3,4-Disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thiones: Synthesis, antimicrobial evaluation and QSAR investigations using Hansch analysis

Article abstract of DOI:10.1002/ardp.200700153

The 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives were synthesized and characterized by physicochemical and spectral means, and the results of antimicrobial study of these compounds against Staphylococcus aureus, Escherichia

Full text of DOI:10.1002/ardp.200700153

Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
M. Minu et al.
231
Full Paper
3,4-Disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-
2-thiones: Synthesis, Antimicrobial Evaluation and QSAR
Investigations Using Hansch Analysis
Maninder Minu1, Ananda Thangadurai1, Sharad R. Wakode1, Shyam S. Agrawal1,
and Balasubramanian Narasimhan2
1 Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
2 Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar,
India
The 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives were synthesized
and characterized by physicochemical and spectral means, and the results of antimicrobial
study of these compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans by
tube dilution method indicated that 4-(4-chlorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 6 and 4-(4-fluorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 12 were the most potential ones. Further, the QSAR studies by
Hansch analysis applied to find out the correlation between physicochemical characteristics of
synthesized compounds with antimicrobial activity demonstrated the contribution of electronic
parameter, total energy (Te) and the topological parameter (valence second order molecular con-
nectivity index (2vv)). Excellent statistically significant models were developed by Hansch
approach (r2 = 0.828–0.898) for the three microorganisms under study. The cross-validated r2
(q2), which is an indication of the predictive capability of the model for all cases was also very
good (q2 = 0.776–0.875).
Keywords: Antibacterial / Antifungal / Quinazoline-2-thione / QSAR / q2 /
Received: July 21, 2007; accepted: November 19, 2007
DOI 10.1002/ardp.200700153
have antimicrobial activity against different pathogenic
microorganisms [6–12].
Introduction
The quantitative structure-activity relationship (QSAR)
study is a useful tool for rational search of bioactive com-
pounds. The QSAR study describes a definite role of a
structural feature in a molecule, in a quantitative term,
with a definite contribution to the activity of a particular
physiochemical property of that structural feature [13].
Keeping in view the diverse therapeutic activities of
quinazolines, we planned to synthesize bioactive hetero-
cycles [14, 15] and performed the correlation of biologi-
cal activities with their physicochemical properties [21–
25]. Here, we report a study on the synthesis and QSAR
investigations of 3,4-disubstituted-1,2,3,4,5,6,7,8-octahy-
droquinazoline-2-thiones for their in-vitro antimicrobial
activity against Staphylococcus aureus, Escherichia coli, and
Candida albicans.
Literature reports reveal that the heterocyclic quinazo-
line derivatives possess various biological activities, e.g.,
anticonvulsant [1], antiphlogistic [2], muscle relaxant [3],
antimalarial, antihistamine [4], and anti-inflammatory
activities [5]. Further, they have also been reported to
Correspondence: Maninder Minu, Delhi Institute of Pharmaceutical Sci-
ences and Research, New Delhi 110 017, India.
E-mail: maninderminu@rediffmail.com
Fax: +91 11 2955-4503
Abbreviations: quantitative structure-activity relationship (QSAR); mini-
mum inhibitory concentration (MIC); molar refractivity (MR); total energy
(Te); highest occupied molecular orbital (HOMO); lowest unoccupied mo-
lecular orbital (LUMO); leave-one-out (LOO)
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

232
M. Minu et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
Table 1. Physicochemical characteristics of 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives.
Comp.
R1
R2
Mol. formula
Mw.
Mp. (8C)
Rf Value
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
H
H
H
C6H5-
CH3-
4-NO2-C6H4-
C10H7-
4-Cl-C6H4-
4-CH3-C6H4-
C6H5-
CH3-
4-NO2-C6H4-
C10H7-
4-Cl-C6H4-
4-CH3-C6H4-
C6H5-
CH3-
4-NO2-C6H4-
C10H7-
4-Cl-C6H4-
4-CH3-C6H4-
Cl
F
OCH3
Cl
Cl
Cl
Cl
Cl
Cl
F
F
F
F
F
F
C14H15ClN2S
C14H15FN2S
C14H18N2OS
278.80
262.23
274.38
418.95
356.88
463.95
469.01
453.40
432.98
402.50
340.43
447.50
452.56
436.95
416.53
414.54
352.46
459.53
464.60
448.98
428.56
208–210
202–204
220–222
102–104
98–100
0.48
0.42
0.38
0.77
0.85
0.81
0.60
0.75
0.87
0.80
0.69
0.76
0.71
0.77
0.86
0.81
0.72
0.67
0.56
0.77
0.74
61
76
84
51
62
46
51
67
72
60
66
62
58
59
61
55
60
56
62
53
58
C20H19 ClN2O2S2
C15H17 ClN2O2S2
C20H18 ClN3O4S2
C24H21ClN2O2S2
C20H18 Cl2N2O2S2
C21H21ClN2O2S2
C20H19FN2O2S2
C15H17FN2O2S2
C20H18 FN3O4S2
C24H21FN2O2S2
C20H18 ClFN2O2S2
C21H21FN2O2S2
C21H22N2O3S2
C16H20N2O3S2
C21H21N3O5S2
C25H24N2O3S2
C21H21ClN2O3S2
C22H24N2O3S2
94–96
116–118
106–108
88–90
174–176
164–166
134–136
128–130
146–148
96–98
138–140
156–158
146–148
140–142
118–120
126–128
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
Chemistry
The intermediates 4-(4-substituted phenyl)-1,2,3,4,5,6,
7,8-octahydroquinazoline-2-thiones 1–3 were prepared
by the reaction of 4-substituted benzylidene cyclohexa-
nones with thiourea in the presence of ethanolic potas-
sium hydroxide. Compounds 1–3 were reacted with vari-
ous substituted sulfonyl chlorides in presence of pyridine
to afford the title compounds (Scheme 1).
