Synthesis, Antimicrobial Activity, and Docking Studies of 2-Mercapto Substituted Quinazolin-4(3H)-one and Their Derivatives

Article abstract of DOI:10.1134/S1070363218040230

An efficient, eco-friendly synthesis of a series of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-3-substituted quinazolin-4(3H)-ones employing quinazolin-4(3H)-one and corresponding halo-acyl/haloalkyl as electrophiles is presented. The products were assayed for anti-bacterial activity on four bacterial species (Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis, and Staphylococcus aureus). In-silico molecular docking studies were carried out.

Full text of DOI:10.1134/S1070363218040230

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 4, pp. 774–779. © Pleiades Publishing, Ltd., 2018.
Synthesis, Antimicrobial Activity, and Docking Studies
of 2-Mercapto Substituted Quinazolin-4(3H)-one
and Their Derivatives1
P. Balaswamya, S. Aravinda*, S. Purushotham Reddya, and B. Satyanarayanaa**
a Department of Chemistry, Osmania University, Hyderabad, Telangana, 500007 India
e-mail: *aravind.iict@gmail.com; **satyambchem@yahoo.com
Received August 24, 2017
Abstract—An efficient, eco-friendly synthesis of a series of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-3-
substituted quinazolin-4(3H)-ones employing quinazolin-4(3H)-one and corresponding halo-acyl/haloalkyl as
electrophiles is presented. The products were assayed for anti-bacterial activity on four bacterial species
(Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis, and Staphylococcus aureus). In-silico molecular
docking studies were carried out.
Keywords: quinazolin-4(3H)-one derivatives, antibacterial activity, molecular docking
DOI: 10.1134/S1070363218040230
INTRODUCTION
solvents such as toluene, benzene, THF, and ethanol in
presence of TBAB and NaOH in water were tested.
Ethanol proved to be the most efficient leading to
formation of compound 5a in 80% yield (Tables 1, 2).
Among many types of therapeutic activities of
quinazolinone derivatives, antibacterial [1–5], is one of
the most pronounced. This encouraged us to focus on
synthesis of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-3-
substituted quinazolin-4(3H)-ones 3a, 3b, and 5a–5h
and screening their antibacterial activity.
Structures of the products were confirmed by IR,
1H and 13C NMR, and Mass spectra.
In vitro antibacterial studies. Quinazolin-4(3H)-
one derivatives were assessed for antibacterial activity
against gram-positive and gram-negative human
pathogenic bacterial strains by using the paper disc
diffusion method. The bacterial strains, Pseudomonas
aeruginosa (MTCC-424), Escherichia coli (MTCC-
443), Bacillus subtilis, and Staphylococcus aureus
(MTCC-96), were compared with the standard drugs
Norfloxacin and Ofloxacin.
Over the recent decade tetra n-butyl ammonium
bromide (TBAB) has emerged as an inexpensive, mild
and environmentally compatible phase transfer catalyst
(PTC) in various organic transformations [6, 7].
Herein, we focused on phase transfer catalysis for the
synthesis of the target compounds. The compounds 3b
and 5h demonstrated the remarkable activity.
RESULTS AND DISCUSSION
All products exhibited antibacterial activity against
gram –ve and gram +ve bacteria (Table 3).
Compounds 3a, 3b, 5d–5f, 5h demonstrated the
highest antibacterial activity with all species.
The synthetic approach to 2-mercapto quinazolin-
4(3H)-one substituted compounds 3a, 3b and 5a–5h is
presented in Schemes 1 and 2.
Molecular docking. The synthesized compounds
3a, 3b and 5a–5h were studied by the molecular
docking method. Molecules were built using Maestro
build panel and prepared by LigPrep 2.0 application.
