Synthesis, characterization and drug-likeness predictions of 1,3-thiazole and benzothiazole derivatives

Article abstract of DOI:10.13005/ojc/340660

Heterocyclic compounds bearing nitrogen and sulphur in the main skeleton are reported to be a bioactive group. Thiazole and benzothiazole moieties are biologically significant class of this group. This research focus on the synthesis and characterization of 1,3-thiazole and benzothiazole derivatives. Drug likeness predictions were also undertaken for these newly synthesized compounds.

Full text of DOI:10.13005/ojc/340660

ISSN: 0970-020 X
CODEN: OJCHEG
2018, Vol. 34, No.(6):
Pg. 3134-3139
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis, Characterization and Drug-Likeness Predictions of
1,3-Thiazole and Benzothiazole Derivatives
ARSHI NAQVI1,2
1Department of Chemistry, College of Science, Taibah University, Al Madina Al Munawwara,
Kingdom of Saudi Arabia.
2Biodiscovery-Solutions for future, Plot No 29, FF2, 2nd street, Pearl Astragal Apartment,
Perumbakkam of Medavakkam, Solinganallur Main Road, Chennai, Tamil Nadu-600100, India.
*Corresponding author E-mail: arshi_84@yahoo.com
http://dx.doi.org/10.13005/ojc/340660
Received: October 16, 2018; Accepted: November 26, 2018)
ABSTRACT
Heterocyclic compounds bearing nitrogen and sulphur in the main skeleton are reported to
be a bioactive group. Thiazole and benzothiazole moieties are biologically significant class of this
group. This research focus on the synthesis and characterization of 1,3-thiazole and benzothiazole
derivatives. Drug likeness predictions were also undertaken for these newly synthesized
compounds.
Keywords: Thiazole, benzothiazole, Synthesis, Drug likeness.
INTRODUCTION
why the synthesis of heterocycles is of continuing
interest to chemists.Nitrogen and Sulphur containing
heterocyclic drug candidates have been reported
to have biological activities like anti-bacterial3
anti-fungal4, anti-oxidant5, anti-cancer6, anti-viral7,
anti-convulsant8, anti-tubercular9, anti-HIV10 etc.
Heterocycles delineate by far to be the
utmost important class of organic chemistry. Both
natural and synthetic heterocyclic molecules
have been immensely explored for their profound
applicability in the field of medicinal, industrial and
agricultural chemistry. A wide array of biological
activity affiliated with heterocyclic compounds has
allured interest in the research of drug discovery1.As
noticed from literature, family of nitrogen and sulphur
heterocycles of both natural as well as synthetic
origin is endowed with vast spectrum of biological
activities and a gigantic amount of them have been
formulated to the clinics globally2.This is the reason
Thiazole, or 1, 3-thiazole, is a heterocyclic
molecule bearing both sulfur and nitrogen
heteroatoms. The most notable component of the
vitamin thiamine (B1) and penicillin is the thiazole
ring.The versatility of thiazole nucleus is manifested
by the feature that construct various bioactive
drugs like antimicrobial (sulfazole), antifungal
(abafungin), antiretroviral (ritonavir), antineoplastic
This is an
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NAQVI et al., Orient. J. Chem., Vol. 34(6), 3134-3139 (2018)
(Tiazofurin)11. Thiazole hybrids have been reported
in possession of many pharmacological properties
and are widely involved in biochemical processes.
Cefdinir is a semi-synthetic cephalosporin (third
generation) which exhibits magnificent activity
against Staphylococcus species12. Norvir (HIV-1
protease inhibitor) constitutes of two non-identical
substituted thiazole rings13. Thiazole/2-amino
thiazole moiety bearing compounds are reported
for the treatment of hypertension14, allergies15,
hypnotics16, pain17, inflammation18, thrombosis19,
tumour20, inflammation21, etc. Thiazoles have also
been reported to be a contributor in the flavor of
brewed coffee22.
determined in open capillary tubes and were
uncorrected. Silica-gel-coated Al plates (Merck & Co.)
were used to check the purity of the compound.
The structure of the compounds was elucidated
by Infra-red (IR, recorded using KBr pellets on Perkin-
Elmer Spectrum-BX-I Infrared Spectrophotometer)
1
and H-NMR (recorded in Dimethyl sulphoxide
(DMSO) on Jeol-300MHz instrument).Microanalysis
of the compounds gave satisfactory results. All the
synthesized compounds were assessed for their
drug likeness properties by web-based software.
Synthesis of 4-Phenyl-1,3-thiazol-2-amine
(1):Thiourea (2mol) and acetophenone (1 mol) were
placed in round bottom flask, bromine (0.95 mol)
was gradually added to this mixture.After addition of
bromine the reaction mixture was heated on steam
bath for 12 hours. The contents were diluted with
water, heated until most of the solid had gone into
the solution. The liquid was filtered under suction,
cooled and the filtrate was alkalized with strong
ammonium hydroxide. The precipitate was filtered
and recrystallized from ethyl alcohol as colorless
needles. Yield: 69.35%; m.p: 149oC; IR(KBr) (cm-1):
710, 780, 905, 1445, 1603, 1627-1685, 3210, 3431;
1H-NMR (300 MHz, DMSO-d6): δ= 2.50 (DMSO), 3.9
(d, -NH2), 7.22-7.30 (m, Ar-H), 7.38-7.44 (m, Ar-H),
7.49 (s, thiazole-H5).Anal.Calc.for C9H8N2S:C 61.34,
H 4.58, N 15.90; Found: C 61.38, H 4.60, N 15.85.
Benzothiazole is an elite bicyclic ring
system. Benzothiazole skeleton embraces to be an
attractive heterocyclic class which is known for its
exciting medicinal traits. 2-substitued benzothiazole
has unfold its usage as a vital structure in various
therapeutics sectors23. The dopamine D2-agonist
pramipexole (Mirapex), used for treating Parkinson’s
disease and restless legs syndrome is comprised
of a fused bicyclic tetrahydrobenzothiazole motif24.
Numerous amounts of biological activity are
associated with this nucleus namely anti-microbial25,
anti-leshmanial26, anti-helmintic27, anti-HIV28, anti-
inflammatory29, anti-cancer30, anti-convulsant31 etc.
Drug likeness is a qualitative criterion
used for drug like property of the compounds.
Different structural and molecular properties like
hydrophobicity, hydrogen bond characteristics,
molecule size etc. are evaluated in order to
determine whether the predicted compound is similar
to the known drugs or not. Generally, Lipinski’s rule
of 5 (RO5) is used to determine the drug likeness
Synthesis of 2-chloro-N-(4-phenyl-1,
3-thiazol-2-yl)acetamide (2): Chloroacetyl chloride
(0.03mol) dissolved in dry benzene (12.0 ml)
was gradually added to the ice cooled solution of
compound 1(0.03 mol) dissolved in dry benzene
(30 ml).The reaction mixture was refluxed for
3 hours. Benzene was stripped off by distillation
and the residue was washed first with aq. sodium
bicarbonate solution (5%) to remove unreacted
chloroacetyl chloride and then with water. The
product was dried and recrystallized from ethanol
as light-yellow crystals. Yield: 73.27%; m.p: 156oC;
IR(KBr) (cm-1): 731, 838, 1542, 1568, 1679, 3082,
of the evaluated drug candidate32-33
.
Since immense portion of biological
potentials are associated with the family
accommodating nitrogen and sulphur heteroatoms
in the skeleton, it was worthy to synthesize and
characterize some of its derivatives viz.1,3-thiazoles
and benzothiazoles and to explore their drug likeness
estimations.
1
3100, 3358; H-NMR (300 MHz, DMSO-d6): δ (in
ppm)= 2.51 (DMSO), 4.12 (m, -CH2), 6.91 (s,
1H, thiazole), 7.39(m, Ar-H), 7.87 (m, Ar-H), 9.37
(s, NHCO). Anal. Calc. for C11H9N2OClS: C 52.28, H
3.59, N 11.08; Found: C 52.22, H 3.60, N 11.05.
MATERIALS AND METHODS
The chemicals were purchased from
Synthesis of N-(4-bromo-2-fluorophenyl)-
Sigma-Aldrich/Merck. Melting points WERE
3-oxo-3-(2-(2-oxo-2-((4-phenylthiazol-2-yl)amino)