The formation of the title products is indicated by the
disappearance of a peak due to NH at the third position
of the starting material [4-(4-substituted phenyl)-
1,2,3,4,5,6,7,8-octahydroquninazoline-2-thiones] in IR
and1H-NMR spectra of all the compounds 4–21. The phys-
icochemical characteristics of the synthesized com-
pounds are presented in Table 1.
The IR and NMR spectra of these compounds have
shown the presence of peaks due to C=S, NH, and aryl
groups. The mass spectra of the title compounds are in
conformity with the assigned molecular structure and
showed molecular ion peaks corresponding to their
molecular formula. Elemental analysis (C, H, N) indicated
Scheme 1. Synthesis of 3,4-disubstituted-1,2,3,4,5,6,7,8-octa-
hydroquinazoline-2-thiones.
were screened for their in-vitro antimicrobial activity
against Gram-positive Staphylococcus aureus, Gram-nega-
that the calculated and observed values were within the tive Escherichia coli and fungi Candida albicans using tube
acceptable limits (l 0.4%). The synthesized compounds
dilution method [16]. The minimum inhibitory concen-
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Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
Synthesis, QSAR Studies of Octahydroquinazoline-2-thiones
233
Table 2. Antimicrobial activity data of 3,4-disubstituted-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives.
activity of quinazolines and their physicochemical char-
acteristics using TSAR 3D version 3.3 for Windows [17].
Compound
pMIC (lm/mL)
S. aureus
E. coli
C. albicans
Results and discussion
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2.14
2.24
2.14
2.72
2.55
2.82
2.72
2.75
2.64
2.65
2.53
2.81
2.75
2.69
2.62
2.62
2.45
2.76
2.67
2.65
2.54
3.33a)
2.35
2.32
2.26
2.67
2.46
2.76
2.72
2.70
2.79
2.70
2.58
2.81
2.66
2.80
2.72
2.77
2.55
2.76
2.67
2.75
2.63
3.33a)
2.35
2.24
2.14
2.67
2.65
2.87
2.83
2.70
2.68
2.76
2.63
2.81
2.75
2.74
2.62
2.77
2.59
2.66
2.76
2.70
2.68
3.16b)
The compounds 4-(4-chlorophenyl)-3-(4-nitrophenylsul-
fonyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione
6
against S. aureus and C. albicans and 4-(4-fluorophenyl)-3-
(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazo-
line-2-thione 12 against E. coli emerged as the most active
antimicrobial agents amongst the synthesized substi-
tuted quinazolines.
In the present study, an attempt has been made to find
structural requirements for the inhibition of different
microbial strains using the Hansch approach on synthe-
sized quinazolines with different molecular descriptors
like log of the octanol-water partition coefficient (log P)
[18], molar refractivity (MR) [19], Kiers molecular connec-
tivity (2vv) and shape (j, ja) topological indices [20], ran-
dic topological index (R) [26], Balaban topological index
(J) [27], Wiener topological index (W) [28], total energy
(Te), energies of highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital
(LUMO) [29, 30]. The values of selected descriptors are pre-
sented in Table 3.
17
18
19
20
21
Standard
a)
Ciprofloxacin.
Fluconazole
b)
In the first step of the regression analysis, the correla-
tration (MIC) values in terms of pMIC in lM/mL are pre- tion between each individual parameter and antimicro-
sented in Table 2. The QSAR studies have been carried out bial activity was calculated (Table 4). It indicated that
to find out the correlation between the antimicrobial high interrelationships were observed between all the
Table 3. Selected molecular descriptors calculated for 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives.