Crystal structures of S. aureus DNA gyrase (PDB id:
4PLB [8], was retrieved from protein data bank
(www.rcsb.org). GLIDE 5.6 [9] was used for
molecular docking. The protein was prepared using
The efficient synthesis of compounds 5a–5h was
carried out in water media. For optimizing the process
TBAB and NaOH were added but the yield was not
improved because of poor solubility of the reactants 1a
and 4 in water. For this reason various mixtures of
1 The text was submitted by the authors in English.
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SYNTHESIS, ANTIMICROBIAL ACTIVITY, AND DOCKING STUDIES
775
Scheme 1. Synthesis of 2-[(2-oxo-2-phenylethyl)thio]-3-phenylquinazolin-4(3H)-one (3a, 3b).
O
O
5
K2CO3 (1.5 eq)
Ethanol (5 mL)
R2
S
R2
4
N
N
R1
R1
O
7
N
1
N
SH
2
Br
O
1a, 1b (1.0 eq)
3a, 3b
2a (1.5 eq)
room temperature, 12 h
R1 = 6-Cl, R2 = Ph (1a, 3a), R1 = 5-I, R2 = Ph (1b), R1 = 6-I, R2 = Ph (3b).
Scheme 2. Synthesis of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-3-substitutedquinazolin-4(3H)-ones (5a–5h).
O
O
NaOH (1.5 eq)
R2
TBAB (10% mmol)
5
R2
4
H2O/EtOH
O
N
N
O
R1
R1
N
SH
7
N
1
S
N
2
X
Br
N
1a−1e (1.0 eq.)
5a−5h
X
4a (X = CH2); 4b (X = O) (1.5 eq.)
room temperature, 12 h
R1 = H; R2 = Ph– (1a); R1 = H; R2 = 4-Cl-C6H4– (1b); R1 = H; R2 = Ph-CH2– (1c); R1 = 6-Cl; R2 = Ph– (1d); R1 = 5-I; R2 = Ph–
(1e); R1 = H, R2 = Ph, X = CH2 (5a); R1 = H, R2 = 4-Cl-C6H4–, X = CH2 (5b); R1 = H, R2 = 4-Cl-C6H4–, X = O (5c); R1 = H,
R2 = Ph-CH2–, X = CH2 (5d); R1 = H, R2 = Ph-CH2–, X = O (5e); R1 = 6-Cl, R2 = Ph–, X = CH2 (5f); R1 = 6-Cl, R2 = Ph–,
X = O (5g); R1 = 5-I, R2 = Ph–, X = O (5h).
protein preparation module applying the default
parameters. Grid was generated around the active site
of the receptor by selecting the co-crystallized ligand.
Receptor Van-der-Waals scaling for the nonpolar
atoms was fixed as 0.9 [10]. Low-energy conformation
of the ligands was selected and docked into the grid
using extra-precision (XP) docking mode. Dock pose
of each ligand was analyzed for interactions with the
receptor.
5h and H atom of Met 1121 of the receptor, with bond
length of 1.95 Å. The co-crystal ligand showed one
H-bond interaction between H atom of the crystal
Table 2. Synthetic data for compounds 5a–5ha
Comp.
R1
R2
X
Yieldb, %
mp, °C
no.
5a
5b
5c
5d
5e
5f
H
Ph
CH2
80
85
85
85
85
80
85
85
142–144
165–167
150–152
177–179
158–160
198–200
178–180
142–144
H
p-Cl-Ph CH2
The binding mode of compound 5h with DNA
gyrase demonstrated one H-bond between O atom of
H
CH2-Ph CH2
H
p-Cl-Ph
CH2-Ph
Ph
O
Table 1. Optimization of the synthesis of compound 5a
H
O
Solvent
H2O
TBABr, mmol % Time, h
Yield, %
6-Cl
6-Cl
5-I
O
10
10
10
10
10
6
6
6
6
6
–
5g
5h
Ph
CH2
O
H2O–Toluene
H2O–Benzene
H2O–THF
20
25
45
80
Ph
a
Reaction conditions: 2-mercapto 3-substituted quinazolin-4(3H)-
one (1.0 mmol), TBAB (1.5 mmol), K2CO3 (1.5 mmol), phenacyl
bromide–amidoalkyl (1.5 mmol) in aqueous media.
Isolated yield.
b
H2O–Ethanol
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BALASWAMY et al.
