharmacophores are the valuable sources that are
utilized in the field of lead identification and development.[5,6]
Natural and synthetic quinoline nucleus containing compounds endowed a broad
spectrum of biological activities.[7,8] Quinoline derivatives displayed vital pharmacological
activities such as antimalarial,[9,10] antimicrobial,[11,12] antifungal,[13,14] antitubercular,[15,16]
anticancer,[17,18] antiviral,[19,20] anti-inflammatory and COX inhibitors,[21,22] carbonic anhydrase
inhibitors,[23] antileishmanial,[24] PIM inhibitors,[25] anticonvulsant and antihypertensive[26]
activities. Thiazole is the important scaffold of several bioactive natural products[27,28] and
reported broad spectrum of biological activity such as antibacterial,[29,30] inflammatory,[31]
antifungal,[32,33] antitubercular,[34,35] antimalarial,[36] anticancer,[37] antiviral,[38] and CNS active
agents.[39] The quinoline tethered azoles are the significant architecture that has received
attention due to their potential biological activity.[40-43] Clubbed thiazolyl-quinoline derivatives
are known for antimicrobial,[44] antibacterial,[45] antiviral,[46] antifungal and anticancer[47]
activities, that have made them prominent target for new antimicrobial agents.
Owing to the significant biological activities of quinoline and thiazole derivatives, we
report herein the synthesis and antimicrobial evaluation of 4-(6-substitutedquinolin-4-yl)-N-
arylthiazol-2-amine derivatives.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
The synthetic route for 4-(6-substitutedquinolin-4-yl)-N-arylthiazol-2-amine derivatives 6a-ab is
presented in Scheme 1. 1-(6-substituted quinolin-4-yl)ethanone[48] 3a-d upon reaction with
bromine in HBr in acetic acid (30% solution) gave 4-(2-bromoacetyl)-6-substituted quinolin-1-
ium bromide 4a-d. Bromo compounds 4a-d upon cyclocondensation reaction with substituted
arylthiourea, 5a-g and sodium carbonate in ethanol gave 4-(6-substituted quinolin-4-yl)-N-
arylthiazol-2-amine, 6a-ab. The structure of newly synthesized quinolinyl-thiazole was
1
13
confirmed by H NMR, C NMR and Mass spectral analysis. All the synthesized compounds
were evaluated for antibacterial and antifungal activity.
2
This article is protected by copyright. All rights reserved.

Scheme 1: Synthetic route of 4-(6-substituted quinolin-4-yl)-N-arylthiazol-2-amine, 6a-ab
The structure of 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine, 6a-ab
was confirmed using spectral analysis. The structure of N-(4-methoxyphenyl)-4-(quinolin-4-
1
yl)thiazol-2-amine, 6c is presented in Figure 1. The H NMR spectrum of 6c revealed a singlet
for methoxy proton attached to phenyl ring at δ 3.74. Two doublets at δ 7.63 and δ 6.96 (J = 9.1
Hz) integrated for two protons each are assigned to for C-2, C-6 and C-3,C-5 protons of phenyl
ring, respectively. N-H and thiazole-H protons appeared at δ 10.46 and 7.96, respectively. The
C-2 and C-3 protons of quinoline ring appeared as doublet with coupling constant J = 5.7 Hz at δ
9.29 and 8.29, respectively. The four quinoline ring protons of C-5, C-6, C-7 and C-8 resonated
between δ 9.13-7.96. The 13C NMR spectrum of compound 6c displayed the methoxy carbon at δ
55.73. The four signals at δ 155.08, 134.18, 119.67 and 114.83 are assigned to C-4′, C-1′, C-2′ C-
6′ and C-3′ C-5′ aromatic carbons, respectively. The three carbons of thiazole ring appeared at δ
165.10, 145.36 and 115.93 corresponds to thiazole-C-2′′, C-4′′ and C-5′′ carbons, respectively.
3
This article is protected by copyright. All rights reserved.

The nine carbons of quinoline ring C-9, C-2, C-4, C-7, C-8, C-6, C-5, C-10 and C-3 resonated at
δ 148.07, 146.31, 140.34, 134.58, 129.66, 128.01, 125.77, 122.70 and 120.94, respectively.
Structure of compound 6c was further confirmed by molecular ion peaks (HRMS) at m/z =
334.1013 (M+H)+. Structure of all synthesized compounds was confirmed accordingly.
Figure 1: Structure of compound 6c.
2.2 | Antimycobacterial activity
Newly synthesized 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine, 6a-ab were
screened for antibacterial activity against Gram-negative bacteria E. coli and P. mirabilis and
Gram-positive bacteria B. subtilis and S. albus using the well diffusion method.[49,50] Standard
drug Streptomycin and DMSO were used as positive and negative control, respectively. The in
vitro antifungal activity was performed against A. niger and A. candida using well diffusion
method.[49,50] The antifungal drugs Fluconazole and Ravuconazole were used as reference. All
the test solutions were prepared in DMSO at 1000 µg/mL concentrations and the wells were
filled with 80 µL (80 µg) of the samples. The result of antimicrobial activity in zone of inhibition
(mm) has been presented in Table 1.
The antimicrobial activity result analysis of 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl
thiazol-2-amine, 6a-ab revealed that, Against E. coli compound 6k showed moderate activity
whereas other compounds were found less active. Against P. mirabilis and B. subtilis all tested
compounds were found less active. Against S. albus, compounds 6a, 6f, 6k and 6l showed
moderate activity with MIC 125 µg/mL, whereas compounds 6b and 6d showed good activity
with MIC 62.5 µg/mL.
The preliminary antifungal activity (Table 1) showed that, most of the 4-(6-substituted quinolin-
4-yl)-N-aryl/pyridyl thiazol-2-amine derivatives presented moderate to good antifungal activity.
The convincing antifungal activities against both fungal strains of compounds 6a-ab lead us to
determine the minimum inhibitory concentration (MIC). To further explore this class of lead
molecules, we screened the compounds 6a-ab for a dose dependent way with the concentrations
4
This article is protected by copyright. All rights reserved.

