Synthesis, biological evaluation and QSAR study of a series of substituted quinazolines as antimicrobial agents

Article abstract of DOI:10.1007/s00044-012-0408-0

A novel series of 1-N-substituted-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2- ylthio)quinazolin-6-yl)urea/thiourea derivatives (6a-6r) and 1-N-substituted-3-(7-(4-methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3, 4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives (14a-14s) were synthesized and screened for antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli. Biological results indicated that the synthesized compounds showed a broad-spectrum activity against tested microorganisms at MIC values between 6.25 and 100 μg/mL. Compound 6r showed a broad spectrum of activity and was found to be active against all tested species. A quantitative structure-activity relationship study has been carried out on the synthesized compounds to get better insights into pharmacophoric features responsible for the antibacterial activity. Genetic function approximation technique was used to identify descriptors that influence biological activity. Hydrophobic (AlogP98), electronic (atomic polarizability), and topological (radius of gyration) descriptors were found to affect the activity significantly. Generated model was found to be statistically significant (r ² = 0.86, predictive index = 0.96) and predictive as indicated by very low residuals in internal and external cross-validation.

Full text of DOI:10.1007/s00044-012-0408-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4096–4109
DOI 10.1007/s00044-012-0408-0
ORIGINAL RESEARCH
Synthesis, biological evaluation and QSAR study of a series
of substituted quinazolines as antimicrobial agents
•
Vipul M. Buha Dharmaraj N. Rana Mahesh T. Chhabria
•
•
•
Kishor H. Chikhalia Bhushan M. Mahajan
•
•
Pathik S. Brahmkshatriya Nisha K. Shah
Received: 3 May 2012 / Accepted: 8 December 2012 / Published online: 21 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A novel series of 1-N-substituted-3-(4-(5-(pyridin-
3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea
derivatives (6a–6r) and 1-N-substituted-3-(7-(4-meth-
ylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
ylthio)quinazolin-6-yl)urea/thiourea derivatives (14a–14s)
were synthesized and screened for antimicrobial activity
against Staphylococcus aureus, Bacillus subtilis, Pseudo-
monas aeruginosa, and Escherichia coli. Biological results
indicated that the synthesized compounds showed a broad-
spectrum activity against tested microorganisms at MIC
values between 6.25 and 100 lg/mL. Compound 6r showed
a broad spectrum of activity and was found to be active
against all tested species. A quantitative structure–activity
relationship study has been carried out on the synthesized
compounds to get better insights into pharmacophoric fea-
tures responsible for the antibacterial activity. Genetic
function approximation technique was used to identify
descriptors that influence biological activity. Hydrophobic
(AlogP98), electronic (atomic polarizability), and topologi-
cal (radius of gyration) descriptors were found to affect the
activity significantly. Generated model was found to be
statistically significant (r2 = 0.86, predictive index = 0.96)
and predictive as indicated by very low residuals in internal
and external cross-validation.
Keywords Antimicrobial agents ꢀ
Quantitative structure–activity relationship ꢀ
Genetic function approximation ꢀ Quinazoline
Introduction
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0408-0) contains supplementary
material which is available to authorized users.
Research of new drug agents possessing antibacterial
activity has attracted considerable attention owing to the
continuing increase in multi-drug resistant microbial
infections in the past few decades. Further, infection
caused by various microorganisms poses a serious chal-
lenge to the medical community, and the need for an
effective therapy has led to the search for novel antimi-
crobial agents. In particular, the emergence of multi-drug
resistant strains of Gram-positive bacterial species such
as methicillin-resistant Staphylococcus aureus (MRSA),
Staphylococcus epidermis, vancomycin-resistant S. aureus
(VRSA), oxacillin-resistant S. aureus (ORSA), and
vancomycin-resistant Enterococcus has raised alarming
concerns necessitating effective drug regimen against bac-
terial infections (Dalhoff, 1994; Livermore, 2000; Poole,
2001, 2004; Abbanat et al., 2003; Bozdogan et al., 2003).
V. M. Buha ꢀ D. N. Rana ꢀ K. H. Chikhalia ꢀ N. K. Shah (&)
Department of Chemistry, Gujarat University,
Ahmedabad 380 009, Gujarat, India
e-mail: nishchem2004@yahoo.co.in
M. T. Chhabria ꢀ B. M. Mahajan
Department of Pharmaceutical Chemistry, L. M. College
of Pharmacy, Ahmedabad 380 009, Gujarat, India
e-mail: mahesh.chhabria@rediffmail.com
P. S. Brahmkshatriya (&)
Institute of Organic Chemistry and Biochemistry, Academy
of Sciences of the Czech Republic and Center
for Biomolecules and Complex Systems,
´
Flemingovo nam. 2, 166 10 Prague 6, Czech Republic
e-mail: pathik26@yahoo.com
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Med Chem Res (2013) 22:4096–4109
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Substituted quinazoline derivatives constitute an
important class of compounds possessing anticancer (Xia
et al., 2001), antitubercular (Mosaad et al., 2004), anti-
inflammatory (Gineinah et al., 2002), anticonvulsant, CNS
depressant, and anti-HIV activity (Rosowsky et al., 1999).
The quinazoline ring skeleton is also widely found
in alkaloids and many biologically active compounds
(Alenxandre et al., 2003). There are many examples in the
literature, which highlight the potential of quinazoline
derivatives for antimicrobial chemotherapy (Knesl et al.,
2006; Jantova et al., 2004; Bedi et al., 2004).
room temperature. The reaction mixture was refluxed for 4 h.
The reaction mixture was cooled to room temperature and
poured in ice-water. The pH was adjusted to 8 with liquid
ammonia. The generated ester was then extracted with diethyl
ether, and the organic layer was concentrated to obtain ethyl
nicotinate which was used directly without further purifica-
tion. Yield: 78 %, bp: 222–224 °C (222–224 °C) (Sharma
et al., 2009).
Nicotinicacid hydrazide (1c)
To a solution of 1b (3.0 g, 0.02 mol) in ethanol (10 mL),
hydrazine hydrate (1.0 g, 0.02 mol) was added portion wise
at reflux temperature. The reaction mixture was heated for
next 30 min after which it was cooled to room temperature to
form a solid mass which was filtered, washed with ethanol,
and recrystallized from ethanol. Yield: 63 %, mp:
161–162 °C (161–163 °C) (Sharma et al., 2009).
Quantitative structure–activity relationship (QSAR)
approach, pioneered by Hansch and Fujita (1964), is one of
the most widely used strategies for ligand-based drug
design. It provides useful insights into the pharmacophoric
features responsible for the biological activity and helps
generate a mathematical model which can help predict
activity of untested compounds quantitatively. In brief,
QSAR study usually leads to a predictive formula by cor-
relation with the biological activity of a homologous series
of compounds and their physicochemical properties (Ertan
et al., 2009). The present study focuses on the synthesis
and biological activity of a series of novel substituted
quinazoline derivatives. To gain insights into the key
substitutions (pharmacophoric groups) which affect the
antimicrobial activity, a QSAR study was carried out using
genetic function approximation embedded in Discovery
Studio 2.1 (Accelrys Inc., USA).
5-(3-Pyridinyl)-1,3,4-oxadiazol-2-thiol (1d)
A mixture of 1c (2.7 g, 0.02 mol), potassium hydroxide
(1.1 g, 0.02 mol), carbon disulfide (1.5 g, 0.04 mol), and
ethanol (30 mL) was refluxed for 5 h. Ethanol was distilled
off under reduced pressure, and the residue was dissolved
in water and acidified with 1 N HCl. The solid obtained
was filtered, washed, dried, and recrystallized from etha-
nol. Yield: 70 %, mp: 220–222 °C.
4-Hydroxy-6-nitroquinazoline (2)
5-Nitroanthrnilonitrile (7.0 g, 0.043 mol) was added por-
tion wise with stirring over 30 min to a mildly refluxed
solution of formic acid (85 mL) and conc. sulfuric acid
(6 mL). The reaction mixture was refluxed for further
30 min, cooled to room temperature, and poured into cru-
shed ice. The precipitates were filtered off, washed, and
recrystallized from ethanol to afford 4-hydroxy-6-nitro-
quinazoline (2). Yield: 6.70 g (82 %), mp: 276–277 °C. 1H
NMR (DMSO-d6): d ppm 12.8 (s, 1H), 8.80 (d, 1H), 8.54
(dd, 1H), 8.32 (s, 1H), 7.86 (d, 1H).