Comp.
log P
MR
0v
0vv
1v
1vv
2v
2vv
Te
LUMO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3.24
2.86
2.47
4.50
2.82
4.46
5.50
5.02
4.97
4.12
2.44
4.08
5.13
4.64
4.59
3.73
2.05
3.69
4.73
4.25
4.20
80.32
75.73
81.98
113.63
93.86
120.96
130.08
118.44
118.67
109.05
89.27
116.37
125.50
113.85
114.09
115.29
95.51
12.54
12.54
13.24
19.02
15.91
21.47
21.59
19.89
19.89
19.02
15.91
21.47
21.59
19.89
19.89
19.73
16.61
22.17
22.29
20.60
20.60
11.70
10.88
11.91
17.14
14.76
18.33
19.30
18.26
18.07
16.33
13.94
17.51
18.48
17.44
17.25
17.36
14.97
18.54
19.51
18.47
18.28
8.74
8.74
9.28
7.14
6.73
7.15
7.97
7.97
8.14
5.71
5.24
5.46
9.56
8.55
10.00
10.76
10.17
10.06
9.09
8.08
9.53
10.29
9.70
9.59
9.31
8.30
9.75
10.51
9.92
–2981.01
–3092.32
–3096.78
–4637.93
–3970.82
–5468.65
–5177.33
–4998.02
–4793.82
–4749.24
–4082.13
–5579.96
–5288.64
–5109.33
–4905.10
–4753.70
–4086.66
–5584.40
–5293.11
–5113.79
–4909.58
–0.35
–0.35
–0.13
–1.03
–1.11
–1.78
–1.08
–1.18
–0.99
–1.04
–1.12
–1.79
–1.09
–1.19
–0.99
–0.94
–1.00
–1.75
–1.00
–1.08
–0.90
12.98
10.38
14.29
14.95
13.38
13.38
12.98
10.38
14.29
14.95
13.38
13.38
13.52
10.91
14.82
15.49
13.91
13.91
11.27
10.00
11.77
12.67
11.78
11.68
10.86
9.59
11.36
12.26
11.37
11.27
11.28
10.02
11.78
12.69
11.79
11.69
12.20
10.41
13.72
14.18
12.82
12.82
12.20
10.41
13.72
14.18
12.82
12.82
12.37
10.58
13.89
14.35
12.99
12.99
122.62
131.74
120.10
120.33
9.81
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M. Minu et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
Table 4. Correlation matrix for antibacterial activity of 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives
against S. aureus.
pMICsa Log P
MR
0v
0vv
1v
1vv
2v
2vv
TE
pMICec pMICca
pMICsa
Log P
MR
0v
1.000
0.690
1.000
0.863
0.837
1.000
0.913
0.763
0.980
1.000
0.891
0.798
0.991
0.981
1.000
0.880
0.801
0.989
0.993
0.976
1.000
0.916
0.762
0.969
0.967
0.988
0.955
1.000
0.926
0.785
0.979
0.996
0.980
0.989
0.977
1.000
0.924
0.767
0.951
0.950
0.978
0.931
0.996
0.964
1.000
–0.948
–0.721
–0.940
–0.986
–0.951
–0.966
–0.944
–0.983
–0.934
1.000
0.689
0.854
0.900
0.883
0.869
0.889
0.897
0.895
–0.924
0.694
0.902
0.917
0.937
0.885
0.952
0.926
0.960
–0.916
0vv
1v
1vv
2v
2vv
TE
Table 5. Table showing statistically significant equations obtained for antimicrobial activity of 3,4-disubstituted-1,2,3,4,5,6,7,8-octahy-
droquinazoline-2-thione used in the present study.
S. No.
QSAR Model
n
r
q2
F
S
pMICsa
1
2
3
4
5
6
7
8
9
0.058 0v + 1.496
0.069 0vv + 1.444
0.082 1v + 1.536
0.103 1vv + 1.473
0.113 2vv + 1.572
0.052 j1 + 1.541
0.060 ja1 + 1.477
–0.420 LUMO + 2.156
0.082 R + 1.536
21
21
21
21
21
21
21
21
21
0.912
0.890
0.880
0.915
0.924
0.912
0.919
0.877
0.880
0.790
0.738
0.790
0.799
0.819
0.789
0.806
0.705
0.709
94.87
72.85
65.25
98.94
111.49
94.06
104.51
63.34
65.25
0.083
0.093
0.097
0.082
0.078
0.083
0.080
0.098
0.097
pMICec
1
2
3
4
5
6
7
0.047 0v + 1.756
0.056 0vv + 1.709
0.082 1vv + 1.752
0.071 2v + 1.776
0.089 2vv + 1.832
0.042 j1 + 1.787
0.124 ja2 + 1.733
21
21
21
21
21
21
21
0.899
0.882
0.888
0.896
0.894
0.905
0.884
0.765
0.730
0.748
0.758
0.766
0.777
0.730
80.71
67.22
71.43
77.88
76.16
86.00
68.63
0.073
0.078
0.076
0.074
0.074
0.071
0.077
pMICca
1
2
0.081 2v + 1.673
–0.0002 Te + 1.694
21
21
0.886
0.885
0.716
0.708
69.96
69.02
0.088
0.088
QSAR Model for antibacterial activity against S. aureus
pMICsa = –0.0002 Te + 1.499
parameters (r A 0.8) except in case of IP (Ionization Poten-
tial), LUMO, and HOMO. Hence, these descriptors cannot
be combined in multiple linear regression analysis. If
combined, it may result in a change in signs of the coeffi-
cients, a change in the values of the previous coefficient,
a change of a significant variable into an insignificant
one or an increase in standard error of the estimate on
addition of an additional parameter to the model [18].
