Design, synthesis and biological evaluation of novel N,4-diphenylthiazol-2-amine derivatives

Article abstract of DOI:10.1007/s00044-019-02495-2

Novel N,4-diphenylthiazol-2-amine derivatives were designed and synthesized employing Hantzsch method. The three-step reaction involved in the synthesis occurred at a faster rate with excellent yields in eco-friendly conditions. The synthesized derivatives were characterized by spectral techniques such as ¹H NMR, ¹³C NMR, FT-IR and GCMS. Single-crystal X-ray diffraction studies also confirmed the formation of title compounds. These compounds were evaluated in vitro for their antimicrobial and anti-inflammatory activities. The results demonstrated that most of the tested compounds showed potent antifungal activity. Interestingly, these compounds also exhibited good anti-inflammatory and moderate antibacterial activity towards sensitive as well as resistant bacterial strains. In silico studies depicted their good binding affinity profile against S. aureus (PDB ID: 1AD4) and C. albicans (PDB ID: 1AI9). [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00044-019-02495-2

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02495-2
ORIGINAL RESEARCH
Design, synthesis and biological evaluation of novel
N,4-diphenylthiazol-2-amine derivatives
AfraQuasar A. Nadaf1 Delicia A. Barretto2 Mahesh S. Najare1 Shivaraj Mantur1 Manjunatha Garbhagudi1
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Supreet Gaonkar1 Shrinivas Joshi3 Imtiyaz Ahmed M. Khazi1
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Received: 2 July 2019 / Accepted: 22 December 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Novel N,4-diphenylthiazol-2-amine derivatives were designed and synthesized employing Hantzsch method. The three-step
reaction involved in the synthesis occurred at a faster rate with excellent yields in eco-friendly conditions. The synthesized
1
derivatives were characterized by spectral techniques such as H NMR, 13C NMR, FT-IR and GCMS. Single-crystal X-ray
diffraction studies also confirmed the formation of title compounds. These compounds were evaluated in vitro for their
antimicrobial and anti-inflammatory activities. The results demonstrated that most of the tested compounds showed potent
antifungal activity. Interestingly, these compounds also exhibited good anti-inflammatory and moderate antibacterial activity
towards sensitive as well as resistant bacterial strains. In silico studies depicted their good binding affinity profile against S.
aureus (PDB ID: 1AD4) and C. albicans (PDB ID: 1AI9).
Graphical Abstract
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Keywords N,4-diphenylthiazol-2-amine Antimicrobial Anti-inflammatory Ciprofloxacin Fluconazole Protein
denaturation assay
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02495-2) contains supplementary
material, which is available to authorized users.
2
* Imtiyaz Ahmed M. Khazi
Department of Biotechnology & Microbiology, Karnatak
University, Dharwad, Karnataka 580003, India
drimkorgchem@gmail.com
3
Novel Drug Design and Discovery Laboratory, Department of
Pharmaceutical Chemistry, S.E.T.’s College of Pharmacy, Sangolli
Rayanna Nagar, Dharwad, Karnataka 580002, India
1
Department of Chemistry, Karnatak University,
Dharwad, Karnataka 580003, India

Medicinal Chemistry Research
Introduction
tinib (antineoplastic agents) (Das et al. 2006), ritonavir
(anti-HIV drug) (De Souza and De Almeida 2003), ravu-
conazole (antifungal agent) (Pasqualotto et al. 2010), nita-
zoxanide (antiparasitic agent) (Fox and Saravolatz 2005),
fanetizole, meloxicam and fentiazac (anti-inflammatory
agents) (Knadler et al. 1986) and nizatidine (antiulcer agent)
(Nauen et al. 2003). Importantly, thiazole bearing products-
Nizatidine, Abafungin and Amiphenazole are among com-
mercially marketed drugs (Fig. 1). Structure-activity rela-
tionship study of thiazole based drugs/leads revealed that
substituent’s on a particular position specifically at position
2 and 4 of the 1, 3- thiazole ring affect the biological out-
comes to a great extent. It has so far been shown that 2, 4-
disubstituted thiazole moiety seems to be an important
pharmacophore in various pharmacologically active agents
(Arora et al. 2015).
The main emphasis of our work was to design and
develop potent antimicrobial and anti-inflammatory agents.
In this regard, we have attempted the synthesis of N-alkyl
derivatives of 2,4-disubstituted thiazole by simple and
efficient synthetic method. Also, their in silico as well as
in vitro antimicrobial and anti-inflammatory properties have
been analyzed.
The rapid advancement of research in the field of medical
sciences in the past decades has led to a significant
improvement in the diagnosis and treatment of infectious
diseases, which has resulted in the better health status of
human beings. However, the inappropriate use of anti-
infectious agents pose one of the major challenges to the
scientific community that needs to be resolved effectively
(Tenover and McDonald 2005; Pfeltz and Wilkinson
2004; Roberts 2004; Dessen et al. 2001; Muroi et al. 2004;
Liaras et al. 2011). The emergence of microbial multidrug
resistance against known antibiotics in recent years has
created an alarming situation and has attracted great
attention for identifying new approaches to design and
explore innovative heterocyclic agents with novel mode of
actions (Narang et al. 2011, 2012; Perez et al. 2014;
Kumar et al. 2009).
Heterocycles are the most appealing chemical structures
that offer promising biological activity and have manifested
potential in the drug discovery process. The biological
activity of heterocycles mainly arises from the heteroatoms
such as nitrogen sulfur and oxygen. This has drawn the
attention of chemists over the years for the designing and
exploration of heterocyclic structures based on structure-
activity relationship (Arora et al. 2016). Of particular
interest is the thiazole ring, which has demonstrated upsurge
interest in drug design and development of novel ther-
apeutic agents. The thiazole ring is integral in the structure
of many biologically active compounds; with sulfur and
nitrogen respectively at 1, 3 positions, this core moiety has
exerted various roles in the lead identification and optimi-
zation. It also plays an important role as a pharmacophoric
and bioisosteric element; as well as a spacer in molecular
frame. In addition, the presence of thiazole ring as a part of
drug structure can be determinant for its physicochemical
and pharmacokinetic properties (Ayati et al. 2015; Das et al.
2016).
Materials and Methods
Chemistry
All the required chemicals and solvents were of reagent
grade purchased from Sigma Aldrich and used without
further purification. The Melting points were determined
and recorded by open capillary method and are uncorrected.
The FT-IR spectra were recorded on Perkin Elmer FT-IR
spectrometer. 1H and 13C NMR data were collected by
using JEOL 400-MHz FT NMR spectrometer in CDCl3.
Chemical shifts (δ) are written in parts per million and are
referenced with respect to Tetra Methyl Silane as internal
standard. Mass spectra were obtained by using GCMS-
QP2010S SHIMADZU instrument.
Thiazole core has been featured in many drug molecules
(Siddiqui et al. 2009) which include Tiazofurin and dasa-
R2
Fig. 1 Marketed drugs
containing thiazole ring
NO2
H
O
R1
N
N
N
H2N
S
N
N
R3
HN
S
N
S
NH2
HN
S
Proposed new compounds
R1,R2 = Cl, Br, NO2, OMe
S
N
N
NH
Nizatidine
Peptic Ulcer and
gastrooesophageal
reflux
Amiphenazaloe
R3 = Eth-1-yl, Isoprop-1-yl,
Prop-1-yl, But-2-yl, Octan-3-yl
Antidote for opiate or
barbiturate overdose
Abafungin
Dermatomycoses

