Synthesis, antimicrobial evaluation and molecular modelling of novel sulfonamides carrying a biologically active quinazoline nucleus

Article abstract of DOI:10.1007/s12272-013-0094-6

A novel series of quinazolines 5-10, triazoloquinazolines 11-17 and triazinoquinazoline 19 bearing a biologically active sulfonamide moiety were synthesized, utilizing methyl 2-isothiocyanato benzoate 2. Some of the newly synthesized compounds revealed promising bacterial growth inhibition, compared with the ampicillin, as the reference drug. A LigandScout approach-generated pharmacophore model for the Staph aureus bacteria growth inhibition was done. The degree of fitting of the test set compounds (3, 4, 6, 8, 11, 17) to the generated hypothetical model revealed a qualitative measure of the more or less microbial inhibition of Staphylococcus aureus. Compounds (7, 8, 10, 12, 15, 17 and 22), which revealed significant activity, are able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (E _conf < 20 kcal/mol).

Full text of DOI:10.1007/s12272-013-0094-6

Arch. Pharm. Res.
DOI 10.1007/s12272-013-0094-6
RESEARCH ARTICLE
Synthesis, antimicrobial evaluation and molecular modelling
of novel sulfonamides carrying a biologically active quinazoline
nucleus
•
Mostafa M. Ghorab Zienab H. Ismail
•
•
Mohamad Abdalla Awwad A. Radwan
ꢀ The Pharmaceutical Society of Korea 2013
Abstract A novel series of quinazolines 5–10, triazolo-
quinazolines 11–17 and triazinoquinazoline 19 bearing a
biologically active sulfonamide moiety were synthesized,
utilizing methyl 2-isothiocyanato benzoate 2. Some of the
newly synthesized compounds revealed promising bacterial
growth inhibition, compared with the ampicillin, as the
reference drug. A LigandScout approach-generated phar-
macophore model for the Staph aureus bacteria growth
inhibition was done. The degree of fitting of the test set
compounds (3, 4, 6, 8, 11, 17) to the generated hypothet-
ical model revealed a qualitative measure of the more or
less microbial inhibition of Staphylococcus aureus. Com-
pounds (7, 8, 10, 12, 15, 17 and 22), which revealed sig-
nificant activity, are able to effectively satisfy the proposed
pharmacophore geometry, using the energy accessible
conformers (Econf \ 20 kcal/mol).
Keywords Sulfonamides ꢀ Quinazolines ꢀ
Fused quinazolines ꢀ Antimicrobial ꢀ
Pharmacophore modelling
Introduction
In the previous papers, we have described the preparation
of heterocyclic compounds with condensed nuclei con-
taining the quinazoline system (Ghorab et al. 1998, 1999,
2000, 2006a, b; Barakat et al. 2007; Abdel-Gawad et al.
2000). Quinazoline derivatives have been reported to
possess a significant activity as antihypertensive (Ram
et al. 1990), antifibrillatory, choleretic, antiphlogistic
(Bekhit et al. 2001), antimitotic (Jiang et al. 1990), anti-
fungal (Lopez et al. 2001) and anticonvulsant agents
(Farghaly and Moharram 1999). Triazoles were reported to
possess diverse pharmacological activities, such as anti-
microbial (Ghorab et al. 2001), antitumor (Heiba et al.
2006) and anti-inflammatory activities (Hardtmann and
Kathawala 1977). In addition 1,2,4-triazine derivatives
were found to posses antimicrobial activity (Zhang et al.
2002). On the other hand, several nitrogen and sulfur-
containing heterocyclic compounds, incorporating sulfon-
amide moiety, were found to possess a wide range of
biological activities (Abou El-Ella et al. 2008; Ismail et al.
2006; Ghorab et al. 2004, 2006a, b; El-Sharief et al. 2002).
In continuation of our interest in the synthesis of hetero-
cycles containing sulfonamide moiety (Ghorab 2000), we
report herein, a facile route for the synthesis of some new
quinazolines having a biologically active triazole or tri-
azine and sulfonamide moieties in one molecule to explore
M. M. Ghorab (&)
Medicinal, Aromatic and Poisonous Plants Research Center
(MAPPRC), College of Pharmacy, King Saud University,
Riyadh, P.O. 2457, Riyadh 11451,
Saudi Arabia
e-mail: mmsghorab@yahoo.com
Z. H. Ismail
Department of Chemistry, Faculty of Science (Girl’s), Al-Azhar
University, Cairo, Egypt
M. Abdalla
Department of Organic Chemistry, Faculty of Pharmacy,
October 6 University, Cairo, Egypt
A. A. Radwan
Pharmaceutical Technology Center (PTC), College of Pharmacy,
King Saud University, P.O. Box 2457, Riyadh 11451,
Saudi Arabia
A. A. Radwan
Department of Pharmaceutical Organic Chemistry, Faculty
of Pharmacy, Assiut University, Assiut 71527, Egypt
123