The linear regression analysis carried out has resulted in
the following best QSAR models, Eq. (1–6). The other stat-
istically significant models obtained are presented in
Table 5.
(1)
(2)
n = 21 r2 = 0.898 q2 = 0.875 s = 0.065 F = 169.19 p a 0.001
pMICsa = 0.090 2v + 1.502
n = 21 r2 = 0.857 q2 = 0.821 s = 0.077 F = 114.35 p a 0.001
QSAR Model for antibacterial activity against E. coli
pMICec = -0.0002 Te + 1.768
(3)
n = 21 r2 = 0.853 q2 = 0.823 s = 0.063 F = 111.18 p a 0.001
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Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
Synthesis, QSAR Studies of Octahydroquinazoline-2-thiones
235
Table 6. Table showing observed and predicted antimicrobial activity of 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thi-
one derivatives.
Compound
pMICsa
Pre.
pMICec
Pre.
pMICca
Pre.
Obs.
Resi
Obs.
Resi
0.02
–0.03
–0.09
0.03
–0.05
–0.03
–0.02
0.00
0.12
0.04
0.05
0.00
–0.10
0.07
0.03
0.11
0.02
Obs.
Resi
0.05
–0.01
–0.13
–0.03
0.05
0.12
0.00
–0.07
–0.08
0.10
0.08
0.11
–0.03
0.02
–0.09
0.09
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2.14
2.24
2.14
2.72
2.55
2.82
2.72
2.75
2.64
2.65
2.53
2.81
2.75
2.69
2.62
2.62
2.45
2.76
2.67
2.65
2.54
2.20
2.23
2.23
2.59
2.43
2.79
2.72
2.67
2.63
2.62
2.46
2.81
2.74
2.70
2.65
2.62
2.46
2.81
2.74
2.70
2.65
–0.06
0.01
–0.09
0.13
0.12
0.03
0.00
0.08
0.01
0.03
2.35
2.32
2.26
2.67
2.46
2.76
2.72
2.70
2.79
2.70
2.58
2.81
2.66
2.80
2.72
2.77
2.55
2.76
2.67
2.75
2.63
2.33
2.35
2.35
2.64
2.51
2.79
2.74
2.70
2.67
2.66
2.53
2.81
2.76
2.73
2.69
2.66
2.53
2.81
2.76
2.73
2.69
2.35
2.24
2.14
2.67
2.65
2.87
2.83
2.70
2.68
2.76
2.63
2.81
2.75
2.74
2.62
2.77
2.59
2.66
2.76
2.70
2.68
2.30
2.25
2.27
2.70
2.60
2.75
2.83
2.77
2.76
2.66
2.55
2.70
2.78
2.72
2.71
2.68
2.57
2.72
2.80
2.74
2.73
0.07
0.00
0.01
–0.01
–0.03
0.00
–0.01
–0.05
–0.07
–0.05
–0.11
0.02
–0.05
–0.09
0.02
–0.06
–0.04
–0.04
–0.05
–0.06
pMICec = 0.048 + 1.734 ja1
(4)
n = 21 r2 = 0.833 q2 = 0.798 s = 0.068 F = 95.98 p a 0.001
QSAR Model for antifungal activity against C. albicans
pMICca = 0.104 2vv + 1.701
(5)
(6)
n = 21 r2 = 0.844 q2 = 0.802 s = 0.074 F = 104.31 p a 0.001
pMICca = 0.096 1vv + 1.610
n = 21 r2 = 0.828 q2 = 0.776 s = 0.079 F = 91.76 p a 0.001
In the above QSAR models, Eq. (1-6), n is the number of
data points, r is the multiple-correlation coefficient, q2 is
,
cross-validated r2 obtained by the leave-one-out’ (LOO)
method, s is the standard error of estimate, F represents
the Fischer ratio between the variances of calculated and
observed activities, and the p-value is the significance
level of the regression. All the QSARs manifest good statis-
tics and account for more than 80% of the total variance
in the antimicrobial activity of quinazolines. The Fischer-
ratio values obtained for the QSARs exceed the tabulated
value by a large margin as desired for a meaningful corre-
lation.
Equations 1 and 2 describe the antibacterial activity of
quinazolines against S. aureus. The negative coefficient of
Te in Eq. (1) indicated that antibacterial activities of qui-
nazolines against S. aureus are indirectly proportional to
its magnitude, i. e. that antibacterial activity increases
Figure 1. Graph between observed and predicted antibacterial
activity of quinazolines against S. aureus.
with the decrease in magnitude of Te. This is evidenced
by the values of Te in Table 3, where the values of Te for
compounds 6 and 12 (Te = –5468.65 and –5579.96,
respectively) are lower than those for other compounds
which makes them the most active compounds (pMICsa =
2.82, 2.81, respectively). Similarly, compound 1 with the
high Te value of –2981.01 has a minimum activity
(pMICsa = 2.14). Similar results were observed for antibac-
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236
M. Minu et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
microbial agents. On the basis of QSAR studies by Hansch
analysis, it can be concluded that the importance of elec-
tron-withdrawing constituents in enhancing the biologi-
cal activity is evident from the contribution of the param-
eter Te. Reduction of total energy (Te) being favorable for
the antibacterial activity indicates that the charge-trans-
fer phenomenon is taking place in drug-receptor interac-
tion upon binding; moreover, the inverse relationship
between Te and the biological activity is shown by their
negative influence on the antibacterial activity. The anti-
fungal QSAR results indicated the positive contribution
of the valence second order molecular connectivity index
(2vv). The positive coefficient of the descriptor suggests
that non-branched molecules will have enhanced anti-
fungal activity.