range from 500 to 3.90 μg/mL. The in vitro antifungal screening results MIC (μg/mL) of
synthesized compounds 6a-ab has been presented in Table 2.
Table 1: Antimicrobial activity in zone of inhibition (mm) of compounds 6a-ab
Compd.
6a
R
R1
E. coli P. mirabilis B. subtilis S. albus
A. candida
12.25
13.4
15.2
10.4
9.8
A. niger
11.6
10.8
15.4
10.2
11.2
10.8
12
H
H
9.2
10.8
10.4
11.2
10.2
9.4
9.8
14.5
19.75
10.4
17.6
11.25
16.6
9.0
H
4-CH3
10.2
9.2
6b
6c
H
4-OCH3 9.2
9.8
H
4-Br
4-Cl
4-F
10.4
11.25
10
6d
6e
H
10.2
10
H
10
10.4
10.2
9.8
9.0
6 f
6g
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
F
H
9.6
9.6
10.5
10.2
10.5
10.8
9.75
10.25
9.6
11.8
8.8
4-CH3
9.0
10.2
9.8
6h
6i
4-OCH3 8.5
10.6
10.4
9.2
12.5
9.0
10.6
11.75
11
4-Br
4-Cl
4-F
8.2
13.8
11
10.8
11.2
11
6J
6k
6l
14.8
13
11.6
9.5
11.4
9
H
9.8
9.4
10.75
11.75
9.8
10
6m
6n
6o
4-CH3
9.0
9.8
9.8
11.6
10.2
10.6
16.6
14.2
14
4-OCH3 10.6
9.0
10
12.2
12.6
12
4-Br
4-Cl
4-F
H
9.6
10.6
10.4
11.8
11
9
6p
6q
6r
14.6
9.8
8.8
9.75
10.4
10.6
10.2
10
11.16
9.6
10.6
9.8
12
6s
14.8
15.4
12
F
4-CH3
4-Br
4-Cl
4-F
-
10.4
8.8
10.6
10.8
11.8
12.4
11
10.5
13.6
10.2
10.6
12.2
12.25
9.25
12.5
21.6
NA
6t
13.4
15.6
14.2
15.4
23.4
12
F
6v
F
11.6
9
14.8
10.6
10.2
8.4
12.8
10.8
20.2
9.6
6w
6x
F
H
9.8
6y
Br
Cl
F
-
8.8
9
6z
-
9.6
10.25
10.6
18.52
NA
10
12
6aa
6ab
14.8
16.2
NA
-
10
10.4
21.6
NA
NA
12.4
NA
25.0
NA
NA
Streptomycin
Fluconazole
Ravuconazole
20.25
28.64
18.35
20.18
NA
NA
5
This article is protected by copyright. All rights reserved.

Table 2: Antimicrobial activity in Minimum Inhibitory Concentration (μg/mL) of compounds
6a-ab
Compd.
6a
R
R1
E. coli P. mirabilis B. subtilis S. albus A. Candida A. niger
H
H
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
>250
>250
>250
125
125
H
4-CH3
6b
6c
62.5
>250
62.5
>250
125
>250
>250
>250
>250
H
4-OCH3 >250
62.5
62.5
H
4-Br
4-Cl
4-F
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
6d
6e
H
H
6 f
6g
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
F
H
4-CH3
6h
6i
4-OCH3 >250
4-Br
4-Cl
4-F
>250
250
6J
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
7.81
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
7.81
6k
6l
125
>250
>250
>250
125
H
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
7.81
6m
6n
6o
4-CH3
4-OCH3 >250
4-Br
4-Cl
4-F
H
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
7.81
6p
6q
6r
62.5
125
6s
125
125
F
4-CH3
4-Br
4-Cl
4-F
-
6t
125
125
F
>250
>250
>250
6v
62.5
125
F
6w
6x
F
125
H
6y
31.25
>250
>250
>250
NA
31.25
>250
250
Br
Cl
F
-
6z
-
6aa
6ab
Streptomycin
Fluconazole
Ravuconazole
-
125
NA
NA
NA
NA
NA
7.81
7.81
7.81
31.25
NA
NA
NA
NA
The result analysis of antifungal activity presented in Table 2 provided some lead compounds
that showed good activity against A. niger. It is notable that the compounds 6c, 6q, 6v and 6y
recorded two-fold less activity against A. niger with respect to the standard drug Ravuconazole.
6
This article is protected by copyright. All rights reserved.

The structure activity relationship analysis revealed that, amongst the N-aryl-4-
(quinolin-4-yl)thiazol-2-amine (6a-f), the compound 6b (R = H, R1 = CH3) showed moderate
activity against A. candida and was less active against A. niger. The compound 6c (R = H, R1 =
OCH3) showed good activity against both fungal strains with MIC 62.5 µg/mL. Compounds 6a,
6d, 6e, 6f found less active against both fungal strains. From compounds N-aryl-4-(6-
bromoquinolin-4-yl)thiazol-2-amine (6g-l) all six derivatives were found less active against both
fungal strains. Amongst N-aryl-4-(6-chloroquinolin-4-yl)thiazol-2-amine (6m-r), compound 6q
(R = Cl, R1 = Cl) reported good activity against A. niger with MIC 62.5 µg/mL which was
twofold less than the standard drug Ravuconazole. Compound 6r (R = Cl, R1 = F) showed
moderate activity against A. niger. From the compounds N-aryl-4-(6-bromoquinolin-4-yl)thiazol-
2-amine (6-x), compounds 6s (R = F, R1 = H) and 6t (R = F, R1 = CH3) showed moderate
activity against both fungal strains. Compounds 6v (R = F, R1 = Br) and 6x (R = F, R1 = F)
showed good activity against A. niger with MIC 62.5 µg/mL however, were found less active
against A. candida. Compound 6w (R = F, R1 = Cl) showed moderate activity against A. niger
strain. Among the compounds 4-(6-substituted quinolin-4-yl)-N-(pyridin-2-yl)thiazol-2-amine,
6y-ab, with respect to standard drug Ravuconazole, compound 6y (R = H) reported comparable
activity against A. niger and good activity against A. candida with MIC 31.25µg/mL. Compound
6ab (R = F) showed moderate activity against A. niger strain with MIC 125 µg/mL.
It is worth mentioning that, amongst the twenty eight derivatives of 4-(6-substituted
quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine, 6a-ab, the 6-chloroquinoline-4-yl at 4-position
and 4-chlorophenyl aniline at 2-position of thiazole (6q), 6-fluoroquinoline-4-yl at 4-position and
4-bromophenyl aniline at 2-position of thiazole (6v) reported good activity against A. niger.
Similarly quinoline-4-yl at 4-position and 4-methoxyphenyl aniline (6c) or pyridin-4-yl amine
(6y) at 2-position of thiazole showed good activity against A. candida and A. niger strains.
Compound 6y showed comparable activity against A. niger with respect to the standard drug
Ravuconazole. It was noticed that when R substituent was fluoro, all the compounds reported
moderate to good activity against A. niger.
3 | CONCLUSIONS
In conclusion, new derivatives of 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-
amine (6a-ab) have been synthesized and evaluated for antibacterial and antifungal activities.
Ten thiazolyl quinoline derivatives reported good activity against A. niger, and five reported
7
This article is protected by copyright. All rights reserved.