Materials and methods
Chemistry
All chemicals and reagents used in the study were of analytic
grade and were used directly. Melting points were deter-
mined in an open glass capillary and are uncorrected. Thin
layer chromatography (TLC) was performed on Silica Gel G
(Merck), and spots were visualized under UV radiation, by
exposure to iodine vapors ,and with various spray reagents,
viz. ninhydrin and dragendorff’s reagents. Elemental anal-
ysis was carried out on a PERKIN ELMER 2400 instrument.
IR spectra were recorded on FT IR Spectrometer Shimadzu
4-Chloro-6-nitroquinazoline (3)
A mixture of 2 (6.0 g, 0.031 mol) and phosphorous penta-
chloride (9.8 g, 0.047 mol) was melted and stirred for 3 h at
160 °C. The mixture was allowed to cool to room tempera-
ture. The resulting solid was washed with petroleum ether,
filtered, dried, and used directly in the next step.
1
8201 PC instrument in KBr pellets. H NMR spectra were
recorded on 400 MHz BRUKER ULTRASHIELD, and
chemical shift values were expressed in d ppm downfield
from the internal standard, tetramethylsilane. The synthetic
pathways are shown in Schemes 1 and 2.
6-Nitro-4-[(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
yl)sulfanyl]quinazoline (4)
Ethyl nicotinate (1b)
A suspension of 3 (5.0 g, 0.023 mol), 1d (3.6 g, 0.023 mol),
and K2CO3 (5.5 g, 0.046 mol) in isopropanol (30 mL) was
To a solution of nicotinic acid (5.0 g, 0.04 mol) in ethanol
(15 mL), conc. sulfuric acid (6.5 mL) was added drop wise at
123

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Med Chem Res (2013) 22:4096–4109
Scheme 1 a Ethanol, conc.
H2SO4, reflux; b hydrazine
hydrate, ethanol, reflux; c CS2/
KOH, ethanol, reflux;
O
O2N
NH
O2N
CN
d HCOOH, conc. H2SO4, reflux;
e PCl5, 160 °C; f IPA, dry
K2CO3, reflux; g Fe, acetic acid/
H2O, rt; h isocyanates/
N
(d)
NH2
2
O
O
O
isothiocyanates, dry DMF, rt
NH2
(e)
O
N
OH
H
N
N
(a)
(b)
N
1c
(c)
1b
1a
Cl
N
N
N
O2N
SH
N
O
N
1d
3
(f)
N
N
N
N
N
N
O
S
N
O
S
O2N
N
(g)
H2N
N
N
4
5
(h)
N
N
R
NH
X
O
S
N
N
HN
N
X=O;
X=S;
6 (a-i)
6 (j-r)
refluxed for 6 h. The reaction mixture was poured into ice-
water, and the resulting solid was filtered off, washed with
water, and dried to afford 6-nitro-4-[(5-(pyridin-3-yl)-
1,3,4-oxadiazol-2-yl)sulfanyl]quinazoline (4). The com-
pound was found to be sufficiently pure to be used in the
next step without further purification. Yield: 4.73 g (56 %),
The reaction mixture was further stirred for next 6 h. The
insoluble material was removed by Celite filtration, and the
filtrate was basified to pH *8 by addition of liquid
ammonia. The resultant solid was filtered off, washed with
water, and recrystallized from ethanol. Yield: 3.40 g
1
(68 %), mp: 181–183 °C. H NMR (DMSO-d6): d 9.23 (s,
1H), 8.70 (d, 1H), 8.43 (dd, 1H), 8.07 (dd, 1H), 7.54 (dd,
1
mp: 245–247 °C. H NMR (DMSO-d6): d 9.87 (d, 1H),
8.91 (s, 1H), 8.82 (s, 1H), 8.53–8.60 (m, 3H), 8.09 (dd,
1H), 7.33 (m, 1H), 7.08–7.15 (d, 2H), 5.03 (broad, 2H).
1H), 7.80 (dd, 1H), 7.34 (t, 1H).
General procedure for the preparation of 1-aryl-3-[4-
((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
4-[(5-(Pyridin-3-yl)-1,3,4-oxadiazol-2-
yl)sulfanyl]quinazolin-6-amine (5)
yl)sulfanyl)quinazolin-6-yl]urea (6)
To a mixture of 4 (4.9 g, 0.014 mol) in water (20 mL)
containing acetic acid (14 mL, 0.224 mol) was added iron
(7.0 g, 0.126 mol) portion wise with stirring at 10–15 °C.
A solution of 5 (1.0 g, 0.003 mol) in DMF (20 mL) and
appropriate aryl isocyanate/isothiocyanate (0.003 mol) was
stirred at room temperature for 24 h. The content of the
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Med Chem Res (2013) 22:4096–4109
4099
Scheme 2 a Ethanol, conc.
H2SO4, reflux; b hydrazine
hydrate, ethanol, reflux; c CS2/
KOH, ethanol, reflux;
d HCONH2, reflux; e HNO3,
conc. H2SO4, rt; f PCl5, 160 °C;
g IPA, dry K2CO3, reflux;
h N-methyl piperazine, dry
K2CO3, DMF, reflux; i Fe,
acetic acid/H2O, rt;
O
O
N
O
N
O2N
Cl
OH
NH2
NH
NH
(d)
Cl
(e)
Cl
9
7
8
O
O
O
(f)
NH2
O
N
OH
H
N
N
(a)
(b)
N
j isocyanates/isothiocyanates,
dry DMF, rt
1c
1b
1a
(c)
Cl
N
N
N
O2N
N
SH
+
O
Cl
10
1d
N
(g)
N
N
N
N
N
N
O
O
S
N
S
N
N
O2N
N
O2N
Cl
(h)
N
12
N
11
H3C
(i)
N
R
N
N
O
N
HN
X
O
S
N
S
N
HN
N
N
H2N
N
(j)
N
N
N
N
H3C
N
13
H3C
14 (a-j)
X=O;
X=S; 14 (k-s)
1-(2-Chlorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
reaction was poured into ice-water, filtered, washed with
water, and recrystallized from ethanol to yield the desired
compound.
2-ylthio)quinazolin-6-yl)urea (6b)
Yield: 55.5 %, mp: 105–107 °C, 1H-NMR (DMSO-d6) d
ppm: 8.89 (s, 1H), 8.78 (s, 1H), 8.60 (dd, 1H), 8.16 (m,
2H), 8.07 (m, 2H), 7.43 (t, 1H), 7.62 (m. 1H), 7.28 (m, 1H),
7.18 (m, 1H), 7.01 (m, 1H), 5.08 (s, 2H). C22H14ClN7O2S;
Calc. C, 55.43; H, 2.88; N, 20.78; Found C, 55.52; H, 2.97;
N, 20.60; MS (ESI) m/z 476.9 (M?1).
1-Phenyl-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl-
thio)quinazolin-6-yl)urea (6a)
Yield: 56.9 %, mp: 145–147 °C, 1H NMR (DMSO-d6) d
ppm: 8.92 (s, 1H), 8.69 (s, 1H), 8.58 (dd, 1H), 8.09 (m,
2H), 7.99 (m, 2H), 7.38 (t, 1H), 7.23–7.24 (m, 2H),
7.16–7.18 (m, 2H), 6.98 (m, 1H), 5.04 (s, 2H).
C22H15N7O2S; Calc. C, 59.63; H, 3.53; N, 22.18; Found
C, 59.85; H, 3.42; N, 22.21; MS (ESI) m/z 442.2
(M?1).
1-(4-Chlorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)urea (6c)
Yield: 33.9 %, mp: 150–152 °C, 1H-NMR (DMSO-d6) d
ppm: 8.0.87 (s, 1H), 8.74 (s, 1H), 8.58 (dd, 1H), 8.08 (m,
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Med Chem Res (2013) 22:4096–4109
2H), 8.03 (m, 2H), 7.53 (d, 2H, j = 6.8 Hz), 7.41 (t, 1H),
7.44 (d, 2H, j = 6.8 Hz), 5.07 (br, 2H). C22H14ClN7O2S;
Calc. C, 55.64; H, 2.93; N, 20.62; Found C, 55.52; H, 2.97;
N, 20.60; MS (ESI) m/z 476.8 (M?1).
Found C, 64.82; H, 3.79; N, 18.89; MS (ESI) m/z 492.2
(M?1).
1-Cyclohexyl-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
ylthio)quinazolin-6-yl)urea (6i)
1-(2-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)urea (6d)
Yield: 72.3 %, mp: 149–151 °C, 1H NMR (DMSO-d6) d
ppm: 8.96 (s, 1H), 8.78 (s, 1H), 8.51 (dd, 1H), 8.17 (m,
2H), 7.98–8.00 (m, 2H), 7.43 (m, 1H), 5.59 (br, 2H), 3.21
(sextet, 1H), 1.41–1.44 (m, 4H), 1.25–1.29 (m, 6H).
