Design, synthesis, docking studies and biological evaluation of 2-phenyl-3-(Substituted benzo[d] thiazol-2-ylamino)-quinazoline-4(3H)-one derivatives as antimicrobial agents

Article abstract of DOI:10.22159/ijpps.2018v10i10.28480

Objective: A new series 2-phenyl-3-(substituted benzo[d] thiazol-2-ylamino)-quinazoline-4(3H)-one was prepared by the fusion method by reacting 2-phenyl benzoxazine with 2-hydrazino benzothiazole and it was evaluated for their antimicrobial activity against gram positive, gram negative bacteria and fungi. Methods: Titled compounds were synthesized by fusion reactions. These compounds were evaluated by in vitro antibacterial and antifungal activity using the minimum inhibitory concentration and zone of inhibition methods. The synthesized compounds were characterized with the help of infrared, NMR and mass spectral studies. The benzothiazole moiety and the quinazoline ring have previously shown DNA gyrase inhibition and target related antibacterial activity. Thus, molecular docking studies of synthesized compounds were carried out (PDB: 3G75) to study the possible interaction of compounds with the target. The batch grid docking was performed to determine the probable. Results: These compounds showed significant activity against gram positive and gram negative bacteria as well against the fungi. The compound A5 was found to be active against B. subtilis, P aeruginosa and C. albican at 12.5 μg/ml MIC. The compound A3 was found to be active against all microbial strains selected at 25 and 12.5 μg/ml MIC. Conclusion: Though the relationship between the activities shown by these compounds in, the antimicrobial study is still to be established, the docking studies conducted found to be consistent with antimicrobial results. Thus the results indicate that the designed structure can be a potential lead as an antimicrobial agent.

Full text of DOI:10.22159/ijpps.2018v10i10.28480

International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 10, Issue 10, 2018
Original Article
DESIGN, SYNTHESIS, DOCKING STUDIES AND BIOLOGICAL EVALUATION OF 2-PHENYL-3-
(SUBSTITUTED BENZO[d] THIAZOL-2-YLAMINO)-QUINAZOLINE-4(3H)-ONE DERIVATIVES
AS ANTIMICROBIAL AGENTS
POOJA PISAL, MEENAKSHI DEODHAR, AMOL KALE, GANESH NIGADE, SMITA PAWAR*
Department of Pharmaceutical Chemistry, PDEA’s Seth Govind Raghunath Sable College of Pharmacy, Saswad, Pune 412301, India
Email: sjpawar4477@gmail.com
Received: 13 Jul 2018 Revised and Accepted: 01 Sep 2018
ABSTRACT
Objective: A new series 2-phenyl-3-(substituted benzo[d] thiazol-2-ylamino)-quinazoline-4(3H)-one was prepared by the fusion method by
reacting 2-phenyl benzoxazine with 2-hydrazino benzothiazole and it was evaluated for their antimicrobial activity against gram positive, gram
negative bacteria and fungi.
Methods: Titled compounds were synthesized by fusion reactions. These compounds were evaluated by in vitro antibacterial and antifungal activity
using the minimum inhibitory concentration and zone of inhibition methods. The synthesized compounds were characterized with the help of
infrared, NMR and mass spectral studies. The benzothiazole moiety and the quinazoline ring have previously shown DNA gyrase inhibition and
target related antibacterial activity. Thus, molecular docking studies of synthesized compounds were carried out (PDB: 3G75) to study the possible
interaction of compounds with the target. The batch grid docking was performed to determine the probable.
Results: These compounds showed significant activity against gram positive and gram negative bacteria as well against the fungi. The compound A5
was found to be active against B. subtilis, P aeruginosa and C. albican at 12.5 µg/ml MIC. The compound A3 was found to be active against all
microbial strains selected at 25 and 12.5 µg/ml MIC.
Conclusion: Though the relationship between the activities shown by these compounds in, the antimicrobial study is still to be established, the
docking studies conducted found to be consistent with antimicrobial results. Thus the results indicate that the designed structure can be a potential
lead as an antimicrobial agent.
Keywords: Benzothiazole, Benzoxazine, Quinazoline, Antimicrobials
© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2018v10i10.28480
INTRODUCTION
MATERIALS AND METHODS
There has been a continual encounter between human and the
multitude of microorganism that cause infection and disease.