Medicinal Chemistry Research
General procedure for the synthesis of target
compounds 1a and 1b
7.42 (d, J 8.7 Hz, 2H), 7.32 (d, J 8.7 Hz, 2H), 6.86 (s, 1H),
4.08 (m, 1H), 1.32 (d, J 7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 164.79, 143.45, 140.94, 137.83, 135.05, 126.97,
124.45, 122.29, 120.57, 113.72, 99.53, 55.17, 20.39;
GCMS: m/z calcd for C18H16ClN3O2S 373.86, found 373
(M+).
Substituted aniline’s (1 g, 0.0107 mmol) and potassium
thiocyante (4.17 g, 0.043 mmol) were dissolved in 10 ml
of conc.HCl and the mixture was refluxed for overnight at
80 °C. The completion of the reaction was monitored by
TLC. The solid formed was filtered, dried and recrystallized
using ethanol to obtain the required thiourea with 78–80%
yield (Hantzsch and Weber 1887).
N-(4-chlorophenyl)-4-(4-nitrophenyl)-N-propylthiazol-2-
amine (3c)
Orange solid; Yield: 90%; m.p. 96–98 °C; FT-IR (cm−1):
1
General procedure for the synthesis of target
1280, 1596, 1530, 1341, 1494, 713; H NMR (400 MHz,
compounds 2a–2d
CDCl3): δ 8.22 (d, J 8.0 Hz, 2H), 7.96 (d, J 8.8 Hz, 2H),
7.42 (d, J 7.1 Hz, 2H), 7.33 (d, J 8.6 Hz, 2H), 6.87 (s, 1H),
3.97 (t, J 7.5 Hz, 2H), 1.74 (m, 2H), 0.97 (t, J 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 170.04, 149.24, 146.87,
143.27, 140.81, 132.98, 130.29, 128.30, 126.42, 124.08,
105.57, 54.64, 21.28, 11.41; GCMS: m/z calcd for
C18H16ClN3O2S 373.86, found 373 (M+).
A mixture of equimolar quantities of the earlier synthesized
thiourea (1 g, 0.0059 mmol) and substituted phenacyl bro-
mide (1.17 g, 0.0059 mmol) were taken in ethanol and
stirred for 2–5 min. The progress of the reaction was
monitored by TLC and the solid separated was filtered,
washed with cold ethanol, dried and recrystallized from
ethanol to get N,4-diphenylthiazol-2-amine in good yields
(Bikobo et al. 2017; Dighe et al. 2011).
N-sec-butyl-N-(4-chlorophenyl)-4-(4-nitrophenyl)thiazol-2-
amine (3d)
General procedure for the synthesis of target
compounds 3a–3t
Brown solid; Yield: 94%; m.p. 84–86 °C; FT-IR (cm−1):
1197, 1595, 1504, 1339, 1480, 711; H NMR (400 MHz,
1
CDCl3): δ 8.22 (d, J 8.2 Hz, 2H), 7.99 (d, J 8.2 Hz 2H),
7.47 (d, J 8.0 Hz, 2H), 7.24 (d, J 7.8 Hz, 2H), 6.80 (s, 1H),
2.15 (m, 1H), 1.77 (m, 2H), 1.26 (d, J 6.5 Hz, 3H), 1.05 (t,
J 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.34,
147.13, 141.96, 139.62, 135.02, 131.64, 130.51, 126.93,
124.08, 123.55, 105.25, 58.96, 28.19, 18.87, 11.78; GCMS:
m/z calcd for C19H18ClN3O2S 387.88, found 387 (M+).
An equimolar mixture of substituted N,4-diphenylthiazol-2-
amine (0.4 g, 0.0014 mmol) and alkyl halide (0.1 mL,
0.0014 mmol) were taken in DMF and stirred overnight at
r.t in the presence of K2CO3. The completion of the reaction
was monitored by TLC and quenched with cold water. The
solid which separated was filtered, dried and recrystallized
using ethanol to give corresponding alkylated product.
N-(4-chlorophenyl)-4-(4-nitrophenyl)-N-(octan-3-yl)thiazol-
2-amine (3e)
N-(4-chlorophenyl)-N-ethyl-4-(4-nitrophenyl)thiazol-2-
amine (3a)
Yellow solid; Yield: 92%; m.p. 76–78 °C; FT-IR (cm−1):
1
Yellow solid; Yield: 92%; m.p. 122–124 °C; FT-IR (cm−1):
1258, 1592, 1536, 1332, 1504, 708; H NMR (400 MHz,
1
1280, 1592, 1530, 1337, 1505, 711; H NMR (400 MHz,
CDCl3): δ 8.22 (d, J 8.9 Hz, 2H), 7.96 (d, J 8.9 Hz, 2H),
7.42 (d, J 8.7 Hz, 2H), 7.32(d, J 8.7 Hz, 2H), 6.86 (s, 1H),
2.16 (m, 1H), 1.34 (m, 10H), 0.87 (t, J 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3): δ 170.71, 149.25, 146.92,
143.82, 141.05, 132.84, 130.29, 128.25, 126.44, 124.10,
105.36, 56.54, 37.83, 30.36, 28.54, 23.93, 23.07, 14.24,
10.58; GCMS: m/z calcd for C23H26ClN3O2S 443.99, found
443 (M+).
CDCl3): δ 8.23 (d, J 8.9 Hz, 2H), 7.98 (d, J 8.9 Hz, 2H),
7.43 (d, J 8.7 Hz, 2H), 7.34 (d, J 8.7 Hz, 2H), 6.89 (s, 1H),
4.08 (q, J 7.1 Hz, 2H), 1.32 (t, J 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 169.56, 149.34, 146.81, 143.01,
140.98, 132.98, 130.34, 128.29, 126.48, 124.17, 105.48,
48.33, 13.19; GCMS: m/z calcd for C17H14ClN3O2S
359.83, found 359 (M+).
N-(4-chlorophenyl)-N-isopropyl-4-(4-nitrophenyl)thiazol-2-
amine (3b)
4-(4-bromophenyl)-N-ethyl-N-(4-methoxyphenyl)thiazol-2-
amine (3f)
Yellow solid; Yield: 90%; m.p. 118–122 °C; FT-IR (cm−1):
1282, 1592, 1530, 1337, 1505, 711; H NMR (400 MHz,
CDCl3): δ 8.22 (d, J 8.9 Hz, 2H), 7.96 (d, J 8.9 Hz, 2H),
Yellow solid; Yield: 90%; m.p. 126–128 °C; FT-IR (cm−1):
1396, 1609, 1593, 729; 1H NMR (400 MHz, CDCl3): δ 7.66
(d, J 8.6 Hz, 2H), 7.56 (d, J 8.6 Hz, 2H), 7.31 (d, J 9.0 Hz,
1