moderate to good activity against C. albicans with MIC 31.25-125 µg/mL concentration. Six
derivatives showed good antibacterial activity against S. albus. Compounds N-(4-
methoxyphenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6c) and N-[4-(quinolin-4-yl)-1,3-thiazol-
2-yl]pyridin-2-amine, (6y) presented good activity against both fungal strains. It is concluded
that, 6-fluoro substituted quinoline derivatives are more effective against fungal strains.
4 | EXPERIMENTAL
The solvents and chemicals used were laboratory grade and purified as per literature methods.
All the reactions were monitored by thin-layer chromatography (TLC). TLC was performed on
Merck 60 F-254 silica gel plates with visualization by UV light. Compounds were purified by
column chromatography was performed on silica gel (100–200 mesh) supplied by Acme
Chemical Co. (Mumbai, Maharashtra, India). Melting points were determined in capillary tubes
1
13
in silicon oil bath using a Veego melting point apparatus and are uncorrected. H NMR and C
NMR spectra were recorded on BRUKER ADVANCE II 500 NMR spectrometer (Bruker
Instruments Inc., Billerica, MA, USA) at either 500-MHz (1H NMR) and 126-MHz (13C NMR)
spectrometer instruments. HRMS spectra were recorded on Bruker Compass Data Analysis 4.2
and the theoretical HRMS was calculated for M+H.
4.1 | General procedure for synthesis of 2-bromo-1-(6-substituted quinolin-4-yl)ethanone,
(4a-d)
To the ice cold solution of 1-(6-substitutes quinolin-4-yl) ethanone (3a-d)[43] in 35%
hydrobromic acid in acetic acid bromine was added slowly for 10-15 minutes. After addition was
over reaction mixture was stirred at room temperature for 10-15 min followed by the reaction
was stirred at 45 °C for 1-2 h and at 80 °C for 2 h. Progress of reaction was monitored by TLC.
After complete conversion, reaction mixture was cooled to the room temperature and poured in
diethyl ether. The solid product obtained was filtered and washed with diethyl ether furnished 2-
bromo-1-(6-substituted quinolin-4-yl)ethanone (4a-d) as pure product with good yields.
4.2 | General procedure for synthesis of 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl
thiazol-2-amine (6a-ab)
8
This article is protected by copyright. All rights reserved.

A solution of 2-bromo-1-(6-substituted quinolin-4-yl)ethanone (4a-d) and aryl / 2-pyridyl
thiourea (5a-g) in ethanol was stirred at 25-30 °C for 5-6 h (TLC). After completion of reaction,
the product was filtered and washed with chilled ethanol and dried in oven at 50-60 °C for 2-4 h
gave 4-(6-substituted quinolin-4-yl)-N-aryl/pyridyl thiazol-2-amine, 6a-ab.
4.2.1 | N-Phenyl-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6a)
1
MF: C18H13N3S; Color: Orange solid; Yield: 68%; Mp. >240 °C; H NMR (500 MHz, DMSO-
d6) δ 10.68 (s, 1H), 9.31 (d, J = 5.7 Hz, 1H), 9.11 (d, J = 8.2 Hz, 1H), 8.32-8.30 (m, 2H), 8.18-
8.15 (m, 1H), 8.03 (s, 1H), 7.99-7.96 (m, 1H), 7.73 (dd, J = 8.6, 0.9 Hz, 2H), 7.40 – 7.32 (m,
2H), 7.02 (t, J = 7.3 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 164.42, 148.12, 146.22, 145.36,
141.17, 140.23, 134.26, 129.72, 129.61, 127.96, 125.78, 122.64, 122.37, 121.06, 117.67, 116.61;
HRMS calculated for C18H14N3S: 304.0908, found m/z = 304.0908 (M+H)+.
4.2.2 | N-(4-Methylphenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6b)
MF: C19H15N3S; Color: Brown solid; Yield: 70%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.57 (s, 1H), 9.30 (d, J = 5.7 Hz, 1H), 9.13 (d, J = 8.6 Hz, 1H), 8.34 – 8.26 (m, 2H), 8.18-8.14
(m, 1H), 8.03 – 7.93 (m, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 2.27 (s, 3H); 13C
NMR (126 MHz, DMSO-d6) δ 164.63, 148.19, 146.27, 145.26, 140.16, 138.75, 134.28, 131.36,
129.99, 129.68, 128.02, 125.77, 122.54, 120.97, 117.86, 116.38, 20.86; HRMS calculated for
C19H16N3S: 318.1065; found m/z = 318.1064 (M+H)+.
4.2.3 | N-(4-Methoxyphenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6c)
MF: C19H15N3OS; Color: Orange solid; Yield: 74%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.46 (s, 1H), 9.29 (d, J = 5.7 Hz, 1H), 9.13 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 5.8 Hz, 2H),
8.15 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 8.00 – 7.93 (m, 2H), 7.63 (d, J = 8.8 Hz, 2H), 6.96 (d, J =
13
8.8 Hz, 2H), 3.74 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 165.10, 155.08, 148.07, 146.31,
145.36, 140.34, 134.58, 134.18, 129.66, 128.01, 125.77, 122.70, 120.94, 119.67, 115.93, 114.83,
55.73; HRMS calculated for C19H16N3OS: 334.1014; found m/z = 334.1013 (M+H)+.
4.2.4 | N-(4-Bromophenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6d)
9
This article is protected by copyright. All rights reserved.

MF: C18H12BrN3S; Color: Orange solid; Yield: 65%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.75 (s, 1H), 9.22 (d, J = 5.7 Hz, 1H), 8.97 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 5.9 Hz, 2H),
8.07 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.96 (s, 1H), 7.90 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.63 (m, J
13
= 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.02, 147.91,
146.22, 145.46, 140.47, 140.34, 134.20, 132.29, 129.80, 127.85, 125.78, 122.77, 121.14, 119.52,
116.90, 113.52; HRMS calculated for C18H13BrN3S: 382.0014; found m/z = 382.0018 (M+H)+,
383.9998 (M+2+H)+.
4.2.5 | N-(4-Chlorophenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6e)
MF: C18H12ClN3S; Color: Brown solid; Yield: 70%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.84 (s, 1H), 9.31 (d, J = 5.7 Hz, 1H), 9.10 – 9.01 (m, 1H), 8.31 (d, J = 5.9 Hz, 2H), 8.16
(ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 8.05 (s, 1H), 7.98 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.76 (d, J = 9.0
13
Hz, 2H), 7.40 (d, J = 9.0 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.07, 147.99, 146.17,
145.39, 140.25, 140.07, 134.24, 129.81, 129.41, 127.86, 125.78, 125.66, 122.69, 121.13, 119.10,
116.93; HRMS calculated for C18H13ClN3S: 338.0519; found m/z = 338.0522 (M+H)+, 340.0497
(M+2+H)+.
4.2.6 | N-(4-Fluorophenyl)-4-(quinolin-4-yl)-1,3-thiazol-2-amine (6f)
MF: C18H12FN3S; Color: Orange solid; Yield: 75%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.64 (s, 1H), 9.23 (d, J = 5.7 Hz, 1H), 9.00 (d, J = 8.6 Hz, 1H), 8.26 – 8.20 (m, 2H), 8.08
(ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.94 (s, 1H), 7.91 – 7.88 (m, 1H), 7.67 (dd, J = 9.1, 4.8 Hz, 2H),
13
7.13 (t, J = 8.9 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.51, 158.64 and 156.74 (1J =
239.4 Hz), 148.16, 146.09, 145.28, 140.11, 137.68 and 137.67 (4J = 1.26 Hz), 134.29, 129.80,
127.92, 125.77, 122.54, 121.06, 119.35 and 119.28 (3J = 8.82 Hz), 116.67, 116.23 and 116.05 (2J
= 22.68 Hz); HRMS calculated for C18H13FN3S: 322.0814; found m/z = 322.0807 (M+H)+.
4.2.7 | 4-(6-Bromoquinolin-4-yl)-N-phenyl-1,3-thiazol-2-amine (6g)
1
MF: C18H12BrN3S; Color: ; Yield: 60%; Mp. >240 °C; H NMR (500 MHz, DMSO-d6) δ 10.70
(s, 1H), 9.64 (d, J = 2.0 Hz, 1H), 9.24 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 5.5 Hz, 1H), 8.22 – 8.10
(m, 3H), 7.73 (dd, J = 8.5, 0.9 Hz, 2H), 7.39 (dd, J = 8.4, 7.6 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H);
13C NMR (126 MHz DMSO-d6) δ 164.35, 146.62, 146.47, 144.92, 141.08, 136.16, 130.33,
10
This article is protected by copyright. All rights reserved.