Recently it has been evidenced that there is an insistent increase in
antibiotic resistance to many common bacterial pathogens such as
Staphylococcus aureus. The number of cases of multidrug-resistant
bacterial infections is increasing day by day. This situation requires
the design of novel antimicrobial agents acting on novel targets.
All the reagents and chemicals used were of analytical grade. The
progress of the reaction and purity of all the synthesized compounds
was monitored by TLC. IR spectra were recorded on Shimadzu FTIR
8400S by using KBr, and the NMR spectra were recorded in NMR
Varian-Mercury 300 MHz spectrometer in CDCl3 and values are
expressed in ppm.
Antimicrobial activity
Zone of inhibition
Benzothiazole derivatives show numerous biological activities such as
antimicrobial [1], anticancer [2], antileishmanial [3], anti-diabetic and
antifungal [4] activities. In recent years’ heterocyclic compounds and
derivatives have attracted strong interest due to their biological and
pharmacological properties. Substituted quinazoline-4-one have been
shown to possess antibacterial, antifungal and antimicrobial activity
[5-7]. Thus, it is revealed from the literature that benzothiazole, as well
as quinazolin-4-one derivatives, hold diverse pharmacological activity.
The compounds were evaluated for the antibacterial activity by the
cup, plate method against gram-positive bacteria S. aureus (ATCC
9144) B. subtilis (ATCC 6633) and gram-negative bacteria E. coli (ATCC
25922), P. aeruginosa (ATCC 9027) and A. Niger (ATCC 16404) and C.
albicans (ATCC 10231), at the concentration: 50 μg/ml, 100 μg/ml,
150 μg/ml. The bacterial strains were obtained from NCL, and fungal
strains were obtained from the microbiology department of Waghire
College, Saswad. The ciprofloxacin 150 μg/ml and 150 μg/ml of
fluconazole were used as reference drugs for antibacterial and
antifungal study respectively. The bacteria were sub-cultured in the
nutrient agar medium containing peptone (1%), beef extract (0.5%),
sodium chloride (0.8%) and agar (2.5%), in distilled water. The
solution was sterilized for 20 min at 15 psi pressure in an autoclave at
120 °C. The basal medium 15-20 ml was poured into the sterile Petri
dishes. After the solidification of the medium, the suspension of the
organism was spread by the spreader and holes of 6 mm diameter
were bored to form cups with the help of a sterile cork borer. In this
cup 20 μl of 50 μg/ml, 100 μg/ml, 150 μg/ml (solvent DMSO) of the
test compounds were added by the micropipette. The zone of
inhibition was measured in mm after incubation at 37 °C for 48 h.
DNA gyrase is a bacterial enzyme that catalyzes the introduction of
negative supercoils in a closed-circular DNA using the energy of the
ATP hydrolysis. Since it was found only in prokaryotes and is vital
for their survival; it has become an attractive target for antibacterial
agents [8]. Benzothiazole and quinazoline derivatives were known
to possess DNA gyrase inhibitory activity [9]. Thus, we thought to
incorporate both leads together with the hope to have better
antimicrobial potential.
Thus, this paper reports the synthesis and antimicrobial activity of
2-phenyl-3-(substituted benzo [d] thiazol-2-ylamino)-2-phenyl-
quinazolin-4(3H)-one. The molecular docking studies were also
carried out to check the possible interactions of compounds with
DNA gyrase active pocket.

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Int J Pharm Pharm Sci, Vol 10, Issue 10, 57-61
Minimum inhibitory concentration
General procedure of synthesis
The microdilution susceptibility test was used for the determination
of antibacterial and antifungal activity. The nutrient broth was
prepared and added in microiter plates except first well in which
inoculum was not added and considered as negative control. A stock
solution of test compounds was prepared in DMSO (200 μg/ml)
followed by twofold dilution at concentrations of (100, 50,
25….3.125 μg/ml). The 75 µl inoculums were added to the other all
wells containing test compounds ranging from 100, 50, 25….3.125
μg/ml. The microtitre plates were then incubated at 37 °C for 48 h,
and minimal inhibitory concentration was measured in the growth
in the form of turbidity. The ciprofloxacin was used as reference
drugs for the antibacterial study while fluconazole was used for
antifungal study [10].