Medicinal Chemistry Research
2H), 6.95 (d, J 9.0 Hz, 2H), 6.67 (s, 1H), 3.83 (s, 3H), 2.9
(q, J 7.1 Hz, 2H), 0.99 (t, J 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 157.24, 150.32, 141.71, 138.54,
134.63, 128.21, 124.73, 114.50, 115.23, 110.54, 102.12,
56.90, 32.11, 14.62; GCMS: m/z calcd for C18H17BrN2OS
389.31, found 390 (M+).
(m, 1H), 1.48 (m, 2H), 1.52 (m, 2H), 1.33 (m, 2H) 1.09 (t, J
7.1 Hz, 3H), 0.96 (t, J 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 157.24, 150.32, 141.71, 138.54, 134.63, 128.21,
124.73, 114.50, 115.23, 110.54, 102.12, 62.52, 56.90,
32.11, 25.23, 18.03, 14.62, 9.62; GCMS: m/z calcd for
C24H29BrN2OS 473.47, found 474 (M+).
4-(4-bromophenyl)-N-isopropyl-N-(4-methoxyphenyl)
thiazol-2-amine (3g)
N-ethyl-N-(4-methoxyphenyl)-4-(4-nitrophenyl)thiazol-2-
amine (3k)
Yellow solid; Yield: 90%; m.p. 122–124 °C; FT-IR (cm−1):
1395, 1606, 1564, 725; 1H NMR (400 MHz, CDCl3): δ 7.66
(d, J 8.6 Hz, 2H), 7.56 (d, J 8.6 Hz, 2H), 7.31 (d, J 9.0 Hz,
2H), 6.95 (d, J 9.0 Hz, 2H), 6.67 (s, 1H), 3.83 (s, 3H), 2.04
(m, 1H), 1.22 (d, J 6.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 157.24, 150.32, 141.71, 138.54, 134.63, 128.21,
124.73, 114.50, 115.23, 110.54, 102.12, 56.90, 32.11,
14.62; GCMS: m/z calcd for C19H19BrN2OS 403.34, found
404 (M+).
Orange red solid; Yield: 90%; m.p. 86–88 °C; FT-IR
(cm−1): 1340, 1592, 1547, 1347, 1505; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J 8.9 Hz, 2H), 7.97 (d, J 8.9 Hz, 2H),
7.27 (d, J 8.9 Hz, 2H), 6.97 (d, J 8.9 Hz, 2H), 6.81 (s,1H),
3.94 (q, 7.1 Hz, 2H), 3.84 (s, 3H), 1.01 (t, J 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 171.40, 159.08, 149.39,
146.74, 141.34, 137.60, 129.13, 126.38, 124.07, 115.34,
105.33, 55.59, 54.68, 11.47; GCMS: m/z calcd for
C18H17N3O3S 355.41, found 355 (M+).
4-(4-bromophenyl)-N-(4-methoxyphenyl)-N-propylthiazol-
2-amine (3h)
N-isopropyl-N-(4-methoxyphenyl)-4-(4-nitrophenyl)thiazol-
2-amine (3l)
Yellow solid; Yield: 94%; m.p. 118–120 °C; FT-IR (cm−1):
1395, 1610, 1564, 725; 1H NMR (400 MHz, CDCl3): δ 7.71
(d, J 8.5 Hz, 2H), 7.48 (d, J 8.5 Hz, 2H), 7.27 (d, J 7.2 Hz,
2H), 6.96 (d, J 8.8 Hz, 2H), 6.59 (s, 1H), 3.93 (t, J 7.5 Hz,
2H), 3.84 (s, 3H), 1.71 (m, 2H), 0.95 (t, J 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 171.41, 158.71, 150.36,
147.07, 137.73, 131.50, 129.38, 127.82, 121.10, 115.37,
101.69, 55.72, 54.66, 20.98, 11.40; GCMS: m/z calcd for
C19H19BrN2OS 403.34, found 404 (M+).
Orange red solid; Yield: 88%; m.p. 80–82 °C; FT-IR
(cm−1): 1335, 1593, 1531, 1331, 1505; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J 8.9 Hz, 2H), 7.97 (d, J 8.9 Hz, 2H),
7.27 (d, J 8.9 Hz, 2H), 6.97 (d, J 8.9 Hz, 2H), 6.81 (s,1H),
3.84 (s, 3H), 3.94 (m, 1H), 1.01 (d, J 7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3): δ 171.52, 159.25, 149.46, 146.36,
140.95, 137.46, 129.16, 126.41, 124.14, 115.40, 105.12,
55.74, 50.47, 21.20; GCMS: m/z calcd for C19H19N3O3S
369.44, found 369 (M+).
N-sec-butyl-4-(4-bromophenyl)-N-(4-methoxyphenyl)
thiazol-2-amine (3i)
N-(4-methoxyphenyl)-4-(4-nitrophenyl)-N-propylthiazol-2-
amine (3m)
Yellow solid; Yield: 94%; m.p. 114–116 °C; FT-IR (cm−1):
1395, 1608, 1565, 725; 1H NMR (400 MHz, CDCl3): δ 7.66
(d, J 8.4 Hz, 2H), 7.50 (d, J 8.4 Hz, 2H), 7.29 (d, J 7.2 Hz,
2H), 6.91 (d, J 8.8 Hz, 2H), 6.69 (s, 1H), 3.81 (s, 3H), 1.69
(m, 1H), 1.20 (m, 2H), 1.01 (d, J 6.6 Hz, 3H), 0.86 (t, J
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.64,
149.09, 138.38, 131.98, 130.40, 129.55, 128.59, 127.62,
122.31, 119.79, 102.27, 57.93, 28.28, 18.91, 11.70; GCMS:
m/z calcd for C20H21BrN2OS 417.36 found 418 (M+).
Orange red solid; Yield: 90%; m.p. 76–78 °C; FT-IR
(cm−1): 1332, 1593, 1536, 1336, 1504; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J 8.9 Hz, 2H), 7.97 (d, J 8.9 Hz, 2H),
7.27 (d, J 8.9 Hz, 2H), 6.97 (d, J 8.9 Hz, 2H), 6.81 (s,1H),
3.94 (t, J 7.1 Hz, 2H), 3.84 (s, 3H), 1.71 (m, 2H), 0.97 (t, J
7.4 Hz, 3H); (100 MHz, CDCl3): δ 171.52, 159.25, 149.46,
146.36, 140.95, 137.46, 129.16, 126.41, 124.14, 115.40,
105.12, 55.74, 54.47, 21.19, 11.39; GCMS: m/z calcd for
C19H19N3O3S 369.44, found 369 (M+).
4-(4-bromophenyl)-N-(4-methoxyphenyl)-N-(octan-3-yl)
thiazol-2-amine (3j)
N-sec-butyl-N-(4-methoxyphenyl)-4-(4-nitrophenyl)thiazol-
2-amine (3n)
Yellow solid; Yield: 92%; m.p. 110–112 °C; FT-IR (cm−1):
1390, 1610, 1565, 730; 1H NMR (400 MHz, CDCl3): δ 7.66
(d, J 8.9 Hz, 2H), 7.49 (d, J 8.9 Hz, 2H), 7.32 (d, J 8.7 Hz,
2H), 6.93 (d, J 8.7 Hz, 2H), 6.48 (s, 1H), 3.86 (s, 3H), 2.92
Orange red solid; Yield: 94%; m.p. 72–74 °C; FT-IR
(cm−1): 1335, 1593, 1531, 1331, 1505; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J 8.9 Hz, 2H), 7.97 (d, J 8.9 Hz, 2H),
7.27 (d, J 8.9 Hz, 2H), 6.97 (d, J 8.9 Hz, 2H), 6.81 (s,1H),