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NAQVI et al., Orient. J. Chem., Vol. 34(6), 3134-3139 (2018)
ethyl)hydrazinyl)propanamide (4): A solution of
compound 2 (0.001 mol) in absolute ethanol (15
ml), 4-Bromo-2-fluoro phenyl malonamic hydrazide
(3) (synthesized according to our reported method34)
(0.001 mol) in ethanol (10 ml) were mixed in a round
bottom flask having condenser carrying a calcium
chloride guard tube, DMF (1 drop) and Pyridine
(1 drop) were added and the mixture was refluxed for
10 hours. Most of the ethanol was distilled off, solid
was collected under suction, washed successively
with water and several time with hot ethanol. The
product was obtained as white crystals. Yield:
50.36%; m.p: 196oC; I.R. (KBr, cm-1) 610, 1038,
1115, 1427, 1536, 1664, 2884, 3049, 3285;1H-NMR
(300 MHz, DMSO-d6): δ(in ppm)= 2.50 (DMSO),
2.89 (s, CH2), 3.03 (s, NH), 3.25 (s, NH), 3.34
(s, CH2), 4.24 (s, NH), 6.62 (s, -C5H thiazole ring),
7.21-7.48 (m, Ar-H), 9.04 (s, CONH). Anal. Calc. for
C20H17N5O3BrFS: C 47.44, H 3.38, N 13.83; Found:
C 47.48, H 3.31, N 13.90.
Calc. for C7H4N2ClFS: C 41.49, H 1.99, N 13.82;
Found: C 41.48, H 1.93, N 13.87.
Synthesis of 2-Chloro-N-(5-chloro-6-
fluorobenzothiazol-2yl)acetamide (6): Chloroacetyl
chloride (0.03 mol) dissolved in dry benzene (12.0 ml)
was gradually added to the ice cooled solution of
compound 4 (0.03 mol) dissolved in dry benzene
(30 ml). The reaction mixture was refluxed for
3 hours on a water bath.Benzene was stripped off by
distillation and the residue was washed first with aq.
sodium bicarbonate solution (5%) to remove reacted
chloroacetyl chloride and then with water. The
product was dried and recrystallised from ethanol in
pale yellow precipitate was obtained.Yield: 83.31%;
m.p:189oC;I.R.(KBr, cm-1) 693, 725, 760, 785, 1647,
1725, 2880, 3315, 3430, 3452; 1H-NMR (300 MHz,
DMSO-d6): δ(in ppm)= 2.51 (DMSO), 4.58 (s, -CH2),
7.78 (d, Ar-H), 8.25 (d, Ar-H), 9.05 (s, -NH). Anal.
Calc. for C9H5N2OCl2FS: C 38.73, H 1.81, N 10.04;
Found: C 38.81, H 1.75, N 10.10.
Synthesisof5-Chloro-6-fluoro-benzothiazol-
2-amine (5): To a pre-cooled glacial acetic acid
(40ml), 0.416 mole of potassium thiocyanate and
0.05 mole of 3-chloro-4-fluoro aniline was added.
The mixture was placed in freezing mixture of ice
and salt and mechanically stirred while 6 ml of
bromine in 24 ml of glacial acid was added from
a dropping funnel maintaining the temperature
0oC. After all the bromine has been added
(105 min.), the solution was stirred for an additional
2 hours at 0oC and at room temperature for 10 hours.
It was allowed to stand overnight during which an
orange precipitate settled at the bottom, water
(30 ml) was added quickly and slurry was heated at
85oC on a steam bath and filtered hot. The orange
residue was placed in a reaction flask and treated
with 10 ml of glacial acetic acid, heated again to
85oC and filtered hot. The combined filtrate was
cooled and neutralized with concentrated ammonia
solution to pH 6 when a dark yellow precipitate was
collected. Recrystallisation from ethanol and water
mixture. The product was obtained as pale-yellow
crystals.Yield: 89.31%; m.p: 168oC; I.R. (KBr, cm-1)
691, 791, 1385, 1638, 2920, 3058, 3249, 3433; 1H-
NMR (300 MHz, DMSO-d6): δ(in ppm)= 2.51 (DMSO),
4.82 (s, -NH2), 7.88 (d, Ar-H), 8.20 (d, Ar-H). Anal.
Synthesis of 3-(2-(2-((5-Chloro-6-fluoro
-benzothiazol-2-yl)amino)-2-oxo-ethyl)hydrazinyl)-
N-(4-fluoro-3-nitrophenyl)-3-oxopropanamide (8): A
solution of compound 5 (0.00 ml) in ethanol (15 ml)
and 3-nitro-4-fluoro malonamic acid hydrazide (7)
(synthesized according to our reported method35)
(0.01ml) in ethanol(10 ml) were mixed in round
bottom flask having condenser covering a calcium
chloride guard tube, DMF and pyridine were added
and mixture was refluxed for 10 hours. The product
was separated, filteredandrecrystallizedfromethanol
to give light brown precipitate. Yield: 72.56%; m.p:
193oC; I.R. (KBr, cm-1) 785, 1044, 1389, 1545, 1640,
1668, 1710, 2930, 3055;1H-NMR (300 MHz, DMSO-
d6): δ(in ppm)= 2.50 (DMSO), 3.20 (s, -CH2), 3.55 (s,
CH2), 4.35 (d, NH), 7.20-7.61 (m, Ar-H), 7.48-8.72
(m, Ar-H), 9.10 (s, CONH), 9.97 (s, CONH), 12.59
(s, NH). Anal. Calc. for C18H13N6O5F2ClS: C 43.34, H
2.63, N 16.85; Found: C 43.48, H 2.61, N 16.80.
Molecular and Drug likeness predictive studies
Chemdraw software was used for sketching
the structures. Molecular properties, Lipinski’s rule
of 5 (RO5) and drug likeness score were predicted
using the software from Molsoft server (http://www.