C22H21N7O2S; Calc. C, 59.05; H, 4.73; N, 21.91; Found C,
69.11; H, 4.82; N, 22.09; MS (ESI) m/z 448.2 (M?1).
Yield: 43.8 %, mp: 158–160 °C, 1H NMR (DMSO-d6) d
ppm: 8.96 (s, 1H), 8.74 (s, 1H), 8.54 (dd, 1H), 8.18 (m,
2H), 7.98–8.01 (m, 2H), 7.53 (m, 1H), 7.48 (t, 1H),
7.02–7.05 (m, 2H), 6.79 (m, 1H), 5.06 (s, 2H), 2.41 (s, 3H).
C23H17N7O2S; Calc. C, 60.65; H, 3.76; N, 21.53; Found C,
60.59; H, 3.78; N, 21.48; MS (ESI) m/z 456.7 (M?1).
1-Phenyl-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
ylthio)quinazolin-6-yl)thiourea (6j)
1-(3-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)urea (6e)
Yield: 68.9 %, mp: 121–123 °C, 1H NMR (DMSO-d6) d
ppm: 8.87 (s, 1H), 8.74 (m, 1H), 8.59 (m, 1H), 8.16 (m,
1H), 7.80 (d, 1H), 7.38 (m, 1H), 6.99–7.03 (m, 4H), 6.59
(m, 1H), 6.34 (m, 2H), 3.63 (s, 1H), 3.59 (s, 1H).
C22H15N7OS2; Calc. C, 57.75; H, 3.30; N, 21.43; Found C,
57.80; H, 3.38; N, 21.39; MS (ESI) m/z 458.4 (M?1).
Yield: 64.5 %, mp: 114–116 °C, 1H NMR (DMSO-d6) d
ppm: 8.94 (s, 1H), 8.76 (s, 1H), 8.52 (dd, 1H), 8.16 (m,
2H), 7.99–8.02 (m, 2H), 7.40 (m, 1H), 7.32 (m, 1H), 7.21
(m, 1H), 7.14 (m, 2H), 5.06 (s, 2H), 2.48 (s, 3H).
C23H17N7O2S; Calc. C, 60.65; H, 3.76; N, 21.53; Found C,
59.44; H, 3.69; N, 21.61; MS (ESI) m/z 456.1 (M?1).
1-(2-Chlorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)thiourea (6k)
1-(4-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)urea (6f)
Yield: 55.6 %, mp: 100–102 °C, 1H NMR (DMSO-d6) d
ppm: 8.83 (s, 1H), 8.70 (m, 1H), 8.57 (m, 1H), 8.07 (m,
1H), 7.77 (d, 1H, ja = 8.4 Hz), 7.34 (m, 1H), 7.09 (d, 1H,
jb = 2.1 Hz), 7.02 (dd, 1H, jac = 8.4 Hz, jbc = 2.1 Hz),
6.98 (m, 1H), 6.64 (m, 1H), 6.43–6.44 (m, 2H), 4.03 (s,
2H). C22H14ClN7OS2; Calc. C, 53.71; H, 2.87; N, 19.93;
Found C, 53.66; H, 2.93; N, 19.86; MS (ESI) m/z 492.1
(M?1).
Yield: 62.2 %, mp: 137–139 °C, 1H NMR (DMSO-d6) d
ppm: 8.89 (s, 1H), 8.64 (s, 1H), 8.52 (dd, 1H), 7.96–7.99
(m, 2H), 7.36 (m, 1H), 7.28 (d, 2H), 7.03 (d, 2H), 5.05 (s,
2H), 2.24 (s, 3H). C23H17N7O2S; Calc. C, 60.65; H, 3.76;
N, 21.53; Found C, 59.85; H, 3.80; N, 22.36; MS (ESI)
m/z 456.2 (M?1).
1-Phenethyl-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
1-(3-Chlorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
ylthio)quinazolin-6-yl)urea (6g)
2-ylthio)quinazolin-6-yl)thiourea (6l)
Yield: 69.9 %, mp: 162–164 °C, 1H NMR (DMSO-d6) d
ppm: 8.88 (s, 1H), 8.68 (s, 1H), 8.55 (dd, 1H), 8.21 (m,
2H), 7.44 (t, 1H), 7.06–7.18 (m, 5H), 6.08 (s, 1H), 4.13 (br,
1H), 3.58 (t, 2H), 3.24 (t, 2H). C24H19N7O2S; Calc. C,
61.39; H, 4.08; N, 20.88; Found C, 61.26; H, 4.00; N,
20.81; MS (ESI) m/z 470.3 (M?1).
Yield: 55.7 %, mp: 189–191 °C, 1H NMR (DMSO-d6) d
ppm: 8.96 (s, 1H), 8.77 (m, 1H), 8.52 (m, 1H), 8.04 (m,
1H), 7.84 (d, 1H, ja = 8.9 Hz), 7.64 (m, 1H), 7.24 (d, 1H,
jb = 2.3 Hz), 7.11 (dd, 1H, jac = 8.9 Hz, jbc = 2.3 Hz),
6.94 (m, 1H), 6.40–6.42 (m, 2H), 4.10 (s, 2H).
C22H14ClN7OS2; Calc. C, 53.71; H, 2.87; N, 19.93; Found
C, 53.77; H, 2.84; N, 19.96; MS (ESI) m/z 492.3 (M?1).
1-Biphenyl-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-
ylthio)quinazolin-6-yl)urea (6h)
1-(4-Chlorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl)thiourea (6m)
Yield: 41.7 %, mp: 173–175 °C, 1H NMR (DMSO-d6) d
ppm: 8.98 (s, 1H), 8.64 (s, 1H), 8.56 (d, 1H), 8.44 (m, 1H),
8.28 (m, 1H), 8.02–8.11 (m, 2H), 7.52–7.58 (m, 2H),
7.33–7.40 (m, 7H), 7.31 (m, 1H), 7.17–7.28 (m, 1H), 6.01
(br, 2H). C28H19N7O2S; Calc. C, 64.98; H, 3.70; N, 18.94;
Yield: 65.4 %, mp: 207–209 °C, 1H NMR (DMSO-d6) d
ppm: 8.87 (s, 1H), 8.73 (m, 1H), 8.55 (m, 1H), 8.11 (m,
1H), 7.83 (d, 1H, ja = 8.6 Hz)), 7.39 (m, 1H), 7.07 (d, 1H,
jb = 2.4 Hz), 1H), 6.99 (dd, 1H, jac = 8.6 Hz,
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4101
1-(4-Fluorophenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
jbc = 2.4 Hz), 6.67 (d, 2H, j = 6.9 Hz), 6.54 (d, 2H,
j = 6.9 Hz), 4.07 (s, 2H). C22H14ClN7OS2; Calc. C, 53.71;
H, 2.87; N, 19.93; Found C, 53.49; H, 2.77; N, 19.83; MS
(ESI) m/z 491.1 (M?1).
2-ylthio)quinazolin-6-yl)thiourea (6r)
Yield: 46.7 %, mp: 129–131 °C, 1H NMR (DMSO-d6) d
ppm: 8.79 (s, 1H), 8.67 (m, 1H), 8.43 (m, 1H), 7.94 (m,
1H), 7.71 (d, 1H, ja = 8.1 Hz), 7.56 (m, 1H), 7.18 (d, 1H,
jb = 1.6 Hz), 7.07 (dd, 1H, jac = 8.1 Hz, jbc = 1.6 Hz),
1-(2-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl) thiourea (6n)
0
0
0 0
6.68 (d, 2H, ja b = 7.02 Hz), 6.59 (d, 2H, ja b = 7.02 Hz),
3.98 (s, 2H). C22H14FN7OS2; Calc. C, 55.57; H, 2.97; N,
20.62; Found C, 55.36; H, 3.10; N, 20.81; MS (ESI)
m/z 476.2 (M?1).
Yield: 49.8 %, mp: 139–141 °C, 1H NMR (DMSO-d6) d
ppm: 8.93 (s, 1H), 8.73 (m, 1H), 8.48 (m, 1H), 8.04 (m,
1H), 7.78 (d, 1H, ja = 8.7 Hz), 7.61 (m, 1H), 7.11 (d, 1H,
jb = 1.9 Hz), 7.06 (dd, 1H, jac = 8.7 Hz, jbc = 1.9 Hz),
6.66 (m, 1H), 6.52 (m, 1H), 6.37–6.40 (m, 2H), 3.89 (br,
2H), 3.04 (s, 3H). C23H17N7OS2; Calc. C, 58.58; H, 3.63;
N, 20.79; Found C, 58.47; H, 3.73; N, 20.68; MS (ESI)
m/z 472.3 (M?1).