The authors have declared no conflict of interest.
Figure 2. Graph between observed and residual antibacterial
activity of quinazolines against S. aureus.
Experimental
terial activity of quinazolines against E. coli with the
molecular descriptor, Te. Being the positive coefficient,
2vv showed an opposite trend in case of antifungal activ-
ity of the quinazolines against C. albicans.
Melting points were determined using Bells India melting point
apparatus (Bells India Ltd., New Dehli, India) and are uncor-
rected. The infrared (IR) spectra were recorded with Shimadzu
8400S-FTIR spectrophotometer (Shimadzu, Tokyo, Japan) in KBr
discs. The 1H-NMR spectra in CDCl3 were recorded on Bruker-DPX
300 NMR spectrophotometer (Bruker Bioscience, Billerica, MA,
USA) using TMS as an internal standard. Mass spectra were
obtained on a Shimadzu-2010A instrument. Elemental analysis
was performed on a Perkin-Elmer 2400 C, H, N analyzer (Perkin
Elmer, Beaconsfield, UK) and values were within the acceptable
limits of the calculated values. Purity of all the synthesized com-
pounds were ascertained by single spot during TLC plates made
of silica gel-G (chromatographic grade) and iodine was used as a
developing agent.
It is worth mentioning that all the generated regres-
sions exhibit good predictive ability as established by
high q2 values (q2 a 0.75) and the best being recorded for
Eq. (1) (q2 = 0.875). Besides the validation made by the
LOO procedure, the generated correlations were also
tested for the ability to reproduce pMIC values of the
compounds in the series, and a comparison was made
with observed values (Table 6). Further, the good agree-
ment between experimental data and model computa-
tion is achieved using the above mentioned model 1 Eq.
(1), was evidenced by Fig. 1.
The plot of residuals of linear regression predicted val-
ues of pMICsa against the experimental pMICsa values
(Fig. 2) indicated that no systemic error exists in the
development of QSAR model as the residuals propagated
on both sides of zero [31].
Chemistry
4-(4-Chlorophenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-
2-thione 1
A
mixture of 2-p-chlorobenzylidene cyclohexanone (2.2 g,
0.01 mol), thiourea (0.76 g, 0.01 mol) and potassium hydroxide
(1 g) in ethanol (100 mL) was heated under reflux for 4 h. The
reaction mixture was concentrated to half of its volume, diluted
with water, then acidified with acetic acid, and left overnight.
The solid thus obtained was filtered, washed with water, and
recrystallized from ethanol. Yield: 61.15%, mp.: 208–2108C; IR
(KBr) cm– 1: 3178 (N-H), 1548 (C=C), 1220 (C=S), 828 (C-H); 1H-NMR
(CDCl3) d: 7.71 (1H, s, NH), 7.18–7.36 (4H, m, ArH), 6.52 (1H, s,
NH), 4.90 (1H, s, N-CH), 1.55-1.99 (8H, m, 46CH2).
Conclusions
The 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazo-
line-2-thione derivatives were synthesized in appreciable
yield, and the spectral data were found in agreement
with the assigned molecular structures. 4-(4-Chloro-
phenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahy-
droquinazoline-2-thione 6 and 4-(4-fluorophenyl)-3-(4-
nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazo-
line-2-thione 12 were found to be the most potential anti-
4-(4-Fluorophenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-
2-thione 2
Compound 2 was prepared by adopting the same procedure as
for compound 1. IR (KBr) cm– 1: 3197 (N-H), 1506 (C=C), 1224
(C=S), 838 (C-H); 1H-NMR (CDCl3) d: 7.67 (1H, s, NH), 6.9–7.48 (4H,
m, ArH), 6.5 (1H, s, NH), 4.92 (1H, s, N-CH), 1.46–2.64 (8H, m,
46CH2).
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Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
Synthesis, QSAR Studies of Octahydroquinazoline-2-thiones
237
4-(4-Methoxyphenyl)-1,2,3,4,5,6,7,8-octahydro-
4-(4-Chlorophenyl)-3-(4-methylphenylsulfonyl)-
quinazoline-2-thione 3
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 9
Compound 3 was prepared by adopting the same procedure as
Compound 9 was prepared by adopting the same procedure as
for compound 1. IR (KBr) cm– 1: 3193 (N-H), 1542 (C=C), 1249
for compound 4. IR (KBr) cm– 1: 3082 (N-H), 1595 (C=C), 1285
1
1
(C=S), 833 (C-H); H-NMR (CDCl3) d: 7.57 (1H, s, NH), 6.88–7.26
(C=S), 1328, 1176 (SO2), 835 (C-H); H-NMR (CDCl3) d: 6.97–7.56
(4H, m, ArH), 6.47 (1H, s, NH), 4.88 (1H, s, N-CH), 3.85 (3H, s,
OCH3), 1.55–1.99 (8H, m, 46CH2).