120 mesh). Melting points were determined on a
Fischer-Johns apparatus. IR spectra were recorded on a
Thermo Nicolet Nexus 670 FT-IR spectrophotometer
using KBr discs. 1H and 13C NMR spectra were
measured on a Bruker Avance 400 and an Innova 75
MHz spectrometers in CDCl3 media using Me4Si as an
internal standard. ESI-MS spectra were measured on a
Finnigan MAT 1020 spectrometer.
Synthesis of 2-[(2-oxo-2-phenylethyl)thio]-3-
phenylquinazolin-4(3H)-ones (3a, 3b) (general proce-
dure). To the mixture of 2-mercapto-3-substituted
quinazolin-4(3H)-one (1a) (1.0 mmol) with K2CO3
(1.5 mmol) in ethanol the respective phenacyl bromide
2 (1.5 mmol) was added upon stirring and the
following stirred at room temperature lasted for 12 h.
The solvent was removed under reduced pressure. The
remaining mixture was extracted with ethyl acetate
followed by evaporation of the solvent and purification
by silica gel (60–120 mesh) using MeOH–CHCl3
(1 : 9) as an eluent to give a corresponding derivative
3a, 3b.
Fig. 1. Dock pose conformation of the most active
compound 5h in the active site of S. aureus DNA gyrase
(H-bond with Met 1121 amino acid).
ligand and O atom of DNA gyrase, bond length 1.98 Å
(Fig. 1). The ligand interaction diagram is presented in
Fig. 2. The docking binding energies of all the com-
pounds are tabulated in Table 4.
Synthesis of 2-{[3-oxo-3-(alkyl/aryl-1-yl)alkyl]thio}-
3-substituted quinazolin-4(3H)-ones (5a–5h). 2-Mer-
capto-3-substituted quinazolin-4(3H)-one (1a) (1.0 mmol),
NaOH (1.5 mmol) and TBAB (10 mmol %) were
dissolved in water–ethanol (3 : 2) mixture. Upon
following stirring, a respective amidoalkyl bromide 4
EXPERIMENTAL
TLC was carried out using pre-coated silica-gel
plates (60 F254, 0.2-mm layer, E. Merck). Column
chromatography was carried out using silica gel (60–
Fig. 2. Ligand interaction diagram for the most active compound 5h.
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SYNTHESIS, ANTIMICROBIAL ACTIVITY, AND DOCKING STUDIES
777
Table 3. Range of minimum inhibitory concentration (MIC)
(1.5 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h, then extracted
with ethyl acetate followed by evaporation of the
solvent and purification on silica gel (60–120 mesh)
using MeOH–CHCl3 (1 : 9) as an eluent to give the
corresponding solid, mostly yellow, products 5a–5h .
valuea
MIC, mg/mL
Compound
6-Chloro-2-[(2-oxo-2-phenylethyl)thio]-3-phenyl-
quinazolin-4(3H)-one (3a). Colourless solid, yield
65%, mp 211–213°C. IR spectrum, ν, cm–1: 2912,
1
1710, 1600, 1500. H NMR spectrum, δ, ppm: 8.10 d
gram +ve
gram –ve
(2H), 8.05 s (1H), 7.75 m (1H), 7.57–7.63 m (6H),
7.40–7.51 m (5H), 7.06 l (1H), 4.75 s (2H). 13C NMR
spectrum, δ, ppm: 193, 166, 162, 147, 137, 136, 134,
132, 130, 129, 128, 127, 124, 121, 120, 36. ESI-
HRMS: m/z: 406.8805 [M + H]+. C22H15ClN2S2O.
3a
32
34
34
>50
3b
27
>50
27
45
21
35
27
35
27
–
26
50
45
45
26
40
30
45
26
≤17
–
34
>50
34
45
28
34
24
34
28
–
27
>50
45
5a
5b
5-Iodo-2-[(2-oxo-2-phenylethyl)thio]-3-phenyl-
quinazolin-4(3H)-one (3b). Pale yellow solid, yield
65%, mp 186–188°C. IR spectrum, ν, cm–1: 3245,
5c
>50
27
5d
1
1698, 1600, 1552. H NMR spectrum, δ, ppm: 8.0 m
5e
35
(1H), 7.76–7.80 m (2H), 7.46–7.50 m (4H), 7.44–7.7.3
m (2H), 7.31 m (1H), 7.27–7.29 m (8H), 4.33 s (2H).