7-Chloroquinazolin-4(3H)-one (8)
A
mixture of 2-amino-4-chlorobenzoic acid (7.0 g,
0.04 mol) and formamide (45 mL) was refluxed for 2 h.
The reaction mixture was cooled to room temperature and
poured into ice-water. The resulting solid was filtered,
washed with water, and dried to afford 7-chloroquinazolin-
4(3H)-one (8). The compound was found to be sufficiently
pure to be used in the next step without further purification.
Yield: 4.3 g (58.5 %), M.P. 252–254 °C, 1H NMR
(DMSO-d6) d ppm: d 8.90 (s, 1H), 7.83 (s, 1H), 7.68 (s,
1H), 7.24–7.31 (m, 2H).
1-(3-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl) thiourea (6o)
Yield: 43.0 %, mp: 159–161 °C, 1H-NMR (400 MHz, D6
DMSO) d ppm: 8.91 (s, 1H), 8.69 (m, 1H), 8.51 (m, 1H),
7.98 (m, 1H), 7.79 (d, 1H, ja = 8.5 Hz), 7.64 (m, 1H), 7.08
(d, 1H, jb = 1.7 Hz), 7.04 (dd, 1H, jac = 8.5 Hz,
jbc = 1.7 Hz), 6.34 (m, 2H), 6.27–6.26 (m, 2H), 3.76 (s,
2H), 2.52 (s, 3H). C23H17N7OS2; Calc. C, 58.58; H, 3.63;
N, 20.79; Found C, 58.62; H, 3.77; N, 20.91; MS (ESI) m/
z 472.2 (M?1).
7-Chloro-6-nitroquinazolin-4(3H)-one (9)
Compound 8 (7.0 g, 0.038 mol) was added portion wise to
a mixture of conc. nitric acid (7.0 mL, 0.057 mol) and
conc. sulfuric acid (15 mL, 0.281 mol) at a temperature not
exceeding 50 °C. The reaction mixture was then heated at
90 °C for 45 min. The reaction mixture was poured into
ice-water. The resulting solid was filtered, washed with
water, and recrystallized from methanol. Yield: 8.1 g
(92.6 %), mp: 300–303 °C, 1H NMR (DMSO-d6) d ppm: d
8.53 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 3.30 (broad, 1H).
1-(4-Methylphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-
2-ylthio)quinazolin-6-yl) thiourea (6p)
Yield: 59.0 %, mp: 197–199 °C, 1H NMR (DMSO-d6) d
ppm: 8.91 (s, 1H), 8.67 (m, 1H), 8.54 (m, 1H), 7.96 (m,
1H), 7.73 (d, 1H, ja = 8.1 Hz), 7.67 (m, 1H), 7.06 (d, 1H,
jb = 2.1 Hz), 7.02 (dd, 1H, jac = 8.1 Hz, jbc = 2.1 Hz),
6.41 (d, 2H, j = 6.9 Hz), 6.29 (d, 2H, j = 6.9 Hz), 4.01 (s,
2H), 2.47 (s, 3H). C23H17N7OS2; Calc. C, 58.58; H, 3.63;
N, 20.79; Found C, 58.67; H, 3.81; N, 21.22; MS (ESI)
m/z 472.2 (M?1).
4,7-Dichloro-6-nitroquinazoline (10)
A mixture of 9 (6.0 g, 0.026 mol) and phosphorous
pentachloride (8.3 g, 0.04 mol) was melted and stirred for
3 h at 160 °C. The mixture was allowed to cool at room
temperature, and the resulting solid was washed with
petroleum ether, filtered, dried, and used directly in the
next step without further purification.
1-(2-Methoxyphenyl)-3-(4-(5-(pyridin-3-yl)-1,3,4-
oxadiazol-2-ylthio)quinazolin-6-yl) thiourea (6q)
Yield: 56.6 %, mp: 222–224 °C, 1H NMR (DMSO-d6) d
ppm: 8.88 (s, 1H), 8.68 (m, 1H), 8.51 (m, 1H), 8.04 (m,
1H), 7.73 (d, 1H, ja = 8.3 Hz), 7.36 (m, 1H), 7.04 (d, 1H,
jb = 1.9 Hz), 6.87 (dd, 1H, jac = 8.3 Hz, jbc = 1.9 Hz),
6.34 (m, 2H), 6.84 (m, 1H), 6.78 (m, 1H), 6.67–6.65 (m,
2H), 4.07 (s, 2H), 3.21 (s, 3H). C23H17N7O2S2; Calc. C,
56.66; H, 3.51; N, 20.11; Found C, 56.59; H, 3.57; N,
20.17; MS (ESI) m/z 488.2 (M?1).
7-Chloro-6-nitro-4-[5-(3-pyridinyl)-1,3,4-oxadiazolyl}-2-
thio]-quinazoline (11)
A suspension of 10 (5.0 g, 0.02 mol), 1d (3.6 g, 0.02 mol),
and K2CO3 (5.5 g, 0.04 mol) in isopropanol (30 mL) was
refluxed for 7 h. The reaction mixture was poured into ice-
water, and the resulting solid was filtered off, washed with
123

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1-(7-(4-Methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3,4-
water, and dried to afford 7-chloro-6-nitro-4-[5-(3-pyridi-
nyl)-1,3,4-oxadiazolyl}-2-thio]-quinazoline 11. The com-
pound was found to be sufficiently pure to be used in the
next step without further purification. Yield: 66.7 %, mp:
225–227 °C, 1H NMR (DMSO-d6) d ppm: d 9.13 (s, 1H),
8.99 (broad, 1H), 8.79–8.82 (m, 2H), 8.32 (s, 1H), 7.78 (d,
1H), 7.32 (m, 1H).
oxadiazol-2-ylthio)quinazolin-6-yl)-3-phenylurea (14a)
Yield: 57.1 %, mp: 125–127 °C, 1H NMR (DMSO-d6) d
ppm: 8.79 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 8.56 (s, 1H),
8.46 (m, 1H), 8.11 (m, 1H), 7.38 (m, 2H), 7.18–7.20 (m,
3H), 6.76 (m, 1H), 5.76 (br, 2H), 3.28 (br, 4H), 3.07 (br,
4H), 2.51 (s, 3H). C27H25N9O2S; Calc. C, 60.10; H, 4.67;
N, 23.36; Found C, 60.02; H, 4.55; N, 23.28; MS (ESI)
m/z 540.4 (M?1).
7-(4-Methylpiperazin-1-yl)-6-nitro-4-[(5-(pyridin-3-yl)-
1,3,4-oxadiazol-2-yl)sulfanyl]quinazoline (12)
A solution of 12 (2.0 g, 0.005 mol) in DMF (20 mL) was
added to K2CO3 (0.8 g, 0.006 mol), and the resulting mixture
was refluxed for 10 min after which a solution of N-methyl
piperazine (0.5 g, 0.005 mol) in DMF (5 mL) was added drop
wise to it. The reaction mixture was refluxed for next 5 h. The
reaction mixture was cooled to room temperature, poured into
ice-water, and the solid precipitates were filtered off, washed
with water, and dried to afford 7-(4-methylpiperazin-1-yl)-6-
nitro-4-[(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)sulfanyl]qui-
nazoline (12). The compound was found to be sufficiently
pure to be used in the next step without further purification.
Yield: 77.2 %, mp: 205–207 °C, 1H NMR (DMSO-d6) d
ppm: d 8.97 (s, 1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.69 (d, 1H),
8.45 (s, 1H), 7.86 (d, 1H), 7.39 (s, 1H), 4.66 (s, 3H), 3.06
(broad, 4H), 2.92 (broad, 4H).
1-(2-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14b)
Yield: 32.2 %, mp: 110–112 °C, 1H NMR (DMSO-d6) d
ppm: 8.83 (s, 1H), 8.76 (m, 1H), 8.67 (s, 1H), 8.63 (m, 1H),
8.61 (s, 1H), 8.13 (m, 1H), 7.43 (m, 1H), 6.99–7.03 (m,
2H), 6.66–6.67 (m, 2H), 5.63 (br, 2H), 3.27 (br, 4H), 3.04
(br, 4H), 2.42 (s, 3H). C27H24ClN9O2S; Calc. C, 56.49; H,
4.21; N, 21.96; Found C, 56.40; H, 4.28; N, 21.89; MS
(ESI) m/z 575.1 (M?1).