Medicinal Chemistry Research
3.84 (s, 3H), 2.95 (m,1H), 1.72 (m, 2H), 1.25 (d, J 7.4 Hz
3H), 0.96 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
171.51, 159.01, 149.46, 146.73, 141.24, 137.57, 129.10,
126.44, 123.99, 115.34, 105.30, 55.54, 54.67, 31.01, 21.19,
11.47; GCMS: m/z calcd for C20H21N3O3S 383.46, found
383 (M+).
1.73 (m, 2H), 0.97 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.46, 157.71, 132.93, 132.32, 132.04, 127.64,
127.48, 123.47, 115.17, 114.76, 100.18, 55.72, 31.08,
21.19; GCMS: m/z calcd for C18H16BrClN2S 407.76, found
408 (M+).
N-sec-butyl-4-(4-bromophenyl)-N-(4-chlorophenyl)thiazol-
2-amine (3s)
N-(4-methoxyphenyl)-4-(4-nitrophenyl)-N-(octan-3-yl)
thiazol-2-amine (3o)
Yellow solid; Yield: 88%; m.p. 82–84 °C; FT-IR (cm−1):
1376, 1530, 1512; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J
8.6 Hz, 2H), 7.50 (d, J 8.6 Hz, 2H), 7.35 (d, J 8.8 Hz, 2H),
7.30 (d, J 8.8 Hz, 2H), 6.79 (s, 1H), 2.91 (m, 1H), 1.69 (m,
2H), 1.23 (d, J 7.4 Hz, 3H), 1.01 (t, J 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 164.64, 149.09, 138.38,
131.98, 130.40, 129.55, 128.59, 127.62, 122.31, 119.79,
102.27, 57.93, 28.28, 18.91, 11.70; GCMS: m/z calcd for
C19H18BrClN2S 421.78, found 422 (M+).
Orange red solid; Yield: 90%; m.p. 68–70 °C; FT-IR
(cm−1): 1335, 1593, 1531, 1331, 1505; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J 8.9 Hz, 2H), 7.97 (d, J 8.9 Hz, 2H),
7.27 (d, J 8.9 Hz, 2H), 6.97 (d, J 8.9 Hz, 2H), 6.81 (s,1H),
3.84 (s, 3H), 2.95 (m,1H), 1.52 (m, 2H), 1.48 (m, 2H), 1.34
(m, 2H), 1.28 (m, 2H), 1.29 (m, 2H), 1.03 (t, J 7.4 Hz, 3H),
0.96 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
171.48, 158.94, 149.43, 146.77, 141.28, 137.60, 129.15,
126.47, 124.07, 115.29, 105.23, 59.64, 55.47, 33.93, 31.03,
25.79, 24.48, 21.08, 17.93, 11.37; GCMS: m/z calcd for
C24H29N3O3S 439.57, found 439 (M+).
4-(4-bromophenyl)-N-(4-chlorophenyl)-N-(octan-3-yl)
thiazol-2-amine (3t)
4-(4-bromophenyl)-N-(4-chlorophenyl)-N-ethylthiazol-2-
amine (3p)
Yellow solid; Yield: 90%; m.p. 76–78 °C; FT-IR (cm−1):
1376, 1530, 1512; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
8.6 Hz, 2H), 7.49 (d, J 8.6 Hz, 2H), 7.41 (d, J 8.8 Hz, 2H),
7.32 (d, J 8.8 Hz, 2H), 6.64 (s, 1H), 3.64 (m, 1H), 1.73 (m,
2H), 1.52(m, 2H), 1.33(m, 2H), 1.30(m, 2H), 1.28(m, 2H),
1.09 (t, J 7.4 Hz, 3H), 0.97 (t, J 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 171.68, 156.58, 150.29, 133.72,
132.17, 131.76, 127.70, 122.30, 121.74, 114.74, 101.91,
55.53, 32.02, 31.71, 31.04, 29.79, 22.82, 21.00, 14.13;
GCMS: m/z calcd for C23H26BrClN2S 477.89, found 488
(M+).
Yellow solid; Yield: 90%; m.p. 94–96 °C; FT-IR (cm−1):
1376, 1530, 1512; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
8.6 Hz, 2H), 7.49 (d, J 8.6 Hz, 2H), 7.41 (d, J 8.8 Hz, 2H),
7.32 (d, J 8.8 Hz, 2H), 6.64 (s, 1H), 3.93 (q, J 7.1 Hz, 2H),
1.07 (t, J 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
168.46, 157.71, 132.93, 132.32, 132.04, 127.64, 127.48,
123.47, 115.17, 114.76, 100.18, 45.72, 12.62; GCMS: m/z
cacd for C17H14BrClN2S 393.73, found 394 (M+).
4-(4-bromophenyl)-N-(4-chlorophenyl)-N-isopropylthiazol-
2-amine (3q)
Biological activity
Antibacterial activity
Yellow solid; Yield: 94%; m.p. 90–92 °C; FT-IR (cm−1):
1376, 1530, 1512; 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J
8.6 Hz, 2H), 7.51 (d, J 8.6 Hz, 2H), 7.32 (d, J 8.8 Hz, 2H),
7.27 (d, J 8.8 Hz, 2H), 6.83 (s, 1H), 3.80 (m, 1H), 1.07 (d, J
7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 164.03,
150.37, 138.93, 133.49, 131.95, 130.06, 129.50, 127.82,
121.95, 119.50, 102.63, 43.37, 14.15; GCMS: m/z calcd for
C18H16BrClN2S 407.76, found 408 (M+).
The newly synthesized compounds were screened for their
antibacterial activity against bacterial strains by macro
dilution
broth
method.
Different
concentrations
(0.125–256 μg/mL) of the synthesized compounds were
added to the respectively labeled sterile Mueller Hinton
Broth (MHB) medium tubes. The tubes were inoculated
with 1 mL lag phase cultures of the Gram-positive bacteria
Staphylococcus aureus and Bacillus subtilis and that of the
Gram-negative bacteria Escherichia coli and Pseudomonas
aeruginosa. The inoculated tubes were incubated at 37 °C
for 24 h followed by observing the inhibition of growth of
the test bacteria in the tubes. The MIC was determined as
the lowest concentration of the synthesized compounds
containing tube showing no visible growth of the test
bacteria.
4-(4-bromophenyl)-N-(4-chlorophenyl)-N-propylthiazol-2-
amine (3r)
Yellow solid; Yield: 86%; m.p. 86–88 °C; FT-IR (cm−1):
1376, 1530, 1512; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
8.6 Hz, 2H), 7.49 (d, J 8.6 Hz, 2H), 7.41 (d, J 8.8 Hz, 2H),
7.32 (d, J 8.8 Hz, 2H), 6.64 (s, 1H), 4.01 (t, J 7.1 Hz, 2H),

Medicinal Chemistry Research
Antibacterial activity against drug-resistant bacteria
Cytotoxicity
The active compounds against the sensitive bacterial strains
were screened for antibacterial activity against resistant
bacterial strains by macro dilution broth method. Different
concentrations (25–500 mg/mL) of the compounds were
added to the respectively labeled sterile MHB medium
tubes. The tubes were inoculated with 1 mL lag phase cul-
tures of the Methicillin-resistant S. aureus and (MDR)
Multidrug-resistant P. aeruginosa obtained from Kuvempu
University, Shimoga. The inoculated tubes were incu-
bated at 37 °C for 24 h followed by observing the inhi-
bition of growth of the test bacteria in the tubes.
Ciprofloxacin was taken as the standard drug. The MIC
was determined as the lowest concentration of the syn-
thesized compounds containing tube showing no visible
growth of the test bacteria.
To evaluate the effects of active compounds on cell viabi-
lity, Human Embryonic kidney Cells (HEK293) were used
to perform the assay by MTT method. MTT is a colori-
metric assay that measures the reduction of yellow 3-(4,5-
dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide
(MTT) by mitochondrial succinate dehydrogenase. The
cells were seeded at a density of ~5 × 103 cells/well in a 96-
well flat-bottom micro plate and maintained at 37 °C in 95%
humidity and 5% CO2 for overnight. Different concentra-
tions (600, 300, 150, 75, 37.5, 18.75 μg/mL) of samples
were treated and the cells were incubated for 48 h. The cells
in well were washed twice with phosphate buffer solution
and 20 μL of the MTT staining solution was added to each
well and plate was incubated at 37 °C. After 4 h, 100 μL of
Dimethyl sulfoxide (DMSO) was added to each well to
dissolve the formazan crystals and absorbance was recorded
at a 570 nm using micro plate reader.
Antifungal activity
The prepared compounds were studied by macrodilution
broth method for their antifungal activity. Different con-
centrations (0.125–256 μg/mL) of the synthesized com-
pounds were added to the respectively labeled sterile
saboraud dextrose broth tubes. The tubes were inoculated
with lag phase cultures of the fungi A. flavus, Tricho-
derma harzianum, Penicillium chrysogenum and yeast C.
albicans. The inoculated tubes were incubated at 27 °C for
48 h followed by observing the inhibition of growth of the
test fungi in the tubes. The MIC was determined as the
lowest concentration of the synthesized compounds con-
taining tube showing no visible growth of the test fungi.
Molecular docking studies
Surflex-Dock was used to investigate detailed inter-
molecular interactions between the ligand and the target
protein. Three-dimensional structure information on the
target protein was taken from the Protein Data Bank
(PDB) entry 4FDO. The proteins were prepared for
docking by adding polar hydrogen atom with
Gasteiger–Huckel charges and water molecules were
removed. The 3D structure of the ligands were generated
by the SKETCH module implemented in the SYBYL
program Tripos International (2012) and its energy-
minimized confirmation was obtained with the help of
the Tripos force field using Gasteiger–Huckel charges
(Dolomanov et al. 2003) and molecular docking was
performed with Surflex-Dock program that is interfaced
with Sybyl-X 2.0. (Sheldrick 1997) and other mis-
cellaneous parameters were assigned with the default
values given by the software.
Anti-inflammatory activity by protein denaturation assay
Anti-inflammatory activity was carried out by protein
denaturation method. Aspirin was used as the standard drug.
The reaction mixture consisted of 50 µL of 1% egg albumin
in PBS and different concentrations (0, 100, 200 µg/mL) of
either test samples or the standard drug were added and final
volume was made upto 2 ml with PBS and incubated for
15 min at room temperature. Denaturation was induced by
keeping at 70 °C in hot water bath for 10 min. The absor-
bance was measured at 660 nm (Labman UV Visible
Spectrophotometer). The percent of inhibition of protein
denaturation was calculated using the following formula:
Results and discussion
Chemistry
The new series of N,4-diphenylthiazol-2-amine derivatives
3a–3t (Table 1) were synthesized by a three-step synthetic
protocol involving eco-friendly conditions. In the initial
step, potassium thiocyante and substituted anilines were
used to prepare the required thioureas. These thioureas
when treated with phenacyl bromide underwent Hantzsch
cyclization rapidly without the use of any catalyst in a very
short time and at room temperature. The product obtained
% inhibition of Protein denaturation activity ¼
½ðAc À AtÞ=AcŠ  100
where, Ac and At are the absorbances of control and test
sample, respectively.