Synthesis of 6-substituted-2-aminobenzothiazoles (B 1-6)
To substituted aniline (0.078 mol) taken in a 250 ml round bottom
flask, ammonium thiocyanate (0.156 mol) and 100 ml acetic acid
was added. Bromine solution (0.02 mol) in acetic acid was added to
the reaction mixture till an orange-yellow color appeared. The slurry
was kept overnight (20 h), the precipitate was dissolved in water
(200 ml), filtered to remove any undissolved matter and was
basified with concentrated ammonia solution. The precipitate
obtained was filtered, washed with water, dried and recrystallized
using ethanol: water (80:20) mixture [11].
Synthesis of 6-substituted-2-hydrazino benzothiazole (BH 1-6)
Concentrated hydrochloric acid (1 ml) was added dropwise with
stirring to hydrazine hydrate (0.12 mol) at 5-6 °C followed by ethylene
glycol (30 ml). Thereafter 2-amino substituted benzothiazole (20
mmol) was added in portions, and the resultant mixture was
irradiated in microwave at power level 7 for 1 h. The reaction progress
was monitored by TLC using toluene: ethyl acetate (75:25) as mobile
phase. The reaction mixture was cooled at room temperature and was
washed with cold water to obtain the product. The resulting crude was
recrystallized from ethanol to obtain the crystalline product [12].
Docking studies
The docking process was carried out to analyze the possible
interactions between newly synthesized compounds and the
selected cavity of the DNA gyrase enzyme. The high-resolution (2.30
A °) X-ray structure of DNA gyrase complexed with pyrazolthiazole
(PDB code 3G75) was imported into Vlife 3.5 MDS, and the ligand
was extracted to leave a cavity. The protein was a dimer which was
converted into monomer by deleting one-chain. Water molecules
were removed from the monomer. The hydrogens were added in the
protein molecule, and energy was minimized using Merck Molecular
Force Field (MMFF). The structure of pyrazolthiazole extracted from
the 3G75 protein was energy minimized using MMFF. The
conformers of pyrazolthiazole, were generated and docked back into
the corresponding binding pocket to determine the ability of the
Biopredicta tool to reproduce the orientation and position of the
inhibitor observed in the crystal structure. The docked
conformations were further scored using dock score. Conformers of
individual 3D optimized synthesized compounds A1 to A6 were
generated using ‘systematic conformational search method’. In a
Synthesis of 2-phenyl-4H-benzo[d] [1,3]-oxazin-4-one
Anthranilic acid (0.01 mol) was dissolved in pyridine. Benzoyl
Chloride (0.01 mol) was added to it and cooled. The reaction mixture
was stirred at room temperature. A little quantity of the sample was
taken and dissolved in water to check the formation of benzoxazine.
As an anthranilic acid, benzoyl chloride and pyridine are water
soluble, they get dissolved in water, but benzoxazine being insoluble,
it forms a precipitate. When benzoxazine was formed, the entire
reaction mixture was poured into a beaker containing 250 ml of
water containing 10 % sodium bicarbonate. The benzoxazine so
formed was filtered, dried and recrystallized from ethanol. A pale
brown colored crystalline compound was obtained. Melting points
were checked. The purity of the compounds was checked by TLC
using benzene and petroleum ether solvent system in 7:3 ratio [13]
systematic conformational search,
a set of rotatable bonds is
identified by the user and for each of these bonds; all possible
conformers are examined as a function of each other. For each
conformer generated by this set of rotations, all internal atomic
distances were computed. A confirmation for which any distance
less than the sum of the van der Waals radii of the interacting
species was not considered. All the generated conformers with
minimum and maximum torsion values were selected in the range
of-180.00 to 180.00, and MMFF force field was selected for
optimization of generated conformers. The optimized conformers
were docked using the grid batch docking method. The interaction
between synthesized compounds and DNA gyrase pocket was
recorded.