1-(3-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-(4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14c)
7-(4-Methylpiperazin-1-yl)-4-[(5-(pyridin-3-yl)-1,3,4-
Yield: 41.5 %, mp: 101–103 °C, 1H NMR (DMSO-d6) d
ppm: 8.83 (s, 1H), 8.73 (m, 1H), 8.65 (m, 1H), 8.62 (s, 1H),
8.85 (s, 1H), 8.16 (m, 1H), 7.53 (m, 1H), 7.40c–7.42 (m,
2H), 7.07–7.09 (m, 2H), 5.67 (br, 2H), 3.26 (br, 4H), 3.02
(br, 4H), 2.43 (s, 3H). C27H24ClN9O2S; Calc. C, 56.49; H,
4.23; N, 21.96; Found C, 56.42; H, 4.19; N, 21.87; MS
(ESI) m/z 575.2 (M?1).
oxadiazol-2-yl)sulfanyl]quinazolin-6-amine (13)
To a suspension of 12 (6.1 g, 0.014 mol) in water (20 mL)
containing acetic acid (14 mL, 0.224 mol) was added iron
(7.0 g, 0.126 mol) portion wise with stirring at 10–15 °C.
The reaction mixture was further stirred for next 5 h. The
insoluble material was removed by Celite filtration, and the
filtrate was basified to pH *8 by addition of liquid ammonia.
The resulting solid was filtered, washed with water, and re-
crystallized from ethanol. Yield: 86.1 %, mp: 189–190 °C,
1H NMR (DMSO-d6) d ppm: d 8.88 (s, 1H), 8.73 (s, 1H),
8.72 (s, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 7.81 (d, 1H), 7.48 (s,
1H), 4.45 (s, 3H), 2.99 (broad, 4H), 2.62 (broad, 4H).
1-(4-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-(4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14d)
Yield: 65.5 %, mp: 123–125 °C, 1H NMR (DMSO-d6) d
ppm: 8.85 (s, 1H), 8.71 (m, 1H), 8.67 (m, 1H), 8.63 (s, 1H),
8.58 (s, 1H), 8.11 (m, 1H), 7.42 (m, 1H), 7.38 (d, 2H), 7.22
(d,2H), 5.66 (br, 2H), 3.29 (br, 4H), 3.08 (br, 4H), 2.42 (s, 3H).
C27H24ClN9O2S; Calc. C, 56.49; H, 4.23; N, 21.96; Found C,
56.58; H, 4.32; N, 22.10; MS (ESI) m/z 575.1 (M?1).
General procedure for the preparation of 1-(7-(4-
methylpiperazin-1-yl)-4-{[5-(pyridin-3-yl)-1,3,4-
oxadiazol-2-yl]sulfanyl}quinazolin-6-yl)-3-
arylurea (14)
A solution of 13 (1.5 g, 0.004 mol) in DMF (20 mL) and
appropriate aryl isocyanate/isothiocyanate (0.006 mol) was
stirred at room temperature for 12 h. The content of the
reaction was poured into ice-water, filtered, washed with
water, and recrystallized from ethanol to yield the desired
compound.
1-(2-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14e)
Yield: 58.2 %, mp: 98–100 °C, 1H NMR (DMSO-d6) d
ppm: 8.77 (s, 1H), 8.69 (m, 1H), 8.61 (m, 1H), 8.54 (s, 1H),
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Med Chem Res (2013) 22:4096–4109
4103
1-(Cyclohexyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14j)
8.49 (s, 1H), 8.07 (m, 1H), 7.54–7.55 (m, 2H), 7.38 (m,
1H), 6.93–6.94 (m, 2H), 5.70 (br, 2H), 3.24 (br, 4H), 3.04
(br, 4H), 2.46 (s, 3H), 2.44 (s, 3H). C28H27N9O2S; Calc. C,
60.74; H, 4.92; N, 22.77; Found C, 60.70; H, 4.89; N,
22.72; MS (ESI) m/z 554.2 (M?1).
Yield: 55.5 %, mp: 117–119 °C, 1H NMR (DMSO-d6) d
ppm: 8.81 (s, 1H), 8.76 (m, 1H), 8.67 (m, 1H), 8.63 (s, 1H),
8.55 (m, 1H), 8.19 (m, 1H), 7.43 (m, 1H), 5.66 (br, 2H),
3.26 (br, 4H), 3.11 (sextet, 1H), 3.08 (br, 4H), 2.52 (s, 3H),
1.49–1.27 (m, 10H). C28H33N9O2; Calc. C, 63.74; H, 6.36;
N, 23.89; Found C, 63.90; H, 6.78; N, 23.81; MS (ESI)
m/z 546.3 (M?1).
1-(3-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14f)
Yield: 55.8 %, mp: 113–115 °C, 1H NMR (DMSO-d6) d
ppm: 8.73 (s, 1H), 8.62 (m, 1H), 8.58 (m, 1H), 8.51 (s, 1H),
8.45 (s, 1H), 8.03 (m, 1H), 7.60 (m, 1H), 7.44 (m, 2H),
6.89(m, 1H), 5.67 (br, 2H), 3.28 (br, 4H), 3.07 (br, 4H),
2.49 (s, 3H), 2.42 (s, 3H). C28H27N9O2S; Calc. C, 60.74; H,
4.92; N, 22.77; Found C, 60.98; H, 5.13; N, 22.87; MS
(ESI) m/z 554.4 (M?1).
1-(7-(4-Methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3,4-
oxadiazol-2-ylthio)quinazolin-6-yl)-3-phenyl thiourea
(14k)
Yield: 78.6 %, mp: 97–99 °C, 1H NMR (DMSO-d6) d
ppm: 8.85 (s, 1H), 8.71 (m, 1H), 8.63 (s, 1H), 8.13 (m, 1H),
7.41 (m, 1H), 6.98–6.95 (m, 2H), 6.87–6.81 (m, 3H), 4.71
(br, 2H), 3.31 (br, 4H), 3.09 (br, 4H), 2.29 (s, 3H).
C28H27ClN9OS; Calc. C, 62.55; H, 5.06; N, 23.45; Found
C, 62.71; H, 5.17; N, 23.68; MS (ESI) m/z 556.3 (M?1).
1-(4-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14g)
Yield: 42.5 %, mp: 120–122 °C, 1H NMR (DMSO-d6) d
ppm: 8.83 (s, 1H), 8.65 (s, 1H), 8.53 (m, 1H), 8.48 (s, 1H),
8.41 (m, 1H), 7.78 (m, 1H), 7.52 (m, 1H), 6.62 (d, 2H,
j = 6.9 Hz), 6.46 (d, 2H, j = 6.9 Hz), 5.67 (br, 2H), 3.23
(br, 4H), 3.02 (br, 4H), 2.31 (s, 3H), 2.40 (s, 3H).
C28H27N9O2S; Calc. C, 60.74; H, 4.92; N, 22.77; Found C,
60.71; H, 4.89; N, 22.69; MS (ESI) m/z 554.1 (M?1).
1-(2-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14l)
Yield: 56.9 %, mp: 122–124 °C, 1H NMR (DMSO-d6) d
ppm: 8.78 (s, 1H), 8.66 (m, 1H), 8.59 (s, 1H), 8.57 (m, 1H),
8.54 (s, 1H), 8.07 (m, 1H), 7.38 (m, 1H), 7.13 (m, 1H),
6.70–6.84 (m, 2H), 6.53 (m, 1H), 4.68 (br, 2H), 3.30 (br,
4H), 3.08 (br, 4H), 2.38 (s, 3H). C27H24ClN9OS2; Calc. C,
54.95; H, 4.10; N, 21.36; Found C, 54.89; H, 4.05; N,
21.28; MS (ESI) m/z 591.4 (M?1).
1-(2-Phenethyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)urea (14h)
Yield: 46.8 %, mp: 168–170 °C, 1H NMR (DMSO-d6) d
ppm: 8.78 (s, 1H), 8.72 (m, 1H), 8.63 (s, 1H), 8.59 (s, 1H),
8.51 (m, 1H), 8.15 (m, 1H), 7.41 (m, 1H), 6.97–6.96 (m,
5H), 5.78 (br, 2H), 3.27 (br, 4H), 3.05 (br, 4H), 2.68 (t,
2H), 2.51 (t, 3H), 2.42 (t, 2H). C30H31N9O2; Calc. C,
65.56; H, 5.68; N, 22.94; Found C, 65.73; H, 5.70; N,
23.08; MS (ESI) m/z 568.1 (M?1).
1-(3-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14m)
Yield: 44.1 %, mp: 115–117 °C, 1H NMR (DMSO-d6) d
ppm: 8.81 (s, 1H), 8.69 (m, 1H), 8.60 (m, 1H), 8.58 (s, 1H),
8.49 (s, 1H), 8.06 (m, 1H), 7.47 (m, 1H), 7.34–7.37 (m,
2H), 7.23 (m, 1H), 7.18 (m, 1H), 4.74 (br, 2H), 3.28 (br,
4H), 3.03 (br, 4H), 2.63 (s, 3H). C27H24ClN9OS2; Calc. C,
54.95; H, 4.10; N, 21.36; Found C, 54.99; H, 4.04; N,
21.38; MS (ESI) m/z 591.2 (M?1).