Medicinal Chemistry Research
1
Table 1 Scope of the reaction
For 3m (R = -OMe, R1 = -NO2, R2 = -Propyl), the H
NMR spectrum showed a signal at δ 6.81 ppm as a singlet
which can be ascertain to C-5 proton of thiazole ring. The
prop-1-yl substituent appeared as a triplet corresponding to
the two protons of CH2 linked to nitrogen at δ 3.94 ppm,
multiplet corresponding to two protons of CH2 at δ 1.71
ppm and triplet corresponding to three protons of CH3 at δ
0.97 ppm. The three protons of O-CH3 resonated as singlet
at δ 3.84 ppm. The GCMS spectrum showed molecular ion
peak at 370[M+] further supported for the formation of
compound 3m. The remaining compounds are in good
agreement with the expected spectral data.
Compounds
R
R1
R2
3a
3b
3c
3d
3e
3f
-Cl
-NO2
-NO2
-NO2
-NO2
-NO2
-Br
Eth-1-yl
-Cl
Isoprop-1-yl
Prop-1-yl
But-2-yl
-Cl
-Cl
-Cl
Octan-3-yl
Eth-1-yl
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-OMe
-Cl
3g
3h
3i
-Br
Isoprop-1-yl
Prop-1-yl
But-2-yl
-Br
-Br
3j
-Br
Octan-3-yl
Eth-1-yl
X-ray diffraction studies
3k
3l
-NO2
-NO2
-NO2
-NO2
-NO2
-Br
Isoprop-1-yl
Prop-1-yl
But-2-yl
Single crystal for compound (3c) was developed by slow
evaporation of ethanol at room temperature. It crystal-
lized under a triclinic system with the space group P-1.
The unit cell dimensions are as follows: a = 9.3433(3) Å,
b = 10.3778(3) Å, c = 10.6275(3) Å, α = 109.6690(10)°,
β = 100.147(2)°, γ = 102.6970(10)°, Z = 2. Data collec-
tion and reduction were performed using Bruker SMART
X2S benchtop crystallographic system, APEX2 software
was used for preliminary determination of the unit cell.
Determination of integrated intensities and unit cell
refinement were performed using SAINT (Smart and
Saint 2001). OLEX2 (version1.2) (Dolomanov et al.
2003) and SHELXS-97(Sheldrick 1997) was used to
solve and refine the crystal structures. Bond lengths and
angles are within the normal ranges [R]. The X-ray
structure parameters and refinement for the compound are
presented in Tables 2–4. The ORTEP and packing dia-
gram of compound (3c) is portrayed in Fig. 2.
3m
3n
3o
3p
3q
3r
Octan-3-yl
Eth-1-yl
-Cl
-Br
Isoprop-1-yl
Prop-1-yl
But-2-yl
-Cl
-Br
3s
3t
-Cl
-Br
-Cl
-Br
Octan-3-yl
was 2, 4-disubstituted thiazole with amine functionality at
second position of thiazole ring (Hantzsch and Weber 1887;
Bikobo et al. 2017; Dighe et al. 2011). The last step
involved nucleophilic substitution yielding the alkyl-
substituted final products (Scheme 1). The overall syn-
thetic protocol was designed to be carried out in eco-
friendly conditions requiring short time with excellent yield
which has been achieved.
The structures of the title compounds were confirmed by
using 1H NMR, 13C NMR, FT-IR, and GCMS spectral
methods. Also, single-crystal X-ray diffraction study of the
derivative 3c confirmed the formation of the designed
moiety. The spectral data of newly synthesized compounds
3a–3t are provided in the experimental section and are in
agreement with the desired structures of the compounds.
In case of compound 3a (R = -Cl, R1 = -NO2, R2 = -Ethyl),
Biological evaluation
All the compounds prepared herein were screened for
their potential in vitro antibacterial activity against Gram-
positive bacteria S. aureus and B. subtilis, Gram-negative
bacteria E. coli and P. aeruginosa, antifungal activity
against A. flavus, T. harzianum, P. chrysogenum and yeast
C. albicans by macrodilution broth method and anti-
inflammatory activity by protein denaturation assay
(Cockerill et al. 2012; Leelaprakash and Dass 2011). The
compounds which showed good activity against the sen-
sitive bacterial strains were further screened against
Methicillin-resistant S. aureus and (MDR) Multidrug-
resistant P. aeruginosa.
1
the H NMR spectrum showed signal at δ 6.89 ppm as a
singlet of thiazole C-5 proton. The characteristic quartet-triplet
pattern of the ethyl chain appeared at δ 4.08 and δ 1.32 ppm,
respectively. The absence of singlet proton around δ 4.0–4.5
ppm which corresponds to the N-H proton confirmed the
formation of 3a. It was further supported by recording 13C
NMR spectrum and the signals in the spectrum accounted for
all the C-atoms present in the compound. The GCMS spec-
trum of 3a showed molecular ion peak at 360[M+] which is in
agreement with its respective molecular formula
C17H14ClN3O2S.
Antibacterial studies
The antibacterial screening of all the synthesized com-
pounds against both Gram-positive and Gram-negative

Medicinal Chemistry Research
O
Scheme 1 Synthetic route for
the target compounds 3a–3t
H
N
R
Br
NH2
KSCN
S
R1
NH2
R = -OMe, -Cl
R
reflux overnight
R = -OMe, -Cl
1a-1b
R1 = -NO2, -Br
EtOH
r.t, 5 min
MeO
S
Cl
MeO
S
Cl
NH
NH
NH
NH
S
S
N
N
N
N
Br
2d
NO2
2c
Br
2b
NO2
2a
DMF, K2CO3 , r.t
R2 Br
MeO
MeO
Cl
Cl
N
N
N
R2
N
N
R2
N
S
R2
R2
S
S
S
N
N
NO2
Br
3p-3t
Br
3f-3j
NO2
3a-3e
3k-3o
R2 =
Eth-1-yl, Isoprop-1-yl, Prop-1-yl , But-2-yl, Octan-3-yl
human pathogenic bacterial strains showed moderate to
good activity and was compared with the standard anti-
biotics Ciprofloxacin and Streptomycin. Screening results
are summarized in Table 5. Compounds 3d and 3o showed
good activity in comparison to the other molecules syn-
thesized and are also similar with both of the standards
against all the bacterial strains. Compounds 3e, 3h, 3l, 3m
and 3t showed good activity whereas 3b, 3c, 3g, 3i, 3j, 3k
and 3r have appeared moderate. The molecules having an
electron-donating as well as electron-accepting groups in
their framework with branched alkyl chains on the Nitrogen
atom exhibited better activity.

Medicinal Chemistry Research
Table 2 Crystal data, data collection and structure refinement of
compound 3c
Table 3 Bond lengths for 3c
Atom
Atom
Length/Å
Atom
Atom
Length/Å
Empirical formula
C18H16ClN3O2S
C(7B)
C(7B)
C(8B)
C(8A)
C(8A)
C(7A)
O(2B)
O(2A)
C(14)
C(14)
C(1)
C(8B)
N(1)
1.428(8)
1.496(4)
1.590(2)
1.484(9)
1.560(3)
1.475(5)
1.100(3)
1.245(17)
1.377(2)
1.391(2)
1.374(3)
1.377(3)
1.431(2)
1.357(2)
1.385(2)
1.466(2)
C(5)
C(4)
C(6)
C(15)
C(17)
N(2)
C(18)
N(3)
N(1)
S(1)
1.368(3)
1.384(3)
1.371(2)
1.374(2)
1.467(2)
1.391(2)
1.300(19)
1.354(2)
1.740(16)
1.367(3)
1.733(18)
1.384(3)
1.714(19)
1.380(2)
1.215(2)
Formula weight
373.85
C(5)
Temperature/K
293(2)
C(9B)
C(7A)
C(9A)
N(1)
C(16)
C(16)
C(16)
C(13)
C(10)
C(10)
C(10)
C(4)
Crystal system
Triclinic
Space group
P-1
a/Å
9.3433(3)
10.3778(3)
10.6275(3)
109.6690(10)
100.147(2)
102.6970(10)
910.84(5)
2
b/Å
N(2)
c/Å
N(2)
α/°
β/°
γ/°
C(15)
C(13)
C(6)
C(3)
Cl(1)
C(2)
S(1)
C(4)
Volume/Å3
C(1)
C(2)
C(3)
Z
C(1)
N(1)
C(11)
C(17)
N(2)
ρ
calcg/cm3
μ/mm−1
1.363
C(12)
C(12)
C(12)
C(11)
N(3)
C(18)
O(1)
0.341
F(000)
Crystal size/mm3
388.0
C(13)
0.180 × 0.135 × 0.070
MoKα (λ = 0.71073)
4.22–60.84
Radiation
2Θ range for data collection/°
Index ranges
molecules with an electron-donating as well as electron-
accepting groups in their framework along with straight
alkyl chain functionality on Nitrogen atom have shown
enhanced results. Screening results are summarized in
Table 6.
−13 ≤ h ≤ 13, −14 ≤ k ≤ 14, −15 ≤
l ≤ 14
Reflections collected
19465
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
5450 [Rint = 0.0232, Rsigma = N/A]
5450/0/264
1.057
Anti-inflammatory activity by protein denaturation
assay
Final R indexes [I > = 2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å−3 0.55/−0.63
R1 = 0.0506, wR2 = 0.1345
R1 = 0.0669, wR2 = 0.1472
The anti-inflammatory activities of the target compounds
3a–3t were evaluated using protein denaturation assay.
Aspirin was used as the standard drug and measured in
terms of the percent of inhibition of protein denaturation.
Amongst all the tested compounds 3j and 3o have showed
good activity compared with the standard whereas 3f–3i and
3k–3n are moderately active. The presence of electron-
donating group and branched alkyl chain might be the
reason for the compounds to show enhanced activity. The
3e–3o series also contain the same electron-donating group
and hence has showed comparatively good activity whereas
rest of them appeared moderate. Screening results are
summarized in Table 7.
CCDC No 1904641
3b, 3d, 3e, 3h, 3k, 3l, 3m, 3o and 3t were further eval-
uated for their in vitro activity against Methicillin-resistant
S. aureus and (MDR) Multidrug-resistant P. aeruginosa. 3o
exhibited good activity with MIC same as that of the
standard against MRSA whereas 3d showed 1.5 to 2 fold
greater MIC’s for both the strains in comparison with the
standard. Rest of the molecules have appeared moderate.
Antifungal studies
Compounds 3a–3t were screened for their antifungal
activity against four strains. Nystatin and Fluconazole
were used as a standard for the comparison of antifungal
activity. Among the tested compounds 3a, 3c, 3k and 3m
have emerged active against all the tested microorganisms
with respect to both the standards. 3b, 3f, 3h, 3p and 3r
have exhibited good activity. All the rest compounds are
moderate against all the fungal strains. The synthesized
Cytotoxicity of the synthesized compounds
The synthesized compounds which exhibited good activity
against the bacterial and fungal strains were tested for their
toxicity against normal cell lines. Human Embryonic kidney
(HEK293) cells have been employed to estimate their
toxicity. From Table 8, the tested compounds have exhib-
ited moderate to low levels of cytotoxicity with IC50 values