M. M. Ghorab et al.
4-(3-Amino-4-oxo-3,4-dihydroquinazolin-2-ylamino)-N-
(substitutedpyrimidin-2-yl)benzenesulfonamides (5, 6)
their antimicrobial activities. In this study, we used the
LigandScout program to establish the microbial growth
inhibitor pharmacophore sites by analyzing a training set of
the synthesized compounds (5, 7, 10, 12–15, 19, 22). The
generated pharmacophore model was validated using a test
set of synthesized compounds (3, 4, 6, 8, 11, 17).
A mixture of 3 or 4 (0.01 mol) and hydrazine hydrate
(1.0 g, 0.02 mol) in n-butanol (30 mL) was refluxed for
5 h. The reaction mixture was cooled, then poured onto ice
water and the obtained solid was recrystallized from
dioxane to give 5, 6, respectively.
Materials and methods
Chemistry
4-(3-Amino-4-oxo-3,4-dihydroquinazolin-2-ylamino)-N-
(pyrimidin-2-yl)benzenesulfonamide (5) Yield, 68 %;
m.p. 228–239 ꢁC; IR (KBr, cm-1): 3390, 3209(NH, NH2),
Melting points were determined on Gallen-kamp melting
point apparatus and are uncorrected. The infrared (IR)
spectra were recorded on shimadzu MR 470 infrared
1
1700(C=O), 1315, 1153 (SO2). H-NMR in (DMSO-d6) d:
5.8 [s, 2H, NH2, D2O exchangeable], 6.7–8.1 [m, 9H, Ar–
H ? CH pyrimidine], 8.6 [s, 2H, 2CH pyrimidine], 9.2 [s,
1H, NH, D2O exchangeable], 11.1 [s, 1H, SO2NH, D2O
exchangeable]. MS (m/z): 409 [M?] (3.2), 228 (100). Anal.
Calcd. For C18H15N7O3S: C, 52.80; H, 3.69; N, 23.95.
Found: C, 52.68; H, 3.53; N, 23.86.
1
spectrophotometer, using the KBr pellets. HNMR spectra
were recorded on a Varian EM 360 (240 MHz) instrument,
using TMS as an internal standard (chemical shift in d
ppm). Microanalytical data (C, H, N) were determined at
the Microanalytical centre, Cairo University, Egypt. Mass
spectra were run using HP Model MS-5988.
4-(3-Amino-4-oxo-3,4-dihydroquinazolin-2-ylamino)-N-(4-
methylpyrimidin-2-yl)benzenesulfonamide (6) Yield, 77 %;
m.p. 205–207 ꢁC; IR (KBr, cm-1): 3365, 3210 (NH, NH2),
1680 (C=O), 1390, 1150 (SO2). 1H-NMR in (DMSO-d6) d:
2.2 [s, 3H, CH3], 5.6 [s, 2H, NH2, D2O exchangeable],
6.7–7.9 [m, 9H, Ar–H ? CH-pyrimidine), 8.2 (s, 1H,
N=CH pyrimidine), 9.1 [s, 1H, NH, D2O exchangeable],
11.0 [s, 1H, SO2NH, D2O exchangeable]. Anal. Calcd. For
C19H17N7O3S: C, 53.89; H, 4.05; N, 23.15. Found: C, 53.67;
H, 4.35; N, 23.46.
Methyl 2-(3-(4-(N-substituted
sulfamoy)phenyl)thioureidobenzoates (3, 4)
To a solution of methyl 2-isothiocyanato benzoate 2
(1.93 g, 0.01 mol) in dimethylformamide (20 mL), sulfa-
diazine or sulfamerazine (0.01 mol) were added. The
reaction mixture was stirred at room temperature for 4 h.
The reaction mixture was poured onto ice water and the
obtained precipitate was filtered and recrystallized from
ethanol to give 3, 4, respectively.
Methyl 2-(3-(4-(N-pyrimidin-2-ylsulfamoy)phenyl)thioureido)
benzoate (3) Yield, 81 %; m.p. [ 300 ꢁC; IR (KBr,
cm-1): 3255, 3220, 3150(3NH), 3035 (CH arom.), 1662
(E)-4-(3-(Substituted benzylideneamino-4-oxo-3,4-
dihydroquinazolin-2-ylamino)-N-substituted
benzenesulfonamides (7–10)
1
(C=O), 1620(C=N), 1265 (C=S), 1346, 1161 (SO2). H-
NMR in (DMSO-d6) d: 3.9 [s, 3H, OCH3], 6.7–7.8 [m, 9H,
Ar–H ? CH pyrimidine], 8.5 [s, 2H, 2CH pyrimidine], 10.9
[s, 1H, SO2NH, D2O exchangeable], 12.1 [s, 2H, 2NH, D2O
exchangeable]. MS (m/z): 443 [M?] (48), 175 (100). Anal.
Calcd. For C19H17N5O4S2: C, 51.46; H, 3.86; N, 15.79.
Found: C, 51.22; H, 3.53; N, 16.10.
A mixture of compound 5 (4.09 g, 0.01 mol) and
required aromatic aldehydes in ethanol (20 mL) was
refluxed for 4 h. The solvent was concentrated, and
the residue was recrystallized from ethanol to give 7–10,
respectively.
(E)-4-(3-(Benzylideneamino)4-oxo-3,4-dihydroquinazolin-2-
ylamino)-N-(pyrimidin-2-yl)benzenesulfonamide(7) Yield,
69 %; m.p. 98–100 ꢁC; IR (KBr, cm-1): 3390, 3270 (2NH),
2930, 2840(CH-aliph.), 1690 (C=O), 1376, 1150 (SO2). 1H-
NMR in (DMSO-d6) d: 6.7–8.1 [m, 14H, Ar–H ? CH
pyrimidine], 9.1 [s, 1H, NH, D2O exchangeable], 9.9 [s, 1H,
N=CH], 11.6 [s, 1H, SO2NH, D2O exchangeable]. MS (m/z):
497 [M?] (3.70), 131(100). Anal. Calcd. For C25H19N7O3S:
C, 60.35; H, 3.85; N, 19.71. Found: C, 60.05; H, 3.51; N,
19.41.
Methyl 2-(3-(4-(N(4-methylpyrimidin-2-yl)sulfamoy)phenyl)
thioureido)benzoate (4) Yield, 74 %; m.p. 279–281 ꢁC; IR
(KBr, cm-1): 3420, 3380, 3150(3NH), 1660(C=O), 1610
(C=N), 1350, 1160 (SO2). 1H-NMR in (DMSO-d6) d: 2.4(s,
3H, CH3), 3.9(s, 3H, OCH3), 6.7–8.1(m, 10H, Ar–
H ? 2CH-pyrimidine), 11.0(s, H, SO2NH, D2O exchange-
able), 12.3(s, 2H, 2NH, D2O exchangeable). Anal. Calcd.
For C20H19N5O4S2: C, 52.50; H, 4.19; N, 15.31. Found: C,
52.35; H, 4.41; N, 15.11.
123