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NAQVI et al., Orient. J. Chem., Vol. 34(6), 3134-3139 (2018)
molsoft.com) were we can draw or import the ligand
file from chemdraw.
(1 and 5) were synthesized from acetophenone and
substituted anilines respectively under different
reaction conditions with different reagents. These
were then allowed to react with chloroacetyl chloride
under same reaction conditions to yield their
respective acetamides (2 and 6).The transformation
of these acetamides into their respective propenamide
(4 and 8) was also achieved by reacting it with different
malonamic acid hydrazides (3 and 7). Compounds
1-4 were synthesized according to scheme 1 and
compounds 5-8 according to scheme 2.
RESULT AND DISCUSSION
The research undertaken was carried out
with the intention to synthesize and characterize
substituted 1,3-thiazole and benzothiazole along
with predicting their physico-chemical properties
and drug likeness scores.
Substituted 1,3-thiazole and benzothiazoles
Cl
O
NH2
Cl
N
N
S
KSCN, Br2
CH3COOH
NH2
Cl
Br2
F
NH2
H2
N
NH2
S
S
F
(5)
(1)
Cl
Cl
O
Cl
Cl
F
N
S
O
H
NH
N
Cl
N
Cl
(6)
O
O
S
(7)
(2)
(3)
H
N
H
H
N
NO2
N
N
N
H
H
H
N
H
N
N
O
O
O
S
N
N
F
(8)
Cl
H
O
O
O
S
(4)
Br
F
F
Scheme 1. Synthesis of compounds 1-4
Scheme 2. Synthesis of compounds 5-8
Prediction of Lipinski’s “Rule of Five”(RO5),
calculation of some important physicochemical
properties such as molecular weight, logP, log S,
polar surface area (PSA), number of hydrogen
bond acceptors (HBA), number of hydrogen bond
donors (HBD), and drug likeness scores was done
employing Molsoft and documented in Table 1. The
drug likeness of the selected compounds is shown
in Fig. 1. Compound 1 has violated one rule from
the RO5 as it has molecular weight >500 but at the
same time it has shown good drug likeness score
of 0.18. Rest of all the compound didn’t violated the
RO5 and their drug likeness scores ranging from
-1.13 to -0.08.
Fig. 1. Drug likeness scores of compounds 1-8