Medicinal Chemistry Research
Table 4 Bond angles for 3c
Atom
Atom
Atom
Angle/˚
Atom
Atom
Atom
Angle/˚
C(8B)
C(7B)
C(7A)
N(1)
C(7B)
C(8B)
C(8A)
C(7A)
C(14)
C(1)
N(1)
113.20(5)
C(5)
C(4)
C(6)
C(3)
C(11)
C(17)
C(2)
C(15)
C(18)
N(1)
N(1)
N(1)
N(1)
N(1)
N(1)
N(2)
N(2)
N(2)
N(2)
N(2)
N(2)
N(3)
S(1)
Cl(1)
C(5)
119.43(15)
120.43(18)
119.45(18)
111.11(13)
118.89(16)
119.88(17)
118.61(16)
121.04(15)
118.45(14)
122.50(2)
117.10(2)
117.80(2)
120.50(2)
31.90(2)
C(9B)
C(9A)
C(8A)
C(13)
C(2)
111.80(11)
101.80(13)
109.30(5)
C(1)
C(4)
C(2)
C(12)
C(16)
C(1)
S(1)
C(15)
C(6)
121.57(17)
119.89(16)
120.27(17)
119.84(16)
114.96(15)
125.90(15)
119.14(14)
118.90(18)
121.87(15)
118.36(15)
119.75(16)
118.00(15)
120.77(14)
121.21(15)
125.18(15)
115.47(12)
119.34(12)
121.45(17)
119.12(16)
C(18)
C(3)
C(6)
C(1)
N(1)
C(16)
C(17)
C(10)
C(10)
C(1)
C(14)
C(13)
C(1)
C(2)
C(1)
N(1)
C(11)
C(11)
N(3)
C(12)
C(12)
C(12)
C(5)
N(3)
C(13)
C(13)
C(6)
C(7A)
C(7A)
C(7B)
C(7B)
C(7B)
O(1)
C(4)
C(10)
C(1)
C(15)
C(15)
C(17)
C(18)
C(18)
C(14)
N(3)
C(16)
C(16)
C(16)
C(13)
C(13)
C(13)
C(10)
C(10)
C(10)
C(4)
C(17)
N(2)
C(7A)
O(2B)
O(2B)
O(1)
N(2)
120.50(14)
23.00(2)
C(14)
C(12)
C(12)
N(1)
O(2A)
O(2A)
C(16)
C(16)
C(16)
C(12)
C(10)
122.50(4)
117.00(2)
118.99(16)
118.40(4)
110.18(13)
88.28(8)
O(2B)
O(1)
N(3)
S(1)
O(2A)
C(10)
C(11)
N(1)
S(1)
C(3)
C(5)
C(3)
C(4)
Cl(1)
Fig. 2 ORTEP and packing
diagram for compound 3c
of the human embryonic kidney cells in the range of
360.8–523.8 μg/mL and none of the compounds exhibited
any significant cytotoxic effects, suggesting good potential
for their in vivo use.
against B. subtilis and E. coli with MIC same as that of
streptomycin and Ciprofloxacin whereas 3o was active
against S. aureus and E. coli. They have also shown good
activity against drug-resistant strains of bacteria. Both
these compounds possess -NO2 group in one of the phenyl
rings and the other having a -Cl and -OMe group,
respectively. Rest of the compounds have showed good to
moderate activity. Amongst the synthesized compounds
containing -OMe and -NO2 groups, eight of them have
showed better activity, whereas the compounds containing
only -NO2 groups appear good comparatively. The com-
pounds without both the groups exhibited lesser activity
than the rest of the compounds. These results suggested
Structure-activity relationship study
The structure-activity relationship study showed that the
substituents on the phenyl rings at 2, 4 positions of thia-
zole play a decisive role in the activity shown by the
compounds. As can be seen, compounds 3d and 3o
showed better activity with MIC ranging between
2.0–4.0 µg/mL. 3d appeared as a promising candidate

Medicinal Chemistry Research
Table 5 Minimum inhibition concentration (MIC) of compounds 3a–3t using standard antibiotics for antibacterial activity
Test organism Staphylococcus
Bacillus
subtilis
Escherichia coli Pseudomonas
aeruginosa
Staphylococcus
aureus (MRSA)
Pseudomonas
aeruginosa (MDR)
aureus
3a
64
16
16
4
64
16
8
128
16
16
2
64
8
nd
nd
3b
250
nd
300
nd
3c
32
4
3d
2
75
100
250
nd
3e
4
8
4
8
200
nd
3f
32
16
8
128
32
8
64
16
8
64
16
8
3g
nd
nd
3h
200
nd
250
nd
3i
32
32
8
16
32
32
4
16
64
16
8
32
32
32
4
3j
nd
nd
3k
250
200
150
nd
400
150
200
nd
3l
4
3m
4
4
8
8
3n
64
2
32
4
32
2
64
4
3o
50
75
3p
64
32
32
64
4
64
16
16
32
8
32
32
16
64
8
64
16
32
128
4
nd
nd
3q
nd
nd
3r
nd
nd
3s
nd
nd
3t
250
50
200
50
Ciprofloxacin
Streptomycin
2
2
2
2
2
2
2
2
–
–
nd not determined
that the compounds containing a strongly electron-
donating (-OMe) and electron-withdrawing groups
(-NO2) in the scaffold have exhibited better antibacterial
activity. The branched longer chains have exhibited better
activity compared with the smaller alkyl groups.
With regards to the antifungal activity, 3a, 3c, 3k and
3m have shown excellent activity with MIC value
(0.5–1.0 µg/mL) lower than that of the standards used.
Rest of the compounds have showed moderate activity.
Infact 3k has appeared very potent against C. albicans
with MIC 0.5 µg/mL. The SAR study depicts that the
compounds having -NO2 group have showed better
activity than the rest of them. One peculiar thing observed
was the compounds having smaller alkyl chains have
appeared potent and the activity decreases as the
branching in the chain increases.
In silico studies
To gain better understanding on the potency of synthesized
compounds and guide further SAR studies we proceeded to
examine the interaction of these compounds using mole-
cular docking studies. These studies also support the results
of the in vitro activity. Docking studies were performed on
the X-ray crystal structure of the dihydropteroate synthetase
(DHPS) complexed with HO-CH2-pterin-pyrophosphate
from S. aureus (PDB ID: 1AD4) and C. albicans dihy-
drofolate reductase (PDB ID: 1AI9) from C. albicans.
Molecular docking was used to explain the binding mode of
the compounds and provide information for further structural
optimization. The docking study was obtained from the PDB
by using Surflex-Dock programme of Sybyl-X software
(Gasteiger and Marsili 1980; Tripos International (2012)).
Structure-activity relationship analysis of anti-
inflammatory activity suggests that only those compounds
which possessed a -OMe and -NO2 group along with
branched longer alkyl chain in the scaffold showed good
activity in comparison with the standard Aspirin. 3j exhib-
ited IC50 285 µg/mL whereas 3o has an IC50 293 µg/mL. An
exception to this is 3f which has an IC50 274 µg/mL with a
smaller ethyl group in its scaffold.
Docking studies of the title compounds with
dihydropteroate synthetase (DHPS) complexed with
HO-CH2-pterin-pyrophosphate from S. aureus (PDB
ID: 1AD4)
All the compounds were docked into the active site of the
DHPS (Fig. 3), the predicted binding energies and the