(8H, m, ArH), 6.5 (1H, s, N-H), 5.4 (1H, s, N-CH), 2.37 (3H, s, CH3),
2.17–2.97 (8H, m, 46CH2); MS m/z: 432 [M+]; Anal. Calcd. for
C21H21ClN2O2S2: C, 58.25; H, 4.88; N, 6.46. Found: C, 58.28; H,
4.85; N, 6.49.
4-(4-Chlorophenyl)-3-phenylsulfonyl-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 4
A mixture of 4-(4-chlorophenyl)-1,2,3,4,5,6,7,8-octahydro-quina-
zoline-2-thione 1 (1.112 g, 0.004 mol) and benzene sulfonylchlor-
ide (0.48 mL, 0.004 mol) in pyridine (10 mL) was heated in a
water-bath for 3.5 h. The reaction mixture was cooled and
poured into diluted HCl. The solid thus obtained was filtered,
4-(4-Fluorophenyl)-3-phenylsulfonyl-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 10
Compound 10 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3062 (N-H), 1531 (C=C), 1226
(C=S), 1328, 1157 (SO2), 840 (C-H); 1H-NMR (CDCl3) d: 7.2–7.7 (9H,
m, ArH), 6.68 (1H, s, NH), 5.65 (1H, s, N-CH), 1.3-2.9 (8H, m,
46CH2); MS m/z: 402 [M+]; Anal. Calcd. for C20H19FN2O2S2: C,
59.68; H, 4.76; N, 6.96. Found: C, 59.65; H, 4.80; N, 6.95.
washed with water, and crystallized from alcohol. IR (KBr) cm– 1
:
3182 (N-H), 1531 (C=C), 1220 (C=S), 1326, 1176 (SO2), 833 (C-H); 1H-
NMR (CDCl3) d: 6.64–7.6 (9H, m, ArH), 6.64 (1H, s, NH), 4.91 (1H,
s, N-CH), 1.25–2.67 (8H, m, 46CH2); MS m/z: 419 [M+]; Anal. Calcd.
for C20H19ClN2O2S2: C, 57.34; H, 4.57; N, 6.69. Found: C, 57.40; H,
4.58; N, 6.65.
4-(4-Fluorophenyl)-3-methylsulfonyl-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 11
4-(4-Chlorophenyl)-3-methylsulfonyl-1,2,3,4,5,6,7,8-
Compound 11 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3114 (N-H), 1531 (C=C), 1226
(C=S), 1319, 1157 (SO2), 838 (C-H); 1H-NMR (CDCl3) d: 7.07–7.6 (4H,
m, ArH), 6.5 (1H, s, NH), 4.68 (1H, s, N-CH), 1.26–3.10 (11H, m,
46CH2, CH3); MS m/z: 340 [M+]; Anal. Calcd. for C15H17FN2O2S2: C,
52.92; H, 5.03; N, 8.22. Found: C, 52.90; H, 5.07; N, 8.25.
octahydroquinazoline-2-thione 5
Compound 5 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3076 (N-H), 1531 (C=C), 1280
1
(C=S), 1380, 1176 (SO2), 835 (C-H); H-NMR (CDCl3) d: 6.96–7.55
(4H, m, ArH), 6.5 (1H, s, NH), 5.0 (1H, s, N-CH), 1.26-3.20 (11H, m,
46CH2, CH3); MS m/z: 35 [M+]; Anal. Calcd. for C15H17ClN2O2S2: C,
50.48; H, 4.80; N, 7.84. Found: C, 50.50; H, 4.85; N, 7.88.
4-(4-Fluorophenyl)-3-(4-nitrophenylsulfonyl)-
4-(4-Chlorophenyl)-3-(4-nitrophenylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 12
Compound 12 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3093 (N-H), 1575 (C=C), 1223
(C=S), 1338, 1157 (SO2), 840 (C-H);1H-NMR (CDCl3) d: 8.01–8.3 (4H,
m, Ar-NO2), 7.01–7.75 (4H, m, ArH), 6.65 (1H, s, NH), 5.54 (1H, s,
N-CH), 1.25–2.82 (8H, m, 4 6 CH2); MS m/z: 447 [M+]; Anal. Calcd.
for C20H18 FN3O4S2: C, 53.68; H, 4.05; N, 9.38. Found: C, 53.65; H,
4.09; N, 9.45.
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 6
Compound 6 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3190 (N-H), 1537 (C=C), 1288
1
(C=S), 1336, 1188 (SO2), 833 (C-H); H-NMR (CDCl3) d: 8.04–8.07
(4H, m, Ar-NO2), 6.90–7.51 (4H, m, ArH), 6.06 (1H, s, NH), 4.84
(1H, s, N-CH), 1.37–3.27 (8H, m, 46CH2); MS m/z: 464 [M+]; Anal.