129.66, 126.65, 126.02, 122.37, 122.28, 121.28, 117.74, 117.54, 116.74; HRMS calculated for
C18H13BrN3S: 382.0014; found m/z = 382.0018 (M+H)+, 383.9998 (M+2+H)+.
4.2.8 | 4-(6-Bromoquinolin-4-yl)-N-(4-methylphenyl)-1,3-thiazol-2-amine (6h)
MF: C19H14BrN3S; Color: Brown solid; Yield: 68%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.47 (s, 1H), 9.52 (d, J = 1.9 Hz, 1H), 9.12 (d, J = 5.4 Hz, 1H), 8.15 (d, J = 5.4 Hz, 1H),
8.10 (dd, J = 9.0, 2.1 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H),
13
7.11 (d, J = 8.2 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.52, 146.80, 146.55, 144.57,
141.20, 140.12, 135.97, 130.20, 129.33, 126.66, 126.39, 122.38, 122.23, 121.32, 120.08, 116.78,
20.88; HRMS calculated for C19H15BrN3S: 396.0170; found m/z = 396.0168 (M+H)+, 398.0147
(M+2+H)+.
4.2.9 | 4-(6-Bromoquinolin-4-yl)-N-(4-methoxyphenyl)-1,3-thiazol-2-amine (6i)
1
MF: C19H14BrN3OS; Color: brown solid; Yield: 65%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.56 (s, 1H), 9.68 (d, J = 1.9 Hz, 1H), 9.30 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 5.4
Hz, 1H), 8.30-8.24 (m, 1H), 8.11 (s, 1H), 7.74 (d, J = 9.1 Hz, 2H), 7.07 (d, J = 9.1 Hz, 2H), 3.85
13
(s, 3H); C NMR (126 MHz, DMSO-d6) δ 164.02, 155.10, 146.79, 146.54, 144.47, 141.19,
134.60, 133.11, 132.36, 129.95, 126.78, 126.52, 122.30, 119.71, 116.71, 114.85, 55.68; HRMS
calculated for C19H15BrN3OS: 412.0119; found m/z = 412.0118 (M+H)+ , 414.0097 (M+2+H)+.
4.2.10 | N-(4-Bromophenyl)-4-(6-bromoquinolin-4-yl)-1,3-thiazol-2-amine (6j)
1
MF: C18H11Br2N3S; Color: Orange solid; Yield: 65%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.88 (s, 1H), 9.55 (d, J = 1.9 Hz, 1H), 9.28 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 5.5
Hz, 1H), 8.25-8.20 (m, 2H), 8.17 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H); 13C
NMR (126 MHz, DMSO-d6) δ 163.97, 146.85, 146.60, 144.52, 141.25, 140.40, 135.95, 132.26,
130.10, 126.64, 126.43, 122.25, 121.41, 119.39, 116.66, 113.52; HRMS calculated for
C18H12Br2N3S: 459.9119; found m/z = 459.9113 (M+H)+, 461.9096 (M+2+H)+, 463.9075
(M+4+H)+.
4.2.11 | 4-(6-Bromoquinolin-4-yl)-N-(4-chlorophenyl)-1,3-thiazol-2-amine (6k)
11
This article is protected by copyright. All rights reserved.

1
MF: C18H11BrClN3S; Color: Orange solid; Yield: 68%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.82 (s, 1H), 9.51 (d, J = 1.9 Hz, 1H), 9.22 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 5.5
Hz, 1H), 8.20-8.14 (m, 2H), 8.11 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H); 13C
NMR (126 MHz, DMSO-d6) δ 164.50, 146.74, 146.52, 144.55, 141.24, 135.97, 134.24, 130.20,
129.55, 128.08, 126.66, 126.39, 122.23, 121.32, 119.78,116.70; HRMS calculated for
C18H12BrClN3S: 415.9624; found m/z = 415.9624 (M+H)+, 417.9600 (M+2+H)+, 419.9776
(M+4+H)+.
4.2.12 | 4-(6-Bromoquinolin-4-yl)-N-(4-fluorophenyl)-1,3-thiazol-2-amine (6l)
1
MF: C18H11BrFN3S; Color: Brown solid; Yield: 65%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.62 (s, 1H), 9.47 (d, J = 1.9 Hz, 1H), 9.14 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 5.5
Hz, 1H), 8.12-8.06 (m, 2H), 8.01 (s, 1H), 7.66 (dd, J = 9.1, 4.8 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H);
13C NMR (126 MHz, DMSO-d6) δ 164.46, 158.61 and 156.72 (1J = 238.16 Hz), 146.79, 146.56,
144.60, 141.24, 137.63 and 137.62 (4J = 1.26 Hz), 135.97, 130.20, 126.66, 126.39, 122.23,
121.32, 119.24 and 119.18 (3J = 7.56 Hz), 116.26 and 116.08 (2J = 22.68 Hz); HRMS calculated
for C18H12BrFN3S: 399.9919; found m/z = 399.9920 (M+H)+, 401.9899 (M+2+H)+.
4.2.13 | 4-(6-Chloroquinolin-4-yl)-N-phenyl-1,3-thiazol-2-amine (6m)
MF: C18H12ClN3S; Color: Orange solid; Yield: 72%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.67 (s, 1H), 9.42 (d, J = 2.2 Hz, 1H), 9.21 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H),
8.24 (d, J = 9.0 Hz, 1H), 8.10-8.08 (m, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 8.4, 7.6 Hz,
2H), 7.03 (t, J = 7.3 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 164.40, 147.01, 146.65, 144.55,
141.14, 133.44, 133.32, 129.60, 126.94, 126.72, 126.32, 122.41, 121.37, 117.76, 117.62, 116.01;
HRMS calculated for C18H13ClN3S: 338.0519; found m/z = 338.0521 (M+H)+, 340.0496
(M+2+H)+.
4.2.14 | 4-(6-Chloroquinolin-4-yl)-N-(4-methylphenyl)-1,3-thiazol-2-amine (6n)
MF: C19H14ClN3S; Color: Brown solid; Yield: 65%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.47 (s, 1H), 9.34 (d, J = 2.2 Hz, 1H), 9.13 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H),
8.15 (d, J = 9.0 Hz, 1H), 8.01 (dd, J = 9.1, 2.3 Hz, 1H), 7.97 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H),
7.09 (d, J = 8.2 Hz, 2H), 2.19 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 164.58, 146.77, 146.64,
12
This article is protected by copyright. All rights reserved.