Medicinal Chemistry Research
Table 6 Minimum inhibition
concentration (MIC) of
compounds 3a–3t using
standard antibiotics for
antifungal activity
Test organism Aspergillus flavus Trichoderma harzianum Penicillium
Candida albicans
chrysogenum
3a
1
1
2
1
3b
6
8
8
4
3c
2
2
2
1
3d
16
64
8
16
64
8
16
64
4
8
3e
32
4
3f
3g
16
8
8
16
4
16
8
3h
16
16
64
1
3i
16
32
1
32
64
1
32
32
0.5
8
3j
3k
3l
32
2
16
2
8
3m
2
1
3n
16
64
8
16
64
16
16
4
16
64
8
8
3o
32
4
3p
3q
16
8
16
8
32
16
8
3r
3s
16
64
2
16
64
2
16
64
2
3t
32
4
Nystatin
Fluconazole
4
4
4
1
Table 7 IC50 (µg/ml) of compounds 3a–3t for anti-inflammatory
Table 8 Cytotoxicity of the active compounds against human
activity by protein denaturation assay
embryonic kidney cells using MTT assay
Sample name
IC50 (µg/mL)
Sample name
IC50 (µg/mL)
Compound name IC50 (µg/mL) Compound name IC50 (µg/mL)
3a
120
104
98
3k
3l
198
201
210
211
293
98
3a
3c
3d
3e
461.4
360.8
396.1
523.8
3k
3l
395.4
410.1
386.6
402.4
3b
3c
3m
3n
3o
3p
3q
3r
3m
3o
3d
95
3e
100
274
210
188
187
285
315
3f
3g
94
3h
80
raised from the nitrogen atom of nitro group with hydrogen
atom of ARG239 (-N-H-ARG239, 2.83 Å).
3i
3s
3t
100
120
3j
The binding interaction of standard Ciprofloxacin with
dihydropteroate synthetase active sites showed three
bonding interactions and the docked view of the same has
been depicted in Fig. 5. The comparative molecular
docking study of synthesized compounds and standard
Ciprofloxacin drug highlighted that the synthesized
compounds exhibited high C-score values binding to the
enzyme in similar a manner as that of Ciprofloxacin. Most
of the synthesized compounds have the same H-bonding
interaction with same amino acid LYS203 as that of
Ciprofloxacin.
Aspirin
observed C-score values of all the compounds are ranging
from 4.64 to 9.75 which are listed in Table 9. As depicted in
Fig. 4, compound 3d makes three hydrogen bonding inter-
actions at the active site of the enzyme (PDB ID: 1AD4).
Among those two interactions were of oxygen atoms of nitro
group present on the phenyl ring attached to C-4 of thiazole
ring with hydrogen atoms of ASN103 and LYS203 (-O-H-
ASN103, 2.44 Å; -O-H-LYS203, 2.15 Å) and the other one
Compound 3k makes five hydrogen bonding interac-
tions at the active site of the enzyme (PDB ID: 1AD4).

Medicinal Chemistry Research
Fig. 3 Docked view of all the
compounds at the active site of
the enzyme PDB ID: 1AD4
Table 9 Surflex docking score
(kcal/mol) of the synthesized
compounds 3a–3t docked into
the active site of the DHPS
Compounds
C scorea Crash scoreb Polar scorec D scored PMF scoree G scoref
Chem scoreg
Ciprofloxacin 5.01
−2.26
−1.59
−0.92
−0.88
−0.81
−5.44
−1.12
−5.82
−1.00
−1.50
−0.79
−1.93
−2.06
−2.91
−2.61
−0.92
−1.71
−1.47
−1.71
−1.60
−1.02
1.91
0.00
0.36
0.85
3.80
3.91
2.43
0.04
2.08
1.72
1.22
0.00
0.37
1.14
1.18
1.25
2.70
0.01
1.20
1.05
0.88
−87.704 −69.857
−83.725 −55.646
−71.419 −39.276
−76.068 −18.796
−29.921 −59.095
−80.116 −24.097
−44.296 −57.889
−117.809 −52.495
−52.028 −64.975
−65.475 −62.187
−33.483 −55.977
−76.750 −65.701
−78.507 −49.014
−63.176 −22.324
−101.281 −26.399
−41.051 −44.343
−23.425 −38.172
−64.801 −50.998
−45.526 −46.867
−50.204 −47.179
−48.823 −63.740
−187.231 −21.485
3o
3t
4.88
4.74
4.68
4.22
3.60
3.58
3.55
3.51
3.45
3.42
3.40
3.17
3.14
3.06
3.05
3.01
2.49
2.37
2.29
2.18
−237.662 −17.549
−193.342 −17.451
−178.984 −15.004
−121.251 −23.035
−236.632 −27.179
−162.298 −20.108
−316.910 −25.819
−160.653 −18.511
−175.167 −18.872
−153.647 −17.968
−220.590 −19.750
−209.947 −19.422
−169.093 −16.548
−219.142 −26.866
−142.739 −17.231
−111.663 −16.781
−185.705 −18.432
−175.813 −18.285
−179.185 −18.273
−168.492 −17.967
3e
3m
3d
3c
3j
3b
3n
3h
3i
3q
3l
3f
3g
3k
3p
3r
3s
3a
aC score (consensus score) integrates a number of popular scoring functions for ranking the affinity of ligand
bound to the active site of a receptor and reports the output of total score
bCrash-score revealing the inappropriate penetration into the binding site. Crash scores close to 0 are
favorable. Negative numbers indicate penetration
cPolar indicating the contribution of the polar interactions to the total score. The polar score may be useful
for excluding docking results that make no hydrogen bonds
dD-score for charge and van der Waals interactions between the protein and the ligand
ePMF-score indicating the Helmholtz free energies of interactions for protein-ligand atom pairs (Potential of
Mean Force, PMF)
fG-score showing hydrogen bonding, complex (ligand-protein) and internal (ligand-ligand) energies
gChem-score points for H-bonding, lipophilic contact and rotational entropy along with an intercept term
Among those two interactions were of oxygen atom of
nitro group present on the phenyl ring linked to the C-2
of thiazole ring through nitrogen atom with hydrogen
atoms of ARG219 (-O-H-ARG219, 1.91 Å and 2.22 Å)
and one hydrogen bonding interaction raised from the
nitrogen atom of nitro group present on the phenyl ring
with hydrogen atom of ARG219 (-N-H-ARG219,
2.84 Å). Two interactions of the oxygen atom of meth-
oxy group present on the phenyl ring attached to the C-4
of thiazole ring with hydrogen atoms of GLN105 (-O-H-
GLN105, 1.87 and 2.72 Å). [Fig.
Supplementary data].
1 and 2 in