Calcd. for C20H18ClN3O4S2: C, 51.77; H, 3.91; N, 9.06. Found: C,
51.74; H, 3.95; N, 9.12.
4-(4-Fluorophenyl)-3-(1-naphthylsulfonyl)-
4-(4-Chlorophenyl)-3-(1-naphthylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 13
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 7
Compound 13 was prepared by adopting the same procedure as
Compound 7 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3190 (N-H), 1506 (C=C), 1226
for compound 4. IR (KBr) cm– 1: 3201 (N-H), 1537 (C=C), 1282
1
(C=S), 1330, 1157 (SO2), 840 (C-H); H-NMR (CDCl3) d: 7.07–8.06
1
(C=S), 1326, 1190 (SO2), 833 (C-H); H-NMR (CDCl3) d: 6.76–7.68
(11H, m, ArH), 6.56 (1H, s, N-H), 5.53 (1H, s, N-CH), 1.04–2.8 (8H,
m, 4 6 CH2); MS m/z: 452 [M+]; Anal. Calcd. for C24H21FN2O2S2: C,
63.69; H, 4.67; N, 6.18. Found: C, 63.65; H, 4.71; N, 6.20.
(11H, m, ArH), 6.42 (1H, s, N-H), 4.83 (1H, s, N-CH), 1.18–3.18 (8H,
m, 46CH2); MS m/z: 469 [M+]; Anal. Calcd. for C24H21ClN2O2S2: C,
61.46; H, 4.51; N, 5.97. Found: C, 61.50; H, 4.53; N, 5.95.
4-(4-Chlorophenyl)-3-(4-chlorophenylsulfonyl)-
4-(4-Fluorophenyl)-3-(4-chlorophenylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 8
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 14
Compound 8 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3132 (N-H), 1591 (C=C), 1282
(C=S), 1328, 1188 (SO2), 831 (C-H);1H-NMR (CDCl3) d: 6.9–7.69 (8H,
m, ArH), 5.63 (1H, s, N-H), 4.83 (1H, s, N-CH), 1.25–3.49 (8H, m,
46CH2); MS m/z: 453 [M+]; Anal. Calcd. for C20H18Cl2N2O2S2: C,
52.98; H, 4.00; N, 6.18. Found: C, 52.94; H, 4.06; N, 6.20.
Compound 14 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3205 (N-H), 1533 (C=C), 1226
(C=S), 1330, 1157 (SO2), 838 (C-H);1H-NMR (CDCl3) d: 7.0–7.69 (8H,
m, ArH), 5.60 (1H, s, N-H), 4.92 (1H, s, N-CH), 1.20-3.42 (8H, m,
46CH2); MS m/z: 437 [M+]; Anal. Calcd. for C20H18ClFN2O2S2: C,
54.97; H, 4.15; N, 6.41. Found: C, 54.95; H, 4.21; N, 6.45.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 231–239
4-(4-Fluorophenyl)-3-(4-methylphenylsulfonyl)-
4-(4-Methoxyphenyl)-3-(4-methylphenylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 15
Compound 15 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3055 (N-H), 1533 (C=C), 1226
(C=S), 1332, 1157 (SO2), 838 (C-H); 1H-NMR (CDCl3) d: 6.8–7.5 (9H,
m, ArH & N-H), 4.64 (1H, s, N-CH), 2.38 (3H, s, CH3), 2.6–2.8 (2H,
m, CH2), 1.25–1.75 (6H, m, 3 x CH2); MS m/z: 416 [M+]; Anal. Calcd.
for C21H21FN2O2S2: C, 60.55; H, 5.08; N, 6.73. Found: C, 60.59; H,
5.12; N, 6.76.
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 21
Compound 21 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3090 (N-H), 1539 (C=C), 1249
(C=S), 1361, 1174 (SO2), 833 (C-H); 1H-NMR (CDCl3) d: 6.8–7.5 (8H,
m, ArH), 6.4 (1H, s, NH), 4.88 (1H, s, N-CH), 3.84 (3H, s, OCH3), 1.59
(3H, s, CH3), 2.7–2.8 (2H, m, CH2), 0.88–1.25 (6H, m, 36CH2); MS
m/z: 428 [M+]; Anal. Calcd. for C22H24N2O3S2: C, 61.65; H, 5.64; N,
6.53. Found: C, 61.71; H, 5.60; N, 6.50.
Biology
4-(4-Methoxyphenyl)-3-phenylsulfonyl-1,2,3,4,5,6,7,8-
Evaluation of antimicrobial activity
octahydroquinazoline-2-thione 16
The synthesized compounds were evaluated for antimicrobial
activity using tube-dilution method. This method depends upon
the inhibition of growth of a microbial culture in a uniform sol-
ution of antibiotic in a liquid medium that is favourable to its
rapid growth in the absence of the antibiotic [16]. In this
method, 1 mL of 10 lg/mL of test solution in DMSO was trans-
ferred to a sterile test tube containing 1 mL of sterile nutrient
media then it was serially diluted to give concentrations of 5,
2.5, 1.25, 0.625, 0.312 lg/mL. To all the tubes, 0.1 mL of micro-
bial suspension in saline was added and the tubes were incu-
bated at 378C for 24 h (bacteria) and 48 h (fungi). After the incu-
bation period, the tubes were observed visually for turbidity and
inhibition was determined by the absence of growth. MIC was
determined by the lowest concentration of sample that pre-
vented the development of turbidity. From the MIC values
observed, the intermediate concentrations between MIC values
were prepared and the accurate MIC values were determined.