144.80, 141.13, 138.70, 133.47, 133.44, 131.39, 129.98, 127.01, 126.45, 126.32, 121.31, 117.77,
115.94, 20.88; HRMS calculated for C19H15ClN3S: 352.0675; found m/z = 352.0678 (M+H)+,
354.0653 (M+2+H)+.
4.2.15 | 4-(6-Chloroquinolin-4-yl)-N-(4-methoxyphenyl)-1,3-thiazol-2-amine (6o)
1
MF: C19H14ClN3OS; Color: Brown solid; Yield: 66%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.46 (s, 1H), 9.39 (d, J = 2.2 Hz, 1H), 9.20 (d, J = 5.5 Hz, 1H), 8.25-8.22 (m, 2H),
8.08 (dd, J = 9.1, 2.3 Hz, 1H), 8.00 (s, 1H), 7.63 (d, J = 9.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H),
3.74 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 165.07, 155.06, 146.94, 146.63, 144.62, 141.38,
134.56, 133.39, 133.31, 126.98, 126.68, 126.33, 121.29, 119.64, 115.36, 114.80, 55.72; HRMS
calculated for C19H15ClN3OS: 368.0624; found m/z = 368.0624 (M+H)+; 370.0600 (M+2+H)+.
4.2.16 | N-(4-Bromophenyl)-4-(6-chloroquinolin-4-yl)-1,3-thiazol-2-amine (6p)
1
MF: C18H11BrClN3S; Color: Orange solid; Yield: 62%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.90 (s, 1H), 9.36 (d, J = 2.2 Hz, 1H), 9.30 (d, J = 5.4 Hz, 1H), 8.37 – 8.30 (m,
13
2H), 8.20 – 8.15 (m, 2H), 7.79 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.9 Hz, 2H); C NMR (126
MHz, DMSO-d6) δ 164.00, 147.24, 146.59, 144.33, 142.49, 140.46, 133.46, 133.21, 132.23,
126.98, 126.73, 126.31, 121.51, 119.47, 116.14, 113.52; HRMS calculated for C18H12BrClN3S:
415.9624; found m/z = 415.9623 (M+H)+, 417.9600 (M+2+H)+, 419.9776 (M+4+H)+.
4.2.17 | N-(4-Chlorophenyl)-4-(6-chloroquinolin-4-yl)-1,3-thiazol-2-amine (6q)
1
MF: C19H14ClN3OS; Color: Orange solid; Yield: 72%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.79 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 9.20 (d, J = 5.3 Hz, 1H), 8.24-8.21 (m, 2H),
8.08 (ddd, J = 9.1, 2.3 Hz, 1H), 8.04 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H);
13C NMR (126 MHz, DMSO-d6) δ 165.07, 146.94, 146.63, 144.62, 141.38, 138.58, 133.39,
132.78, 130.00, 129.36, 127.03, 126.30, 125.28, 123.68, 121.29, 115.45; HRMS calculated for
C19H15ClN3OS: 372.0129; found m/z = 372.0132 (M+H)+, 374.0105 (M+2+H)+.
4.2.18 | 4-(6-Chloroquinolin-4-yl)-N-(4-fluorophenyl)-1,3-thiazol-2-amine (6r)
1
MF: C18H11ClFN3S; Color: Yellow solid; Yield: 68%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.61 (s, 1H), 9.26 (d, J = 2.2 Hz, 1H), 9.13 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 5.5
13
This article is protected by copyright. All rights reserved.

Hz, 1H), 8.15 (d, J = 9.1 Hz, 1H), 8.00 (dd, J = 9.1, 2.3 Hz, 1H), 7.99 (s, 1H), 7.66 (dd, J = 9.1,
4.8 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 164.52, 158.64, 156.74
(1J = 238.16 Hz), 146.90, 146.47, 144.67, 141.19, 137.66 and 137.65 (4J = 1.26 Hz), 133.53,
133.39, 126.87, 126.57, 126.30, 121.40, 119.35 and 119.28 (3J = 8.82 Hz), 116.20 and 116.02 (2J
= 22.68 Hz); HRMS calculated for C18H12ClFN3S: 356.0424; found m/z = 356.0428 (M+H)+,
356.0402 (M+H)+.
4.2.19 | 4-(6-Fluoroquinolin-4-yl)-N-phenyl-1,3-thiazol-2-amine (6s)
MF: C18H12FN3S; Color: Yellow solid; Yield: 74%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.73 (s, 1H), 9.29 (d, J = 5.5 Hz, 1H), 9.03 (dd, J = 11.0, 2.8 Hz, 1H), 8.39 (dd, J = 9.3,
5.3 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1H), 8.12 (s, 1H), 8.11 – 8.07 (m, 1H), 7.80 – 7.73 (m, 2H),
13
7.42 (dd, J = 8.5, 7.5 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H); C NMR (126 MHz, DMSO-d6) δ
164.47, 162.04 and 160.07 (1J = 248.22 Hz), 146.40, 145.84, 145.74 and 145.70 (4J = 5.04 Hz),
141.16, 139.21, 129.57, 127.05 and 126.97 (3J = 10.08 Hz), 126.82 and 126.73 (3J = 11.34 Hz),
123.56 and 123.35 (2J = 26.46 Hz), 122.45, 121.30, 117.75, 117.72, 115.97, 111.94 and 111.74
(2J = 25.2 Hz); HRMS calculated for C18H13FN3S: 322.0814 ; found m/z = 322.0807 (M+H)+.
4.2.20 | 4-(6-Fluoroquinolin-4-yl)-N-(4-methylphenyl)-1,3-thiazol-2-amine (6t)
MF: C19H14FN3S; Color: Pink solid; Yield: 65%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-d6)
δ 10.55 (s, 1H), 9.23 (d, J = 5.4 Hz, 1H), 8.99 (d, J = 11.0 Hz, 1H), 8.33 (dd, J = 9.3, 5.2 Hz,
1H), 8.28 (d, J = 5.4 Hz, 1H), 8.08 – 8.00 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz,
13
2H), 2.27 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 164.55, 162.06 and 160.09 (1J = 248.22
Hz), 146.43, 145.87, 145.74 and 145.70 (4J = 5.04 Hz), 141.16, 139.21, 133.50, 130.49, 127.18
and 127.10 (3J = 10.08 Hz), 126.85 and 126.76 (3J = 11.34 Hz), 123.61 and 123.40 (2J = 26.46
Hz), 121.32, 117.75, 115.95, 111.92 and 111.72 (2J = 25.2 Hz), 20.85; HRMS calculated for
C19H15FN3S: 336.0971; found m/z = 336.0973 (M+H)+.
4.2.21 | 4-(6-Fluoroquinolin-4-yl)-N-(4-methoxyphenyl)-1,3-thiazol-2-amine (6u)
MF: C19H14FN3OS; Color: Brown solid; Yield: 55%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.49 (s, 1H), 9.26 (t, J = 5.7 Hz, 1H), 9.04 – 8.94 (m, 1H), 8.43 – 8.33 (m, 1H), 8.31 (t, J =
7.1 Hz, 1H), 8.08 (s, 1H), 8.05 – 7.99 (m, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H),
14
This article is protected by copyright. All rights reserved.