13C NMR spectrum, δ, ppm: 194, 167, 165, 144, 140,
138, 135, 134, 132, 131, 129, 122, 98, 37. ESI-HRMS:
m/z: 497.9987 [M + H]+. C22H15IN2O2S.
5f
32
5g
45
5h
27
Norfloxacin
Ofloxacin
≤15
–
2-{[3-Oxo-3-(piperidin-1-yl)propyl]thio}-3-phenyl-
quinazolin-4(3H)-one (5a). IR spectrum, ν, cm–1:
≤15
≤16
1
a
The MIC values are interpreted as an average of triplets.
3377, 1710, 1594, 1499. H NMR spectrum, δ, ppm:
Table 4. Glide score, E model score, and ADME properties of the synthesized compounds
Comp.
no.
Glide score
(XP)
E model
score
QPlog QPlog
QPP
QPlog
BBd
QPPMD
CKe
Human oral
MWt
Po/wa
3.51
4.02
2.89
3.83
2.70
4.20
2.89
3.05
4.22
4.74
Sb
Cacoc
absorptionf, %
3a
3b
5a
5b
5c
5d
5e
5f
–5.42
–5.06
–4.32
–4.62
–3.83
–5.72
–4.77
–4.28
–5.58
–6.03
–56.87
–57.53
–58.76
–58.99
–48.99
–65.61
–55.69
–62.97
–62.39
–61.07
393.5
427.9
429.9
407.5
409.5
427.9
429.9
521.4
406.9
498.3
–4.76 1115.94
–5.52 1116.12
–4.05 1101.24
–4.80 1156.68
-3.33 1141.12
–5.76 1500.92
–4.05 1101.41
–4.10 1361.89
–4.76 1613.57
–0.475
–0.316
–0.289
–0.589
–0.563
–0.203
–0.289
–0.183
–0.198
–0.302
1142.39
2819.64
2788.44
1147.50
1134.68
3506.07
2788.06
3528.96
2966.99
2584.08
100.00
100.00
100.00
100.00
100.00
100.00
100.00
87.93
5g
5h
100.00
100.00
–5.96 1773.28
a
b
Predicted octanol/water partition coefficient log P (acceptable range 2.0–6.5). Predicted aqueous solubility in mol/L (acceptable range
c
d
6.5–0.5). Predicted caco cell permeability in nm/s (acceptable range: <25 is poor and >500 is great). Predicted blood brain barrier
permeability (acceptable range 3–1.2). e Predicted apparent MDCK cell permeability in nm/s (acceptable range: <25 is poor and >500 is
great). f Percentage of human oral absorption (acceptable range: <25 is poor and >80% is high).
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BALASWAMY et al.
7.95 s (2H), 7.76 s (1H), 7.44 t (2H), 7.52 m (2H) and
7.3 m (4H), 3.41 m (4H) 3.31 m (2H), 2.73 t (2H),
1.52 m (2H), 1.39 m (4H). 13C NMR spectrum, δ, ppm:
175, 165, 163, 145, 135, 132, 130, 129, 127, 125, 123,
122, 121, 48, 30, 28, 24, 23. ESI-HRMS: m/z:
393.5896 [M + H]+. C22H23N3O2S.
6-Chloro-2-{[3-oxo-3-(piperidin-1-yl)propyl]thio}-
3-phenylquinazolin-4(3H)-one (5g). IR spectrum, ν,
cm–1: 2924, 1708, 1606, 1541, 1408. 1H NMR
spectrum, δ, ppm: 8.09 d (1H), 7.64 s (1H), 7.41–7.56
m (6H), 3.31–3.48 m (9H), 2.75 t (2H), 1.55 s (2H),
1.39–1.46 m (4H). 13C NMR spectrum, δ, ppm: 173,
167, 165, 142, 135, 132, 131, 129, 122, 121.5, 121, 48,
30, 28, 24, 23. ESI-HRMS: m/z: 427.1134 [M + H]+.