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NAQVI et al., Orient. J. Chem., Vol. 34(6), 3134-3139 (2018)
Table 1: Lipinski's rule of five with additional parameters and drug likeness scores
Compound No.
Mol. wt.
Log Pa
Log Sb
PSAc
HBAd
HBDe Drug likeness score
1
2
3
4
5
6
7
8
176.04
252.01
288.99
505.02
201.98
277.95
245.04
498.03
2.74
2.94
0.24
2.69
3.14
3.33
0.10
1.91
-3.64
-4.59
-2.63
-6.50
-3.83
-4.71
-2.61
-6.10
30.77
33.16
71.38
94.08
30.76
33.15
72.08
127.84
2
3
3
6
2
3
3
8
2
1
4
4
2
1
4
4
-1.13
-0.18
-0.49
0.18
-0.95
-0.08
-0.17
-0.36
aSolubility parameter, bCalculated lipophilicity [in log(moles/L)], cPolar surface area (A2), dNumber of hydrogen
bond acceptor, eNumber of hydrogen bond donors
CONCLUSION
properties. Substituted 1,3-thiazole (4) violated one
rule out of “rule of five”, still it emerged as the most
potent drug candidate in predictive studies with drug
likeness score of 0.18.
This study encompassed on the synthesis
of substituted 1,3-thiazole and benzothiazole
derivatives which were characterized using spectral
and elemental techniques. Compounds 1-8 were
successfully synthesized and characterized.
Drug likeness predictive study was undertaken to
establish the RO5 and some of their physicochemical
ACKNOWLEDGEMENT
Author is thankful to the Director CDRI,
Lucknow for providing elemental and spectral data.
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