13
3.80 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 165.24, 161.96 and 159.99 (1J = 248.22 Hz),
155.15, 146.51 and 146.46 (4J = 6.3 Hz), 146.07, 138.40 and 139.35 (4J = 6.3 Hz), 134.57,
130.28, 127.32 and 127.14 (2J = 22.68 Hz), 126.81 and 126.72 (3J = 11.34 Hz), 123.36
and123.27 (3J = 11.34 Hz), 121.21, 119.88, 119.82, 114.79, 111.92 and 111.75 (2J = 21.42 Hz),
55.73; HRMS calculated for C19H15FN3OS: 352.0920; found m/z = 352.0923 (M+H)+.
4.2.22 | N-(4-Bromophenyl)-4-(6-fluoroquinolin-4-yl)-1,3-thiazol-2-amine (6v)
1
MF: C18H11BrFN3S; Color: Orange solid; Yield: 70%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.85 (s, 1H), 9.26 (d, J = 5.3 Hz, 1H), 8.86 (dd, J = 10.9, 2.7 Hz, 1H), 8.37 (dd, J
= 9.3, 5.4 Hz, 1H), 8.29 (d, J = 5.3 Hz, 1H), 8.11 – 8.03 (m, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.57
13
(d, J = 8.9 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.06, 162.02 and 160.05 (1J = 248.22
Hz), 146.48, 145.07 and 145.03 (4J = 5.04 Hz), 140.51, 140.13 and 140.09 (4J = 5.04 Hz),
132.25, 127.84 and 127.77 (3J = 8.82 Hz), 126.79 and 126.71 (3J = 10.08 Hz), 123.17 and 122.95
(2J = 27.72 Hz), 121.48, 119.54, 115.59, 113.53, 111.60 and 111.40 (2J = 25.2 Hz); HRMS
calculated for C18H12BrFN3S: 399.9919; found m/z = 399.9921 (M+H)+, 401.9899 (M+2+H)+.
4.2.23 | N-(4-Chlorophenyl)-4-(6-fluoroquinolin-4-yl)-1,3-thiazol-2-amine (6w)
1
MF: C18H11ClFN3S; Color: Orange solid; Yield: 75%; Mp. >240 °C; H NMR (500 MHz,
DMSO-d6) δ 10.81 (s, 1H), 9.22 (d, J = 5.4 Hz, 1H), 8.83 (dd, J = 10.9, 2.8 Hz, 1H), 8.33 (dd, J
= 9.3, 5.4 Hz, 1H), 8.26 (d, J = 5.4 Hz, 1H), 8.05 – 8.01 (m, 2H), 7.74 (d, J = 8.9 Hz, 2H), 7.38
13
(d, J = 8.9 Hz, 2H); C NMR (126 MHz, DMSO-d6) δ 164.12, 162.06 and 160.09 (1J = 248.22
Hz), 146.36, 146.16, 145.43 and 145.39 (4J = 5.04 Hz), 140.10, 139.60 and 139.58 (4J = 2.26
Hz), 129.36, 127.44 and 127.36 (3J = 10.08 Hz), 126.81 and 126.72 (3J = 11.34 Hz), 125.70,
123.38 and 123.17 (2J = 26.46 Hz), 121.45, 119.13, 115.93, 111.71 and 111.51 (2J = 25.2 Hz);
HRMS calculated for C18H12ClFN3S: 356.0424; found m/z = 356.0428 (M+H)+, 358.0402
(M+2+H)+.
4.2.24 | N-(4-Fluorophenyl)-4-(6-fluoroquinolin-4-yl)-1,3-thiazol-2-amine (6x)
MF: C18H11F2N3S; Color: Orange solid; Yield: 70%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 10.59 (s, 1H), 9.14 (d, J = 5.4 Hz, 1H), 8.78 (dd, J = 11.0, 2.8 Hz, 1H), 8.24 (dd, J = 9.3,
5.4 Hz, 1H), 8.18 (d, J = 5.4 Hz, 1H), 8.00 – 7.88 (m, 2H), 7.65 (dd, J = 9.1, 4.8 Hz, 2H), 7.11 (t,
15
This article is protected by copyright. All rights reserved.

J = 8.9 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 164.62, 162.03 and 160.06 (1J = 248.22 Hz),
158.68 and 156.78 (1J = 239.4 Hz), 146.34, 146.13, 145.48 and 145.44 (4J = 5.04 Hz), 139.60
and 139.57 (4J = 3.78 Hz), 137.71 and 137.69 (4J = 2.52 Hz), 127.41 and 127.33 (3J = 10.8 Hz),
126.81 and 126.72 (3J = 11.34 Hz), 123.38 and 123.17 (2J = 26.46 Hz), 121.38, 119.45 and,
119.39 (3J = 7.56 Hz), 116.20 and 116.02 (2J = 22.68 Hz), 115.56, 111.77 and 111.57 (2J = 25.2
Hz); HRMS calculated for C18H12F2N3S: 340.0720; found m/z = 340.0723 (M+H)+.
4.2.25 | N-[4-(Quinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine (6y)
MF: C17H12N4S; Color: Brown solid; Yield: 55%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-d6)
δ 11.70 (s, 1H), 9.23 (d, J = 5.5 Hz, 1H), 9.12 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 4.9 Hz, 1H), 8.31
-8.27 (m, 3H), 8.20 (d, J = 5.4 Hz, 1H), 8.11 – 8.01 (m, 1H), 7.85 – 7.75 (m, 1H), 7.15 (d, J = 8.3
Hz, 1H), 7.05 – 7.00 (m, 1H); 13C NMR (126 MHz, DMSO-d6) δ 160.85, 151.82, 146.90,
146.74, 145.30, 145.28, 141.20, 138.80, 132.98, 131.56, 128.90, 127.12, 126.67, 121.36, 118.66,
117.06, 111.56; HRMS calculated for C17H13N4S: 305.0861; found m/z = 305.0865 (M+H)+.
4.2.26 | N-[4-(6-Bromoquinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine (6z)
MF: C17H11BrN4S; Color: Brown solid; Yield: 58%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 11.77 (s, 1H), 9.36 (d, J = 1.5 Hz, 1H), 9.25 (d, J = 5.4 Hz, 1H), 8.38 (d, J = 4.1 Hz, 1H),
8.22-8.16 (m, 3H), 8.07 (s, 1H), 7.81 – 7.77 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 6.8,
5.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 160.97, 151.86, 147.00, 146.81, 145.42, 145.38,
141.27, 138.83, 136.09, 130.10, 126.88, 126.49, 122.38, 121.86, 118.32, 117.07, 111.59; HRMS
calculated for C17H12BrN4S: 382.9966; found m/z = 382.9969 (M+H)+, 384.9946 (M+2+H)+.
4.2.27 | N-[4-(6-Chloroquinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine (6aa)
MF: C17H11ClN4S; Color: Brown solid; Yield: 65%; Mp. >240 °C; 1H NMR (500 MHz, DMSO-
d6) δ 11.75 (s, 1H), 9.26 – 9.19 (m, 2H), 8.37 (dd, J = 4.9, 0.9 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H),
8.22 (d, J = 5.4 Hz, 1H), 8.11 – 8.04 (m, 2H), 7.82 – 7.75 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.01
13
(dd, J = 6.8, 5.4 Hz, 1H); C NMR (126 MHz, DMSO-d6) δ 160.92, 151.85, 147.01, 146.80,
145.42, 145.36, 141.19, 138.83, 133.60, 133.47, 126.92, 126.61, 126.46, 121.82, 118.26, 117.07,
111.58; HRMS calculated for C17H12ClN4S: 339.0471; found m/z = 339.0473 (M+H)+, 341.0446
(M+2+H)+.
16
This article is protected by copyright. All rights reserved.