C22H22ClN3O2S.
3-(4-Chlorophenyl)-2-{[3-oxo-3-(piperidin-1-yl)-
propyl]thio}quinazolin-4(3H)-one (5b). IR spectrum,
ν, cm–1: 3430, 1726, 1601, 1511. 1H NMR spectrum, δ,
ppm: 7.98 d (1H), 7.50 d (3H), 7.48 s (1H), 7.28 d
(1H), 7.21(s, 2H), 3.40 s (6H), 2.28 m (4H), 1.53 m
(2H), 1.38 m (4H). 13C NMR spectrum, δ, ppm: 174,
163, 160, 148, 134, 131, 129, 128, 127, 123, 122, 121,
50, 34, 27, 25. ESI-HRMS: m/z: 427.1134 [M + H]+.
C22H22ClN3O2S.
5-Iodo-2-[(3-morpholino-3-oxopropyl)thio]-3-
phenylquinazolin-4(3H)-one (5h). IR spectrum, ν, cm–1:
1
3221, 1680, 1560, 1362. H NMR spectrum, δ, ppm:
7.96 d (1H), 7.71 m (1H), 7.22–7.33 m (8H), 3.7 s
(2H), 3.6 s (4H), 3.40 s (6H), 2.74 d (2H). 13C NMR
spectrum, δ, ppm: 172, 162, 153, 143, 141, 134, 129,
128, 127,124, 123, 121, 64, 47, 44, 33, 32, 25. HRMS:
m/z: 521.0312 [M + H] +. C21H20IN3O3S.
3-Benzyl-2-{[3-oxo-3-(piperidin-1-yl)propyl]-
thio}quinazolin-4(3H)-one (5c). IR spectrum, ν, cm–1:
1
3080, 1702, 1605, 1518, 1403. H NMR spectrum, δ,
Antibacterial tests. Inoculation of all microbes
obtained from Microbial Type Culture Collection
(MTCC) in autoclaved LB broth media and incubated
over night at 37°C for bacterial growth. From that 0.2
ml of the bacterial culture was taken and inoculated by
using spreader on freshly prepared autoclaved agar
plates, Petri dishes. After sterilizing of the 5 mm
sample disc, the compounds 3a, 3b, and 5a–5h were
dissolved in DMSO and kept on microbial plate along
with positive controls Norfloxacin for Staphylococcus,
Pseudomonas and Ofloxacin for Bacillus and E. coli.
Incubation was carried out at 37°C overnight in a BOD
incubator. Zones of inhibition were measured. The
minimum inhibitory concentration (MIC) values were
determined by the micro broth dilution method.
ppm: 7.98 d (1H), 7.78 m (1H), 7.43 d (1H), 7.23–7.37
m (6H), 5.67 s (2H), 3.46 m (6H), 2.78 t (4H), 1.57 m
(2H), 1.48 m (4H). 13C NMR spectrum, δ, ppm: 176,
160, 155, 148, 141, 134, 130, 129, 128, 126, 124, 121,
47, 44, 33, 29, 27, 26. ESI-HRMS: m/z: 407.1734 [M +
H]+. C22H25N3O2S.
3-(4-Chlorophenyl)-2-[(3-morpholino-3-oxopropyl)-
thio]quinazolin-4(3H)-one (5d). IR spectrum, ν, cm–1:
1
2924, 1721, 1606, 1444. H NMR spectrum, δ, ppm:
8.07 s (1H), 7.65 s (1H), 7.47 m (3H), 7.29 m (3H),
3.55 m (4H), 3.41 d (6H), 2.75 t (2H). 13C NMR
spectrum, δ, ppm: 170, 165, 160, 146, 136, 132, 130,
129, 128, 127, 123, 122, 120, 64, 56, 30, 27. ESI-
HRMS: m/z: 429.0987 [M + H]+. C21H20ClN3O3S.