1-Biphenyl-3-(7-(4-Methylpiperazin-1-yl)-4-(5-(pyridin-3-
yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-yl)urea (14i)
Yield: 31.0 %, mp: 135–137 °C, 1H NMR (DMSO-d6) d
ppm: 8.86 (s, 1H), 8.73 (m, 1H), 8.61 (m, 1H), 8.59 (s, 1H),
8.67 (m, 1H), 7.80 (m, 1H), 7.54–7.60 (m, 6H), 7.48–7.50
(m, 4H), 6.08 (br, 2H), 3.37 (br, 4H), 3.08 (br, 4H), 2.61 (s,
3H). C33H29N9O2S; Calc. C, 64.37; H, 4.75; N, 20.47;
Found C, 64.32; H, 4.75; N, 20.48; MS (ESI) m/z 616.1
(M?1).
1-(4-Chlorophenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14n)
Yield: 45.5 %, mp: 134–136 °C, 1H NMR (DMSO-d6) d
ppm: 8.83 (s, 1H), 8.68 (m, 1H), 8.65 (m, 1H), 8.57 (m,
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Med Chem Res (2013) 22:4096–4109
1-(Cyclohexyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
1H), 8.53 (s, 1H), 8.09 (m, 1H), 7.44 (m, 1H), 6.77 (d, 2H),
6.65 (d, 2H), 4.83 (br, 2H), 3.39 (br, 4H), 3.08 (br, 4H),
2.37 (s, 3H). C28H26ClN9OS; Calc. C, 58.79; H, 4.58; N,
22.04; Found C, 58.94; H, 4.62; N, 22.18; MS (ESI)
m/z 591.3 (M?1).
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14s)
Yield: 66.7 %, mp: 98–100 °C, 1H NMR (DMSO-d6) d
ppm: 8.77 (s, 1H), 8.73 (m, 1H), 8.64 (s, 1H), 8.59 (s, 1H),
8.48 (m, 1H), 8.08 (m, 1H), 7.39 (m, 1H), 4.73 (br, 2H),
3.34 (br, 4H), 3.08 (br, 4H), 3.19 (sextet, 1H), 2.31 (s, 3H),
1.47–1.44 (m, 4H), 1.37–1.27 (m, 6H). C28H33N9OS; Calc.
C, 61.86; H, 6.12; N, 23.19; Found C, 61.84; H, 6.17; N,
23.83; MS (ESI) m/z 562.7 (M?1).
1-(2-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14o)
Yield: 74.7 %, mp: 130–132 °C, 1H NMR (DMSO-d6) d
ppm: 8.79 (s, 1H), 8.72 (m, 1H), 8.64 (m, 1H), 8.58 (s, 1H),
8.51 (s, 1H), 8.09 (m, 1H), 7.58 (m, 1H), 7.44–7.41 (m,
2H), 6.96–6.93 (m, 2H), 4.98 (br, 2H), 3.27 (br, 4H), 3.08
(br, 4H), 2.47 (s, 3H). C29H29N9OS; Calc. C, 63.14; H,
5.30; N, 22.85; Found C, 63.31; H, 5.42; N, 22.97; MS
(ESI) m/z 570.6 (M?1).
Biology
Synthesized compounds were evaluated for their
antimicrobial activity against Gram-negative bacteria
(Pseudomonas aeruginosa ATCC 27853, Escherichia coli
25922) and Gram-positive bacteria (S. aureus 25923 and
Bacillus subtilis 6633). The minimum inhibitory concen-
trations (MIC) of the synthesized compounds were deter-
mined using broth dilution method as recommended by
National Committee for Clinical Laboratory Standards
(NCCLS, 1982). In the present biological protocol, soya-
bean casein digest medium was used, which was made up
of casein enzymic hydrolysate (17.0 g), papaic digest of
soyabean meal (3.00 g), sodium chloride (5.00 g), dipo-
tassium phosphate (2.50 g), and dextrose (2.50 g). The
media was dissolved in 1,000 mL distilled water by heating
the mixture. The media was then sterilized in an autoclave
at 15 lbs pressure at 121 °C for 20 min. The sterilized
medium was then dispersed in each borosilicate tube so as
to attain synthesized drug concentrations as 3.125–100 lg/
mL. Finally, the inoculums of standard suspension, i.e.
0.1 mL of culture of two Gram-positive and two Gram-
negative organisms—106 bacilli per mL were added. The
tubes were incubated at 37 °C for 24 h. The presence or
absence of growth was taken as end point (MIC). The test
compounds were dissolved in suitable solvent such as
dimethyl sulfoxide, ethanol, dilute HCl as the case may be
so as to prepare drug concentrations of 3.125–100 lg/mL.
Standard antibacterial agents like penicillin, streptomycin,
ampicillin trihydrate, gentamycin sulfate, and ofloxacin
were also screened under identical conditions.
1-(3-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14p)
Yield: 37.3 %, mp: 130–132 °C, 1H NMR (DMSO-d6) d
ppm: 8.73 (s, 1H), 8.66 (s, 1H), 8.57 (m, 1H), 8.54 (s, 1H),
8.49 (m, 1H), 7.87 (m, 1H), 7.53 (m, 1H), 7.40 (m, 1H),
7.38 (m, 1H), 6.72–6.74 (m, 2H), 4.37 (br, 2H), 3.27 (br,
4H), 3.11 (br, 4H), 2.70 (s, 3H), 2.58 (s, 3H).
C28H27N9OS2; Calc. C, 59.03; H, 4.78; N, 22.13; Found C,
59.09; H, 4.68; N, 22.10; MS (ESI) m/z 570.5 (M?1).
1-(4-Methylphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14q)
Yield: 44.2 %, mp: 110–112 °C, 1H NMR (DMSO-d6) d
ppm: 8.76 (s, 1H), 8.70 (s, 1H), 8.59 (m, 1H), 8.48 (s, 1H),
8.43 (m, 1H), 7.67 (m, 1H), 7.42 (m, 1H), 6.78 (d, 2H,
j = 7.6 Hz), 6.33 (d, 2H, j = 7.6 Hz), 4.66 (br, 2H), 3.29
(br, 4H), 3.08 (br, 4H), 2.62 (s, 3H), 2.56 (s, 3H).
C28H27N9OS2; Calc. C, 59.03; H, 4.78; N, 22.13; Found C,
59.12; H, 4.75; N, 22.18; MS (ESI) m/z 570.6 (M?1).
1-(2-Methoxyphenyl)-3-(7-(4-methylpiperazin-1-yl)-4-(5-
(pyridin-3-yl)-1,3,4-oxadiazol-2-ylthio)quinazolin-6-
yl)thiourea (14r)
QSAR analysis
Data set
Yield: 55.8 %, mp: 198–200 °C, 1H NMR (DMSO-d6) d
ppm: 8.81 (s, 1H), 8.73 (m, 1H), 8.64 (s, 1H), 8.61 (m, 1H),
8.59 (s, 1H), 8.12 (m, 1H), 7.44 (m, 1H), 7.27 (m, 1H),
6.83–6.79 (m, 2H), 6.73 (m, 1H), 4.70 (br, 2H), 3.32 (br,
4H), 3.07 (br, 4H), 3.26 (s, 3H), 2.38 (s, 3H).
C28H27N9OS2; Calc. C, 61.36; H, 5.15; N, 22.21; Found C,
61.67; H, 5.23; N, 22.39; MS (ESI) m/z 586.2 (M?1).
To gain insights into which substituents significantly affect
the biological activity, a QSAR study has been carried out
between various physiochemical parameters of the syn-
thesized compounds and their antimicrobial activity against
S. aureus. Chemical structures and antimicrobial activity of
123

Med Chem Res (2013) 22:4096–4109
4105
Table 1 Results of antimicrobial activity of substituted quinazoline derivatives (MIC in lg/mL)
N
R
N
N
R
N
N
X
NH
O
S
N
N
X
NH
O
S
N
HN
N
N
HN
N
N
X = O; 14 (a-j)
X = S; 14 (k-s)
X = O; 6 (a-i)
X = S; 6 (j-r)
Comp. no.