4.2.28 | N-[4-(6-Fluoroquinolin-4-yl)-1,3-thiazol-2-yl]pyridin-2-amine (6ab)
1
MF: C17H11FN4S; Color: Brown solid; Yield: 62%; Mp. >240 °C; H NMR (500 MHz, DMSO-
d6) δ 11.74 (s, 1H), 9.25 (d, J = 5.5 Hz, 1H), 9.08 (dd, J = 10.9, 2.7 Hz, 1H), 8.37 (d, J = 4.9 Hz,
1H), 8.33 (dd, J = 9.3, 5.3 Hz, 1H), 8.30 (d, J = 5.5 Hz, 1H), 8.16 (s, 1H), 8.11 – 8.01 (m, 1H),
7.85 – 7.75 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.04 – 6.99 (m, 1H); 13C NMR (126 MHz, DMSO-
d6) δ 162.03 and 160.06 (1J = 248.22 Hz), 160.80, 151.84, 146.82, 146.19 and 146.15 (4J = 5.04
Hz), 145.67, 145.27, 139.09 and 139.06 (4J = 3.78 Hz), 138.83, 126.85 and 126.77 (3J = 10.8
Hz), 123.65 and 123.44 (2J = 26.46 Hz), 121.36, 118.66, 117.06, 112.35 and 112.15 (2J = 25.2
Hz), 111.56; HRMS calculated for C17H12FN4S: 323.0767; found m/z = 323.0770 (M+H)+.
ACKNOWLEDGMENTS
Authors would like to acknowledge to S. P. Mandali Pune and Late. Dr. T. R. Ingale family for
providing infrastructure facilities. Authors would like to thanks CIF, Savitribai Phule Pune
University, Pune, India for spectral analysis and S. P. Mandali’s Bhide Foundation Pune has also
acknowledged for lending support with their biological activities. ADS is thanks to CSIR-for
award of SRF, Award No 08/319(0004)/2017-EMR-1
Conflict of interest
The authors declare that they have no conflict of interest.
Supporting Information: Additional supporting information may be found online in the
Supporting Information section.
Notes and references:
[1] a) H. Getahun, I. Smith, K. Trivedi, S. Paulin, H.H. Balkhy, Bulletin of the World Health
Organization, 2020, 98, 442-442A; b) https://www.who.int/bulletin/volumes/98/7/20-
268573/en/; c) https://www.who.int/antimicrobial-resistance/interagency-coordination-
group/IACG_final_report_EN.pdf (accessed July 1, 2019)
[2] WHO Report, 2018, https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-
resistance Antibiotic resistance.
[3] B. Aslam, W. Wang, M. I. Arshad, M. Khurshid, S. Muzammil, M. H. Rasool, M. A. Nisar,
R. F. Alvi, M. A. Aslam, M. U. Qamar, M. K. F. Salamat, Z. Baloch, Infection and Drug
Resistance 2018, 11, 1645.
17
This article is protected by copyright. All rights reserved.

[4] G. Beruve, Expert opin drug discov. 2016, 11, 281.
[5] N. Kerru, L. Gummidi, S. Maddila, K. K. Gangu, S. B. Jonnalagadda, Molecules, 2020,
25, 1909-1951.
[6] S. Pathania, R. K. Narang, R. K. Rawal, Eur. J. Med. Chem. 2019, 180, 486-508.
[7] M. Kukowska, Eur J Pharm Sci. 2017,109, 587-615.
[8] A. Weyesa, E. Mulugeta, RSC Advances, 2020, 10, 20784–20793.
[9] K. N. Olafson, T. Q. Nguyen, P. G. Vekilov, J. D. Rimer, Chem. Eur. J. 2017, 23, 1–11.
[10] B. Sureshkumar, Y. S. Mary, C. Y. Panicker, S. Suma, S. Armaković, S. J. Armaković, C.
Van Alsenoy, B. Narayana, Arabian J. Chem. 2020, 13, 632-648.
[11] N. C. Desai, B. Y. Patel, K. A. JadeJa, B. P. Dave, Nov. Appro. Drug. Des. Dev. 2017, 1(4),
1-4.
[12] S. N. Dighe, T. A. Collet, Eur. J. Med. Chem. 2020, 199, 1-12.
[13] X. Yin, Y. Sun, R. K. Lawoe, G. Yang, Y. Liu, X. Shang, H. Liu, Y. Yang, J. Zhu, X. RSC
Adv. 2019, 9, 30087-30099.
[14] C. M. M. Gómez, V. V. Kouznetsov, M. A. Sortino, S. L. Álvarez, S. A. Zacchino, Bioorg.
& Med. Chem. 2008, 16, 7908–7920.
[15] E. Pitta, M. K. Rogacki, O. Balabon, S. Huss, F. Cunningham, E. M. Lopez-roman, J.
Joossens, K. Augustyns, L. Ballell, R. H. Bates, P. Van Der Veken, J. Med. Chem. 2016,
59, 6709−6728,
[16] S. Gatadi, S. Nanduri, Bioorg. Chem., 2020, 95, 103534.
[17] S. Jain, V. Chandra, P. Kumar, K. Pathak, D. Pathak, A. Vaidya, 2019, Arabian J. Chem.
12, 4920-4946.
[18] R. Hamdy, S. A. Elseginy, N. I. Ziedan, A. T. Jones, A. D. Westwell, Molecules, 2019, 24,
1274-1287,
[19] P. Shaha, D. Naika, N. Jariwalab, D. Bhadaneb, S. Kumara, S. Kulkarnib, K.K. Bhutania,,
I.P. Singha, Bioorganic Chemistry 80, 591–601(2018)
[20] R. Musharrafieh, J. Zhang, P. Tuohy, N. Kitamura, S. S. Bellampalli, Y. Hu, R. Khanna, J.
Wang, J. Med. Chem. 2019, 62, 4074−4090.
[21] S. MukherJee, M. Pal, Drug Discovery Today, 2013, 18, 389-398.
[22] A. M. Mohassab, H. A. Hassan, D. Abdelhamid, M. Abdel-aziz, K. N. Dalby, T. S. Kaoud,
Bioorg. Chem., 2017, 75, 242–259,
18
This article is protected by copyright. All rights reserved.