General Procedure for Synthesis of 2-phenyl-3-(substituted
benzo[d]thiazol-2-ylamino)-quinazolin-4(3H)-one (A1-6)
0.1 mol of Substituted 2-hydrazino benzothiazole (BH1-6) was
heated with 0.2 mol of substituted benzoxazin-4-one in a 50 ml
beaker on a sand bath. The mixture was heated (controlled heating)
with constant stirring until the product formed. Then the mixture
was allowed to cool, and the product was suspended in water. The
product obtained was recrystallized with ethanol. (80:20)
NH2
NH4SCN 0.1mol
N
NH2
R
S
Br2/ glacial acetic acid
R
Substituted Aniline
B(1-6)
substituted 2-amino benzothiazole
0.078 mol
Con.HCl,ethylene
NH2NH2
glycol
N
NHNH2
S
R
substituted 2-hydrazino benzothiazole BH(1-6)
O
O
Heat
N
0.2 mol
2 phenyl-benzo[d][1,3]oxazin-4-one
O
N
N
H
N
N
R= 6-H,6-Cl, 6-OCH3 ,6-CH3,
6-COCH3, 6-NO2
S
R
2- phenyl-3-(substituted benzo[d]thiazol-2-ylamino)-
quinazolin-4(3H)-one
(A1-6)
Fig. 1: Scheme of synthesis
58

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Int J Pharm Pharm Sci, Vol 10, Issue 10, 57-61
Table 1: Data for 2-phenyl-3-(substituted benzo[d]thiazol-2-ylamino)-2-phenylquinazolin-4(3H)-one (A1-6)
Compound
R
IR
NMR (ppm)
%
yield
A1
A2
A3
A4
H
3124 (N-H), 3063 (Ar-CH)1619(C=N); 1712(C=O), 1265 (C-N),
702(C-S)
3163 (N-H), 3047 (Ar-CH), 2985(CH),1604 (C=N) 1681(C=O), 1261
(C-N), 1137(C-O-C), 812(C-S)
3135 (N-H), 3070 (Ar-CH); 1681(C=N); 1766(C=O), 1257 (C-N),
768(C-S)
3132 (N-H), 3089 (Ar-CH); 2924(CH) 1651(C=N) 1731(C=O), 1150
(C-N), 783(C-S)
7.09-8.98 (m,13H, Ar-H); 11(s, 1H,-NH)
78
OCH3
Cl
7.1-8.9 (m, 12H, Ar-H), 12 (s, 1H, NH),
3.24(s, 3H,-OCH3)
6.9-8.7(m, 12H, Ar-H), 11.3(s, 1H, NH)
70
60
65
CH3
NO2
2.39(s, 3H, CH3), 11.4 (s, 1H, NH), 7.29-
8.11(m, 12H)
7.31-9.01(m, 12H), 11.9 (s, 1H, NH),
7.38-8.52 (m, 12H), 11.9 (s, 1H, NH)
2.59(s,3H, CH3),
A5
A6
3194 (N-H), 3081 (Ar-CH); 1519(C=N); 1681(C=O), 1334 (C-N),
60
65
COCH3 3383 (N-H), 3063 (Ar--CH); 1689(C=N); 1712(C=O), 1265 (C-N)
RESULTS AND DISCUSSION
of NH-NH2 stretch at 3243-3317 cm-1 in the IR spectrum also
confirms the formation of 2-phenyl-3-(substituted benzo[d]thiazol-
2-ylamino)-2-phenylquinazolin-4(3H)-ones.
The compounds B (1-6) were prepared as per reported method from
para-substituted anilines by stirring with ammonium thiocyanate
and bromine in acetic acid. The reaction mainly involves formation
of intermediate phenylthiourea and cyclisation of which affords 6-
substituted 2-amino benzothiazole. The target compounds A(1-6)
were synthesized by the route indicated in fig. 1. The compounds
were prepared by heating substituted 2-hydrazino benzothiazoles
(BH1-6) with 2 phenyl-benzo[d] [1,3] oxazin-4-one. The synthesized
structures were confirmed by spectral analysis by 1H NMR, IR and
were found consistent with the spectral data. IR spectra of A(1-6)
In the 1H NMR spectrum, a broad singlet at 9-12 ppm is seen for
hydrazine protons. The aromatic protons were seen as multiplet
signals at 6.89-9.05 ppm. The methoxy protons were seen downfield
due to the presence of oxygen and seen as a singlet at 3.24 ppm and
methyl protons as a singlet at 2.39 ppm.
Antimicrobial activity
The minimum inhibitory concentration of A (1-6) compounds was
determined using a double dilution method. A zone of inhibition was
determined using the cup plate method using ciprofloxacin and
fluconazole as standard drugs for antibacterial and antifungal activity.
revealed characteristic aromatic CH stretch between 3047-3120 cm-
1
The C=N in benzothiazole is seen at 1519-1600 cm-1. The carbonyl
.