Medicinal Chemistry Research
Fig. 4 Docked view of
compound 3d at the active site
of the enzyme PDB: 1AD4
Fig. 5 Interaction of
ciprofloxacin at the binding site
of the enzyme (PDB ID: 1AD4)
Docking studies of the title compounds with
Candida albicans dihydrofolate reductase (PDB ID:
1AI9)
As depicted in Fig. 8 Fluconazole makes four hydrogen
bonding interaction at the active site of the enzyme (PDB
ID: 1AI9) and all the four hydrogen bonding interaction
were raised from the nitrogen atom of triazole ring with
hydrogen atom of amino acid residues SER78, LYS57, &
ARG56 (-N-H-SER78; H-LYS57 & H-ARG56).
Compound 3b makes three hydrogen bonding interactions
at the active site of the enzyme (PDB ID: 1AI9), nitrogen
atom of nitro group makes an interaction with hydrogen atom
of LYS57 (-O-H-LYS57; 1.91 Å), oxygen atom of nitro
group makes an interaction with hydrogen atom of LYS57
(-O-H-LYS57; 2.85 Å) and remaining another hydrogen
bonding interaction raised from the nitrogen atom of thiazole
ring with hydrogen of ARG79 (O-H-ARG79; 2.08 Å).
[Fig. 3 and 4 in Supplementary data].
The docking study revealed that all the compounds have
very good docking score against C. albicans. Table 10
depicts their predicted binding energies and C-score values.
Figure 6 represents the docked view of all the synthesized
compounds at the active site of the enzyme PDB ID 1AI9.
As depicted in Fig. 7 compound 3k makes five hydrogen
bonding interactions at the active site of the enzyme
(PDB ID: 1AI9), among those two interactions were of
oxygen atom of nitro group with hydrogen atoms of
LYS57 (-O-H-LYS57; 1.98 and 2.50 Å), oxygen atom
of nitro group makes an interaction with hydrogen atom
of ARG56 (-O-H-ARG56; 2.56 Å), nitrogen atom of nitro
group makes an interaction with hydrogen atom of
LYS57 (-O-H-LYS57; 2.62 Å) and remaining another
hydrogen bonding interaction raised from the nitrogen
atom of thiazole ring with hydrogen of ARG79 (O-H-
ARG79; 2.01 Å).
Also, the studied compounds have shown the same
type of interaction with amino acid residue as that of
fluconazole standard drug. The comparative molecular
docking study of synthesized compounds and standard
fluconazole drug highlighted that the synthesized com-
pounds exhibited high C-score value. Fluconazole

Medicinal Chemistry Research
Table 10 Surflex docking score
(kcal/mol) of the synthesized
compounds 3a–3t docked into
the active site of the Candida
albicans dihydrofolate reductase
Compounds C scorea Crash scoreb Polar scorec D scored
Flucanazole 5.30 −65.170
PMF scoree G scoref
−9.240 −232.46
Chem scoreg
−2.19
−1.05
−1.19
−0.88
−2.97
−0.82
−2.83
−1.43
−3.06
−1.26
−2.50
−2.47
−4.39
−2.23
−1.39
−1.47
−4.21
−1.59
−3.21
−1.39
−1.31
1.85
2.64
0.44
2.53
0.14
2.19
1.19
0.89
1.11
0.00
2.91
3.28
0.00
0.00
0.03
0.91
0.03
0.01
0.69
0.14
0.04
−8.9900
3k
3c
3a
3t
6.63
6.07
5.90
5.90
5.47
5.25
5.03
4.97
4.40
4.35
4.25
4.08
4.05
3.70
3.49
3.45
3.17
3.07
2.38
2.25
−98.563 −35.803
−78.716 −45.256
−96.9080 −33.218
−190.578 −23.840
−253.443 −22.308
−190.098 −24.194
−303.364 −30.433
−190.700 −24.158
−250.974 −25.976
−228.257 −21.117
−257.743 −22.679
−209.763 −20.316
−209.532 −26.550
−189.435 −26.378
−281.273 −25.582
−243.366 −26.488
−201.692 −20.579
−195.363 −21.877
−300.537 −24.305
−209.565 −21.637
−241.681 −24.223
−171.675 −22.185
−169.674 −22.166
−138.236
−3.0020
3b
3m
3p
3o
3h
3i
−96.7850 −36.453
−112.018 −25.505
−73.6420 −18.556
−88.2650 −31.763
−96.0820
22.538
−108.093 −48.659
−100.515 −43.782
−125.340 −18.964
3l
3e
3i
−116.270
−91.3800
−101.165
−1.0150
6.9150
25.574
3f
3r
3j
−112.921 −45.163
3d
3s
3q
3g
−91.9240
−110.655
−89.9660
−90.7530
28.452
1.9300
15.254
9.2080
aC score (consensus score) integrates a number of popular scoring functions for ranking the affinity of ligand
bound to the active site of a receptor and reports the output of total score
bCrash-score revealing the inappropriate penetration into the binding site. Crash scores close to 0 are
favorable. Negative numbers indicate penetration
cPolar indicating the contribution of the polar interactions to the total score. The polar score may be useful
for excluding docking results that make no hydrogen bonds
dD-score for charge and van der Waals interactions between the protein and the ligand
ePMF-score indicating the Helmholtz free energies of interactions for protein-ligand atom pairs (Potential of
Mean Force, PMF)
fG-score showing hydrogen bonding, complex (ligand-protein) and internal (ligand-ligand) energies
gChem-score points for H-bonding, lipophilic contact and rotational entropy along with an intercept term
Fig. 6 Docked view of all the
compounds at the active site of
the enzyme PDB ID: 1AI9
C-score value 5.30 whereas the five out of twenty com-
pounds synthesized have higher C-score values than the
Fluconazole. Thus, from these studies we corroborate the
experimental findings, which suggest that N,4-diphe-
nylthiazol-2-amine derivatives may act by inhibiting the
dihydrofolate reductase enzyme.

Medicinal Chemistry Research
Fig. 7 Docked view of
compound 3k at the active site
of the enzyme PDB: 1AI9
Fig. 8 Interaction of fluconazole
at the binding site of the enzyme
(PDB ID: 1AI9)
Conclusion
The compounds have shown moderate to good anti-
bacterial activity against Gram-positive and Gram-
negative strains. 3d and 3o have shown good activity
comparatively than the rest of the compounds towards
sensitive as well resistant strains. Docking studies have
indicated their good binding profile. Most of the synthe-
sized compounds have same H-bonding interaction with
same amino acid LYS203 as that of Ciprofloxacin indi-
cating similar mode of binding. The compounds 3o and 3j
have shown good anti-inflammatory activity against
aspirin as standard. The toxicity study of the active com-
pounds has manifested them to be nontoxic against normal
Human embryonic cell lines. Hence, these compounds can
be considered as promising candidates to antimicrobial
and anti-inflammatory agents.
An efficient and simple synthetic protocol was employed
for the synthesis of novel N,4-diphenylthiazol-2-amine
derivatives employing Hantzsch method followed by
nucleophilic substitution. The synthesized derivatives were
1
characterized by analytical techniques such as H NMR,
13C NMR, FT-IR, GCMS and single-crystal X-ray diffrac-
tion study.
From the biological screening of N,4 diphenylthiazol-
2-amine derivatives, it was found that most of the com-
pounds appeared active against all the bacterial and fungal
strains. Amongst the synthesized compounds 3a, 3e, 3k &
3m exhibited potent antifungal activity against all the four
strains. The studied compounds showed same type of
interaction with amino acid residue as that of standard
drug Fluconazole and their comparative molecular dock-
ing study highlighted that the synthesized compounds
exhibited high C-score value. Thus, from these studies we
corroborate the experimental findings which suggest that
derivatives may act by inhibiting the dihydrofolate
reductase enzyme.
Acknowledgements We are thankful to the University Scientific
Instruments Centre (USIC and SAIF), Karnatak University, Dharwad
for providing the spectral data, DST-INSPIRE, New Delhi, India, for
providing financial support under DST/INSPIRE Fellowship/2016/
IF160657 and DST-PURSE PHASE-II program for providing neces-
sary facilities. One of the authors MSN is thankful to UGC-SRF for
financial support.

Medicinal Chemistry Research
Compliance with ethical standards
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electronegativity-a rapid access to atomic charges. Tetrahedron
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Conflict of interest The authors declare that they have no conflict of
interest.
Knadler MP, Bergstrom RF, Callaghan JT, Rubin A (1986) Nizatidine:
an H2-blocker its metabolism and disposition in man. Drug
Metab Dispos 14:175–182
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Kumar P, Narasimhan B, Sharma D, Judge V, Narang R (2009)
Hansch analysis of substituted benzoic acid benzylidene/furan-2-
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Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Leelaprakash G, Dass SM (2011) Invitro anti-inflammatory activity of
methanol extract of Enicostemma axillare. Int J Drug Dev Res 3
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