[23] P. S. Thacker, P. Shaikh, A. Angeli, M. Arifuddin, C. T. Supuran, J. Enzyme Inhib. Med.
Chem. 2019, 34(1), 1172–1177.
[24] N. Barak, M. Taha, F. Rahim, A. Wadood, S. Imran, M.A. Alqahtani, Y.A. Bamarouf, M.
Ibrahim, A. Mosaddik, M. Gollapalli, Bioorg. Chem., 2019, 85, 109–116.
[25] S. Martínez-Gonzalez, S. Rodríguez-Arístegui, C. A. G. Omezdela-Oliva, A. I. Hernandez,
E. G. Cantalapiedra, C. Varela, A. B. García, O. Rabal, J. Oyarzabal, J.R. Bischoff, J. Klett,
M. Albarran, A. Cebria, N. Ajenjo, B. García-Serelde, E. Gomez-Casero, M. Cuadrado-
Urbano, D. Cebrian, C. Blanco-Aparicio, J. Pastor, Eur. J. Med. Chem. 168, 87-109. 2019.
[26] N. Muruganantham, R. Sivakumar, N. Anbalagan, V. Gunasekaran, J. T. Leonard, Biol.
Pharm. Bull. 2004, 27(10), 1683—1687.
[27] A. Rouf, C. Tanyeli, Eur. J. Med. Chem. 2015, 97, 911–927.
[28] D. Das, P. Sikdar, M. Bairagi, Eur. J. Med. Chem. 2016, 109, 89-98.
[29] M. A. Seleem, A. M. Disouky, H. Mohammad, T. M. Abdelghany, A. S. Mancy, S. A.
Bayoumi, A. Elshafeey, A. El-morsy, M. N. Seleem, A. S. Mayhoub, J. Med. Chem. 2016,
59(10), 4900-4912.
[30] S. Bondock, T. Naser, Y. A. Ammar, Eur. J. Med. Chem. 2013, 62, 270–279.
[31] S. H. Shelke, P. C. Mhaske, M. Nandave, S. Narkhade, N. M. Walhekar, V. D. Bobade,
Bioorg. Med. Chem. Lett. 2012, 22(20), 6373-6376.
[32] J. Nalawade, A. Shinde, A. Chavan, S. Patil, M. Suryavanshi, M. Modak, P. Choudhari, V.
D. Bobade, P. C. Mhaske, Eur. J. Med. Chem. 2019, 179, 649-659.
[33] S. M. Jagadale, A. P. Chavan, A. Shinde, V. Sisode, V. D. Bobade, P. C. Mhaske, Med.
Chem. Res. 2020, 29, 989-999.
[34] Y. K. Abhale, A. V. Sasane, A. P. Chavan, S. H. Shekh, K. K. Deshmukh, S. Bhansali, L.
Nawale, D. Sarkar, P. C. Mhaske, Eur. J. Med. Chem., 2017, 132, 333-340.
[35] Y. K. Abhale, A. V. Sasane, A. P. Chavan, K. K. Deshmukh, S. S. Kotapalli, R. Ummanni,
S. F. Sayyad, P. C. Mhaske, Eur. J. Med. Chem. 2015, 94, 340-347.
[36] J. M. Bueno, M. Carda, B. Crespo, A. C. Cuñat, C. de Cozar, M. L. León, J. A. Marco, N.
Roda, J. F. Sanz-Cervera, Bioorg. Med. Chem. Lett. 2016, 26(16), 3938-3944.
[37] A. R. Sayed, S. M. Gomha, E. A. Taher, Z. A. Muhammad, H. R. El-Seedi, H. M. Gaber,
M. M. Ahmed, Drug. Des. Devel. Ther. 2020, 14, 1363-1375.
[38] I. P. Singh, S. Gupta, S. Kumar, Med. Chem. 2020, 16, 4-23.
19
This article is protected by copyright. All rights reserved.

[39] C. B. Mishra, S. Kumari, M. Tiwari, Eur. J. Med. Chem. 2015, 92, 1-34.
[40] K. M. El-gamal, M. S. Hagrs, H. S. Abulkhair, Bulletin of Faculty of Pharmacy, 2016, 54,
263–273.
[41] K. D. Thomas, A. V. Adhikari, N. S. Shetty, Eur. J. Med. Chem. 2010, 45, 3803–3810.
[42] J. Zhang, S. Wang, Y. Ba, Z. Xu, Eur. J. Med. Chem. 2019, 174, 1–8.
[43] P. P. Thakare, A. D. Shinde, A. P. Chavan, N. V. Nyayanit, V. D. Bobade, P. C. Mhaske.
ChemistrySelect, 2020, 5, 4722-4727.
[44] V. Dhakane, D. Jagtap, G. Gavande, Current Trends in Pharmacy and Pharmaceutical
Chemistry 2020, 2, 41–48.
[45] Y. Li, N. Sun, H. Ser, W. Long, Y. Li, C. Chen, B. Zheng, X. Huang, Z. Liu, Y. Lu, RSC
Advances. 2020, 10, 15000–15014.
[46] M. Llinàs-Brunet, M. Bailey, G. Bolger, C. Brochu, A-M. Faucher, J. Ferland, M. Garneau,
E. Ghiro, V. Gorys, C. Grand-Maître, T. Halmos, N. Lapeyre-Paquette, F. Liard, M.
Poirier, M. Rhéaume, Y. Tsantrizos, D. Lamarre, J. Med. Chem., 2004, 47(7), 1605-1608.
[47] E. Ali, M. D. Altintop, O. Atli, B. Sever, G. Iscan, G. Gormus, A. Ozdemir, Lett. in Drug
Design & Discovery, 2018, 15(2), 193-202.
[48] M. G. A. Shvekhgeimer, Chem. Het. Comp. 2004, 40(3), 257-294.
[49] National Committee for Clinical Laboratory Standards, Method for dilution antimicrobial
susceptibility tests of bacteria that grow aerobically, Approv. Stand. M100-S12, Wayne
PA, NCCLS (2002).
[50] A. B. Joshi, M. Mali, V. Kulkarni, Int. J. Curr. Microbiol. App. Sci. 2015, 4(10), 678-685.
20
This article is protected by copyright. All rights reserved.