R
X
Microorganisms
Gram-positive bacteria
Gram-negative bacteria
S. aureus
ATCC (25923)
B. subtilis
ATCC (6633)
P. aeruginosa
ATCC (27853)
E. coli
ATCC (25922)
6a
C6H5
O
O
O
O
O
O
O
O
O
S
12.5
25
25
50
25
6b
2-Cl–C6H4
4-Cl–C6H4
2-CH3–C6H4
3-CH3–C6H4
4-CH3–C6H4
CH2CH2C6H5
4-C6H5–C6H5
Cyclohexyl
C6H5
12.5
12.5
50
75
25
6c
6.25
25
25
75
6d
75
25
6e
25
25
50
12.5
50
6f
12.5
12.5
12.5
25
75
12.5
75
6g
50
50
6h
12.5
50
75
100
50
6i
100
100
50
6j
50
75
50
6k
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
2-CH3–C6H4
3-CH3–C6H4
4-CH3–C6H4
2-OCH3–C6H4
4-F–C6H4
S
25
50
25
6l
S
6.25
25
25
75
50
6m
6n
S
12.5
50
100
100
100
75
25
S
75
25
6o
S
75
75
50
6p
S
25
25
50
6q
S
12.5
6.25
25
25
50
25
6r
S
6.25
12.5
50
50
12.5
25
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
14p
14q
14r
C6H5
O
O
O
O
O
O
O
O
O
O
S
50
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
2-CH3–C6H4
3-CH3–C6H4
4-CH3–C6H4
CH2CH2C6H5
4-C6H5–C6H5
Cyclohexyl
C6H5
25
100
25
50
6.25
25
12.5
6.25
100
25
50
50
12.5
50
12.5
50
100
50
25
25
12.5
25
50
50
6.25
25
50
12.5
50
100
12.5
25
25
50
50
25
50
50
25
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
2-CH3–C6H4
3-CH3–C6H4
4-CH3–C6H4
2-OCH3–C6H4
S
25
6.25
25
12.5
50
25
S
6.25
25
12.5
50
S
12.5
75
50
S
50
25
100
25
S
50
25
100
50
S
12.5
12.5
50
50
S
25
50
25
123

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Med Chem Res (2013) 22:4096–4109
Table 1 continued
Comp. no.
R
X
S
Microorganisms
Gram-positive bacteria
Gram-negative bacteria
S. aureus
ATCC (25923)
B. subtilis
ATCC (6633)
P. aeruginosa
ATCC (27853)
E. coli
ATCC (25922)
14s
Cyclohexyl
100
75
50
25
Penicillin
Streptomycin
1.562
6.25
0.05
0.05
0.25
1.562
6.25
0.25
1
12.5
3.125
NA
2
6.25
3.125
10
Ampicillin trihydrate
Gentamycin sulfate
Ofloxacin
0.5
0.125
10
0.125
NA Not active
the synthesized quinazoline derivatives are given in
Table 1. For the QSAR analysis, MIC values were con-
verted to negative logarithm scale (pMIC) to achieve nor-
mal distribution. Thirty-seven compounds were randomly
divided into training and test sets, the former set consisting
of 20 compounds and the remaining 17 compounds were
taken in the test set to ensure that the model is able to
predict a large diversity of compounds in the test set
(external validation). The structures of all compounds were
sketched by using Visualizer module of Discovery studio
2.1 software (Accelrys Inc., USA). Compounds were
optimized using PM6 method in MOPAC2009 (Stewart,
2007) until the root mean square gradient value becomes
genetic algorithm to evolve population of equations that
best fit the training set data. It automates the search for
QSAR models by combining a genetic algorithm with
statistical tools (Karki and Kulkarni, 2001). QSAR analysis
using GFA begins with generation of population of equa-
tions (set at 100 by default in the Discovery studio). From
this set of 100 equations, two good equations are selected
as ‘‘parents’’, and genetic crossover operations were per-
formed at random and a new model created from each
parents. The number of crossing over was set by default at
5,000. Each equation fitted to the experimental data using
linear term, and the equations are ranked according to
quality using Friedman’s lack of fit (LOF) measure equa-
tion [Eq. (1)].
˚
smaller than 0.01 kcal/mol A. Thus optimized structures
were used for calculation of various descriptors.
2
LOF ¼ LSE=½1 ꢁ ðc þ dpÞ=mꢂ
ð1Þ
Descriptor calculation
Where ‘LSE’ is the least square error, ‘c’ is the number
of basis function, ‘d’ is the smoothing parameter, ‘p’ is the
number of descriptors, and ‘m’ is the number of
observations.
Various structural, thermodynamic, quantum mechanical,
steric, electronic, and geometric descriptors were computed
using calculated molecular properties protocol of the Dis-
covery Studio (Table S1, Supplementary Information). In
total, 80 descriptors were calculated. A correlation matrix
of the molecular descriptors was prepared, and highly
correlated descriptors with a correlation value of 0.5 or
above were removed from the study. Remaining descrip-
tors were used to develop QSAR models.
Validation
Statistical significance of relationship between molecular
descriptors and antimicrobial activity was analyzed by
variance inflation factor (VIF) analysis, cross validation/
internal validation with training set, and external validation
with external data set (test set). VIF analysis was per-
formed to check inter-correlation of descriptors, which is
calculated from Eq. (2). VIF value larger than ten indicates
that information of descriptors can be hidden by correlation
of descriptors and multicollinearity (Khan et al., 2009,
Peterangelo and Seybold, 2004).
Regression analysis
Genetic function approximation (GFA, Hopfinger and
Rogers, 1994) was used to build QSAR models. GFA
algorithm offers a new approach to build structure–activity
models. GFA technique (Fan et al., 2001) generates a
population of equations rather than one single equation for
correlation between biological activity and physicochemi-
cal properties. GFA involves the combination of multi-
variate adaptive regression splines (MARS) algorithm with
VIF ¼ 1=1 ꢁ r2
ð2Þ
where ‘r2’ is the multiple correlation coefficient of one
descriptor’s effect regressed on the remaining molecular
descriptors.
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Med Chem Res (2013) 22:4096–4109
4107
Cross-validation (internal validation)
formamide afforded 7-chloroquinazolin-4(3H)-one (8).
Nitration of 8 was achieved by stirring it in the mixture of
fuming HNO3 and conc. H2SO4 at room temperature to
yield 7-chloro-6-nitroquinazolin-4(3H)-one (9). Treatment
of 2 and 9 with PCl5 afforded respected chloro analogs 3
and 10, respectively. Both of these products were found to
be unstable at room temperature and were directly used in
the next step without further purification. Condensation of
3 and 10 with 1d in the presence of anhydrous K2CO3
afforded intermediates 4 and 11 in moderate to good yields,
respectively. Halo-amine condensation of 11 with N-
methyl piperazine in the presence of K2CO3 yielded 12.
Reduction of 4 and 12 in acetic acid–water in the presence
of iron powder afforded 5 and 13, respectively. Finally,
condensations of 5 and 13 with corresponding aryl isocy-
anates/aryl isothiocyanates in anhydrous DMF at room
temperature afforded compounds 6a–6r and 14a–14s,
respectively, in good practical yields.
Cross-validation techniques by leave-one out/leave-some
out/leave-many out employing the training set molecules
insure the robustness of QSAR models. Value of correla-
tion coefficient greater than 0.6 indicates robustness of
generated models. It is calculated from the following
equation:
X
ꢀ
ꢁ
2
rc2v ¼ 1 ꢁ ½
Y
ObsðtrainingÞ ꢁ YPredðtrainingÞ
=
X
ꢀ
ꢁ
2
Y
ObsðtrainingÞ ꢁ YMeanðtrainingÞ
ꢂ
ð3Þ
External validation
It has been shown that optimal statistical characteristics
(high values of r and F, low values of s and LOF) need not
be the proof of a highly predictive model (Roy and Roy,
2007). External predictability of the model was determined
by calculating the value of predictive r2 (rp2red) using the
following equation.
Biology
X
ꢀ
ꢁ
2
rp2red ¼ 1 ꢁ ½
Y
PredðtestÞ ꢁ YObsðtestÞ
=
Synthesized compounds (6a–6r and 14a–14s) were
screened for their antimicrobial activity against both the
Gram-positive and Gram-negative bacterial strains. Results
of the biological screening are shown in Table 1. The
standard drugs penicillin, streptomycin, ampicillin trihy-
drate, gentamycin sulfate, and ofloxacin were also screened
for their antimicrobial activity under similar experimental
conditions.
X
ꢀ
ꢁ
2
Y
ObsðtestÞ ꢁ YMeanðtrainingÞ
ꢂ
ð4Þ
Results and discussion
Chemistry
In the present study, we synthesized two series of substituted
quinazoline derivatives (6a–6r and 14a–14s). For both the
series, 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol (1d) was
used as starting material which was prepared from ethyl
nicotinate (1b) which, in turn, was prepared by refluxing
nicotinic acid (1a) in ethanol as solvent and in the presence of
catalytic amount of conc. sulfuric acid. Compound 1b was
treated with hydrazine hydrate in ethanol at reflux temper-
ature to yield nicotinic acid hydrazide (1c) in good yield.