(C=O) peak of quinazolinone is seen at 1731-1681 cm-1. The absence
Table 2: Minimum inhibitory concentration (MIC) of 2-phenyl-3-(substituted benzo[d]thiazol-2-ylamino)-2-phenylquinazolin-4(3H)-one
(A1-6)
Compound
A1
A 2
A 3
A 4
A 5
A 6
S. aureus
B. subtilis
25
25
2525
25
12.512
50
E. coli
25
50
251220
50
251220
50
P. aeruginosa
25
25
2512
50
A. niger
25
25
25
50
C. albicans
25
25
25
50
12.5
50
50
50
25
50
50
50
12.512
50
25
50
MIC given in µg/ml
The compound A-5 with nitro substitution at the 6th position of
benzothiazole was found to hold potential antibacterial and
antifungal activity against B. subtilis, P. aeruginosa and C. albicans.
(table 2) The compound A5 was found to be active against B.
subtilis, P aeruginosa and C. albican at 12.5 µg/ml MIC.
action but lesser than fluconazole. From the results it can be said
that the compound with nitro group substitution holds antibacterial
and antifungal potential comparable to standard drugs.
Docking
To predict the probable interactions of newly synthesized
compounds with the active site of DNA gyrase enzyme, docking
studies were carried out using MDS V-life 3.5 software. The dock
score, hydrophobic interactions, Van der Waal interactions and
hydrogen bonds formed with surrounding amino acids were used
to predict the binding modes, binding affinities and orientation of
docked compounds in the active sites of DNA gyrase enzyme.
The compound A3 was found active against all microbes at 25
µg/ml MIC. It was evident from the results of the zone of inhibition
that compound A-5 and compound A-3 holds potential
antibacterial activity.
The zone of inhibition was determined using the cup plate method.
Effect of standard drug, ciprofloxacin and synthesized compounds
A1 to A-6 revealed that the synthesized compounds A1 to A6 are
showed statistically significant antibacterial activity than standard
ciprofloxacin, suggesting the compounds have similar antibacterial
action but lesser than ciprofloxacin.
The active site (cavity no 1) was defined to include residues within
10.0 A ° radius of any of the interaction. The docking procedure
was validated by docking the pyrazolthiazole extracted from PDB
active pocket. The molecular docking results revealed a docking
score of-4.8kcal/mol for pyrazolthiazole, and it forms a single
hydrogen bond with Ser-55. The compound A-3 and A-5 which are
the most active compound as antibacterial possess dock score of-
5.13,-5.27 kcal/mol respectively.
Effect of standard drug, fluconazole and synthesized compounds A1
to A-6 revealed that the synthesized compounds A1 to A6 are
showed statistically significant antifungal activity than standard
fluconazole, suggesting the compounds have similar antifungal
59

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Int J Pharm Pharm Sci, Vol 10, Issue 10, 57-61
Fig. 2: Data expressed as mean±SEM. Data analyzed by two-way ANOVA followed by Dunnet test. All test groups are compared with the
control group, Ciprofloxacin ***p<0.001
Fig. 3: Data expressed as mean±SEM. Data analyzed by two-way ANOVA followed by Dunnet test. All test groups are compared with the
control group, fluconazole ***p<0.001
Table 3: Dock score and binding interactions of newly synthesized compounds A (1-6)
Compound
Dock score (kcal/mol)
A1
A2
A3
A4
A5
A6
Reference
-5.3
-5.11
-5.13
-5.25
-5.27
-5.00
-4.8
CONCLUSION
A5 and A3 showed prominent antibacterial and antifungal activity.
As some synthesized compounds show good activity which develops
a productive environment for the development of a new class of
antimicrobial agents.
The number of substituted benzothiazoles fused with quinazoline
moieties was synthesized and screened for antibacterial and
antifungal activity. The antimicrobial activities for the synthesized
compounds (A1-6) have been shown in table 2, fig. 2 and fig. 3
Ciprofloxacin was used as a standard for antibacterial activity.
Similarly, fluconazole was used for antifungal activity as standard.
All the newly synthesized compounds showed moderate to good
potency against different bacterial strains. Out of which compound
ACKNOWLEDGMENT
The authors wish to thank Principal, S. G. R. S College of Pharmacy,
Saswad Pune for providing required facilities to carry out this
research work.
60

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Int J Pharm Pharm Sci, Vol 10, Issue 10, 57-61
AUTHORS CONTRIBUTIONS
All the authors have contributed equally
CONFLICT OF INTERESTS
Declared none
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