The double strength nutrient broth (I. P.; Indian Pharmacopoeia)
and sabouraud dextrose broth (I. P.) [32] were used as a medium
in case antibacterial and antifungal activity, respectively.
Compound 16 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3040 (N-H), 1508, (C=C), 1251
(C=S), 1371, 1174 (SO2), 835 (C-H); 1H-NMR (CDCl3) d: 6.9–7.51 (9H,
m, ArH), 6.47 (1H, s, NH), 4.88 (1H, s, N-CH), 3.85 (3H, s, OCH3),
1.25–2.70 (8H, m, 46CH2); MS m/z: 414 [M+]; Anal. Calcd. for
C21H22N2O3S2: C, 60.84; H, 5.34; N, 6.75. Found: C, 60.81; H, 5.40;
N, 6.72.
4-(4-Methoxyphenyl)-3-methylsulfonyl-1,2,3,4,5,6,7,8-
octahydroquinazoline-2-thione 17
Compound 17 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3024 (N-H), 1539 (C=C), 1249
1
(C=S), 1353, 1174 (SO2), 833 (C-H); H-NMR (CDCl3) d: 6.88–7.26
(4H, m, ArH), 6.52 (1H, s, NH), 4.88 (1H, s, N-CH), 3.82 (3H, s,
OCH3), 1.25–2.80 (11H, m, 46CH2); MS m/z: 352 [M+]; Anal. Calcd.
for C16H20N2O3S2: C, 54.51; H, 5.72; N, 7.94. Found: C, 54.54; H,
5.75; N, 7.99.
4-(4-Methoxyphenyl)-3-(4-nitrophenylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 18
Compound 18 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3101 (N-H), 1531 (C=C), 1249
(C=S), 1338, 1174 (SO2), 833 (C-H);1H-NMR (CDCl3) d: 8.1–8.06 (4H,
m, Ar-NO2), 6.85–7.72 (4H, m, ArH), 6.5 (1H, s, NH), 5.6 (1H, s, N-
CH), 3.82 (3H, s, OCH3), 1.25–2.85 (8H, m, 46CH2); MS m/z: 459
[M+]; Anal. Calcd. for C21H21N3O5S2: C, 54.88; H, 4.60; N, 9.14.
Found: C, 54.85; H, 4.62; N, 9.17.
QSAR-Studies
The calculation of molecular descriptors of 3,4-disubstituted-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives as well
as the regression analysis were carried out by using the molecu-
lar package TSAR 3D version 3.3 [17]. The descriptors were calcu-
lated as per standard procedure [26–30].
The LOO cross-validation procedure was applied to estimate
the predictive capability of the QSAR models [33]. The cross-vali-
dated coefficient, q2 was calculated with the following equation:
4-(4-Methoxyphenyl)-3-(1-naphthylsulfonyl)-
q2 = 1 – [Rc (cpred –cactual)2/c (Rcactual –cmean)2]
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 19
Compound 19 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3096 (N-H), 1533 (C=C), 1249
(C=S), 1336, 1174 (SO2), 833 (C-H); 1H-NMR (CDCl3) d: 6.83–7.8
(11H, m, ArH), 6.52 (1H, s, N-H), 4.88 (1H, s, N-CH), 3.82 (3H, s,
OCH3), 1.25–2.82 (8H, m, 46CH2); MS m/z: 465 [M+]; Anal. Calcd.
for C25H24N2O3S2: C, 64.63; H, 5.20; N, 6.02. Found: C, 64.60; H,
5.22; N, 6.08.
where cpred, cactual and cmean are predicted, actual, and mean val-
ues of the target property, respectively. And PRESS = Rc (cpred
–
cactual)2 is the sum of predictive sum of squares.
References
4-(4-Methoxyphenyl)-3-(4-chlorophenylsulfonyl)-
1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 20
Compound 20 was prepared by adopting the same procedure as
for compound 4. IR (KBr) cm– 1: 3082 (N-H), 1541 (C=C), 1249
(C=S), 1355, 1174 (SO2), 833 (C-H); 1H-NMR (CDCl3) d: 6.88–7.7 (8H,
m, ArH), 6.47 (1H, s, N-H), 4.88 (1H, s, N-CH), 3.82 (3H, s, OCH3),
1.25–2.82 (8H, m, 46CH2); MS m/z: 449 [M+]; Anal. Calcd. for
C21H21ClN2O3S2: C, 56.17; H, 4.71; N, 6.23. Found: C, 56.14; H,
4.75; N, 6.27.
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Synthesis, QSAR Studies of Octahydroquinazoline-2-thiones
239
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