CONCLUSIONS
3-Benzyl-2-[(3-morpholino-3-oxopropyl)thio]-
quinazolin-4(3H)-one (5e). IR spectrum, ν, cm–1:
We have synthesized 2-[3-(alkyl/aryl-1-yl)thio]-3-
substituted quinazolin-4(3H)-ones (3a, 3b, 5a–5h)
according to the new protocol using TBAB as PTC in
water–ethanol media with excellent yields. Antibac-
terial activity tests of the products indicated com-
pounds 3b, 5h as highly active. The binding mode of
the synthesized compounds with protein active site
was predicted using the molecular docking technique.
1
2923, 1708, 1601, 1521, 1343. H NMR spectrum, δ,
ppm: 7.95 s (1H), 7.75 m (1H), 7.41 d (1H), 7.34–7.24
m (6H), 5.68 s (2H), 3.53 s (4H), 3.41 s (6H), 2.76 s
(2H). 13C NMR spectrum, δ, ppm: 172, 162, 153, 143,
140, 134, 129, 128, 127, 123, 122, 65, 47, 45, 33, 32,
25. ESI-HRMS: m/z: 409.1532 [M + H]+. C22H23N3O3S.
6-Chloro-2-[(3-morpholino-3-oxopropyl)thio]-3-
phenylquinazolin-4(3H)-one (5f). IR spectrum, ν, cm–
1: 2923, 1686, 1554, 1430. 1H NMR spectrum, δ, ppm:
8.08 d (1H), 7.66 s (1H), 7.41–7.53 m (5H), 3.33–3.53
m (9H), 2.76 d (J = 6.8 Hz, 2H) 1.35–1.59 m (6H). 13C
NMR spectrum, δ, ppm: 173, 167, 165, 142, 135, 132,
131, 130, 129, 123, 122, 121, 48, 30, 28, 24, 23. ESI-
HRMS: m/z: 429.0985 [M + H]+. C21H20ClN3O3S.
ACKNOWLEDGMENTS
The author Balaswamy Puligilla is thankful to
Central Electrochemical Research Institute (CSIR) for
providing financial assistance and Department of
Chemistry, Osmania University for providing facility,
constant support and encouragement.
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779
Song, W., and Chang, M., J. Med. Chem., 2016, vol. 59,
p. 5011. doi 10.1021/acs.jmedchem.6b00372
6. Amantini, D., Fringuelli, F., Pizzo, F., and Vaccaro, L.,
J. Org. Chem., 2001, vol. 66, p. 6734. doi 10.1021/
jo015814s
REFERENCES
1. Kumar, A., Sharma, P., Kumari, P., and Kalal, B.L.,
Bioorg. Med. Chem. Let., 2011, vol. 21, p. 4353. doi
10.1016/j.bmcl.2011.05.031
2. Veena Vani, K., Ramesh, G., and Venkata Rao, C.,
J. Het. Chem., 2016, vol. 53, p. 719. doi 10.1002/
jhet.2353
7. Khurana, J.M. and Kumar, S., Tetrahedron Lett., 2009,
vol. 50, p. 4125. doi 10.1016/j.tetlet.2009.04.125
8. Schrödinger, L.L.C., Glide, Version 4.0. New York, 2005.
9. Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A.,
Klicic, J.J., Mainz, D.T., and Shenkin, P.S., J. Med.
Chem., 2004, vol. 47, p. 1739. doi 10.1021/jm0306430
10. Qikprop 3.4, Schrödinger, L.L.C, New York, 2010.
3. Jatav, V., Kashaw, S., and Mishra, P., Med. Chem. Res.,
2008, vol. 17, p. 205. doi 10.1007/s00044-007-9054-3
4. Aly, A.A., Chin. J. Chem., 2003, vol. 21, p. 339. doi
10.1002/cjoc.20030210324
5. Bouley, R., Ding, D., Peng, Z., Bastian, M., Lastochkin, E.,
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