Finally, cyclization with carbon disulfide in the presence of
potassium hydroxide afforded desired 5-(pyridin-3-yl)-
1,3,4-oxadiazole-2-thiol (1d) (Schemes 1, 2).
Most of the synthesized compounds proved to be potent
against both the Gram-positive and Gram-negative bacte-
rial species. Compounds 6c, 6l, 6r, 14c, 14h, and 14m
showed results comparable with streptomycin against
S. aureus (ATCC 25923), whereas 6r, 14d, and 14l were
found to be equipotent to streptomycin against B. subtilis
(ATCC 6633). Against Gram-negative organisms, com-
pounds 6f and 14l exhibited results comparable with pen-
icillin and ofloxacin against P. aeruginosa (ATCC 27853),
whereas compounds 6e, 6r, 14d, 14h, and 14m were found
to be active comparable with ampicillin trihydrate against
E. coli (ATCC 25922). Compounds 6c, 14a, 14h, 14l, and
14m showed moderate to good activity against all micro-
organisms, whereas compounds with cyclohexyl substitu-
ents did not show activity against all organisms, which
suggests that phenyl group (with or without substitution) at
N-1 of the urea/thiourea is an essential pharmacophoric
feature for the antibacterial activity. In general, substituted
phenyl urea/thiourea derivatives were found to be more
potent than unsubstituted derivatives against all four
microorganisms.
1-Aryl-3-[4-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)sul-
fanyl)quinazolin-6-yl]urea derivatives (6a–6r) and 1-(7-(4-
methylpiperazin-1-yl)-4-{[5-(pyridin-3-yl)-1,3,4-oxa-
diazol-2-yl]sulfanyl}quinazolin-6-yl)-3-arylurea derivatives
(14a–14s) were obtained in good practical yields by using
multistep chemical synthesis (Schemes 1, 2).
For synthesis of 6a–6r, 5-nitroanthranilonitrile was used
as starting material which upon reflux with formic acid in
the presence of conc. H2SO4 as catalyst, yielded
4-hydroxy-6-nitroquinazoline (2) in good yield. For syn-
thesis of 14a–14s, 2-amino-4-chlorobenzoic acid (7) was
used as starting material which upon refluxing with
It was found that presence of electron-withdrawing group
on the phenyl ring of both the urea and thiourea derivatives
significantly increases the activity. Corresponding alkylated
123

4108
Med Chem Res (2013) 22:4096–4109
derivatives were found to be less active as compared with
halogenated derivatives. Within the halogenated derivatives,
in general, 3-substitution was found to be the most favorable,
in particular, against S. aureus. This is true for the chlori-
nated analogs. However, 4-fluoro derivatives were found to
be highly potent against S. aureus. Also, it was observed that
thioderivatives have little, if any, advantage over corre-
sponding urea derivatives for activity against S. aureus.
Indeed, most of the thiourea compounds were found equally
or less active than urea derivatives against S. aureus, with the
exception of compound 14q which was found to be more
active than 14g. Incorporation of N-methyl piperazine ring at
the seventh position of quinazoline moiety compounds did
not result in significant increase in the activity. Indeed,
compounds 6a–6r were found to be equally or more active
than 14a–14s against Gram-positive bacteria with the only
exception of 14l which was found to be eight times more
active than the corresponding unsubstituted analog (6k)
against B. subtilis.
Charifson, 2001). PI represents a measure of the rank-
order prediction within the set of compounds: 1 stands for
an always correct prediction, 0 for a random, and -1 for an
always incorrect prediction.
For a statistically significant model, it is necessary that
the descriptors used in the equation should not be inter-
correlated with each other. The inter-correlation of the
descriptors used to generate various models was found to
be very low (Table S2, Supplementary Information). Also,
to further check the inter-correlation of descriptors, vari-
ance inflation factor analysis was performed. VIF values
for the selected descriptors were found to be 8.24
(AlogP98), 8.69 (LogD), 7.66 (Apol), 2.03 (RadofGyr).
VIF values of the descriptors below ten indicate low inter-
correlation of the descriptors used in the selected model
(Roy and Roy, 2007).
The model was also evaluated for its capacity to predict
the activity of training set and test set compounds, i.e.,
internal and external cross validation, respectively. The
models displayed satisfactory values of predicted r2 (rp2red
)
[Eq. (5)]. The model also showed satisfactory r2cv indicating
the robustness of the model. Moreover, it was quite
encouraging to see that compounds were predicted in
correct order [PI = 0.96, Eq. (5)]. The correlation between
observed and predicted biological activity for the training
set compounds, and the results of internal and external
cross-validation can be found in Supplementary informa-
tion (Figure S1, Table S3 and S4, respectively).
Against Gram-negative species, none of the compounds
showed MIC value below 12.5 lg/mL. Compound 14k was
found to be the best with MIC value of 12.5 lg/mL against
both Gram-negative microorganisms. In consistent with
the observations of Gram-negative bacteria, all alkylated
derivatives showed poor activity with the exception of 6e
and 6f. Effect of chloro substitution was found to be
scattered, and hence it was difficult to generate any
meaningful SAR.
Very low residuals in the internal and external cross-
validation sets indicate robustness and predictability of the
model for structurally similar compounds. It is seen from
the results that hydrophobic descriptors predominantly
affected the biological activity. AlogP98 (atom-based
AlogP method, Ghose et al., 1998) and LogD (octanol–
water partition coefficient) positively affected antimicro-
bial activity, which suggests that more lipophilic analogs
are likely to be active compounds. Apol (sum of atomic
polarizabilities), which is an electronic descriptor also
made positive contribution to the activity. Indeed, it is seen
from the structure that compounds with polar functional
groups (chloro and fluoro) were found to be potent (as
exemplified from high activity of 6c, 6l, 6r, 14c, and 14m)
while those with non-polar alkyl functional groups were
found to be less active (6n, 6o, 14o, and 14p). Less activity
of 6j and 14k is also attributed to the absence of polar
substituents (R = H). RadofGyr (radius of gyration or
gyradius) is the name of several related measures of the
size of an object, a surface, or an ensemble of points. It is
calculated as the root mean square distance of the objects’
parts from either its center of gravity or a given axis. This
topological descriptor showed negative contribution toward
biological activity. This suggests that size of the molecule
must be kept in mind while designing future similar
QSAR study
To extract information about which physicochemical
properties of compounds influence antibacterial activity, 15
QSAR equations were generated with four preselected
descriptors from correlation matrix using GFA technique.
Following is the best model generated along with its
regression statistics:
pMIC ¼ 4:92352 þ 0:84363 ꢃ AlogP98 þ 0:00235
ꢃ Apol þ 1:00311 ꢃ LogD ꢁ 0:64461
ꢃ RadofGyr
ꢀ
ꢁ
r2 ¼ 0:86; PI ¼ 0:96; rc2v q2 ¼ 0:75; rp2red ¼ 0:81;
F ¼ 22:81; LOF ¼ 0:08; LSE ¼ 0:01
ð5Þ
r2 is the correlation coefficient of the model, rc2v (q2) is
the cross-validated correlation coefficient, r2pred is the
correlation coefficient for test set molecules, F is
Fischer’s coefficient for absolute significance of the
model, LOF is Friedman’s lack-of-fit, LSE is least square
error. In addition to the standard statistical parameters, we
also calculated predictive index (PI) (Pearlman and
123

Med Chem Res (2013) 22:4096–4109
4109
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analogs with moderate to small sized molecules (with low
value of RadofGyr) favoring the antimicrobial activity.
We also extended our QSAR study to all three other
organisms. However, we could not obtain satisfactory
results. The correlation coefficients (r2) were found to be
low (B. subtilis, 0.25; E. coli, 0.32; P. aeruginosa, 0.11).
We understand that for a better description of the structure–
activity relationships for antimicrobial activity against
these microorganisms, we need to significantly modify the
terms of the QSAR study (training set and test set mole-
cules, descriptors used in the calculations, etc.). However,
this exercise is beyond the scope of the present study.
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Conclusion
Synthesized quinazoline derivatives were found to be
active against various microbial strains. The QSAR study
provided useful insights into the structural features
required for the antibacterial activity. Developed models
were found to be statistically significant and predictive in
nature as indicated by low values of residuals in training
and test sets. Hydrophobic, electronic, and topological
parameters were found to govern the activity. The present
study would be helpful in the future design of structurally
similar antibacterial agents.
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