Quinazolinones: synthesis and pharmacophore studies
(E)-4-(3-(2-Hydroxybenzylideneamino)-4-oxo-3,4-dihy-
droquinazolin-2-ylamino)-N-(pyrimidin-2-yl)benzenesul-
fonamide (8) Yield, 71 %; m.p. 205–207 ꢁC; IR (KBr,
cm-1): 3500 (OH), 3210, 3180(2NH), 1708(C=O), 1315,
Calcd. For C26H19N7O3S: C, 61.29; H, 3.76; N, 19.24.
Found: C, 61.06; H, 3.52; N, 19.11.
4-(2-(2-Hydroxyphenyl)-9-oxo-[1,2,4]triazolo[5,1-b]qui-
nazolin-3(9H)-yl)-N-(4-methylpyrimidin-2-yl)benzenesul-
fonamide (12) Yield, 80 %; m.p. [ 300 ꢁC; IR (KBr,
cm-1): 3402 (OH), 3232 (NH), 1685 (C=O), 1604 (C=N),
1
1130 (SO2). H-NMR in (DMSO-d6) d: 6.9–8.1 [m, 13H,
Ar–H ? CH pyrimidine], 8.6 [s, 2H, 2N=CH pyrimidine],
8.8 [s, 1H, NH, D2O exchangeable], 9.3 [s, 1H, N=CH],
9.9 [s, 1H, OH, D2O exchangeable], 11.4 [s, 1H, SO2NH,
D2O exchangeable]. MS (m/z): 513 [M?] (1.67), 240
(100). Anal. Calcd. For C25H19N7O4S: C, 58.47; H, 3.73;
N, 19.09. Found: C, 58.19; H, 3.42; N, 19.25.
1
1326, 1126 (SO2). H-NMR in (DMSO-d6) d: 2.3 [s, 3H,
CH3], 6.8–8.1 [m, 14H, Ar–H ? 2CH pyrimidine], 10.2 [s,
1H, OH, D2O exchangeable], 11.6 [s, 1H, SO2NH, D2O
exchangeable]. Ms (m/z): 525 [M?] (0.1), 175(100). Anal.
Calcd. For C26H19N7O4S: C, 59.42; H, 3.64; N, 18.66.
Found: C, 59.13; H, 3.48; N, 18.39.
(E)-4-(3-(2-Methoxybenzylideneamino)-4-oxo-3,4-dihydroq
uinazolin-2-ylamino)-N-(pyrimidin-2-yl) benzenesulfonamide
(9) Yield, 82 %; m.p. 158–160 ꢁC; IR (KBr, cm-1): 3444,
3336 (2NH), 2927, 2839 (CH-aliph.) 1681 (C=O), 1604
(C=N), 1303, 1164 (SO2). 1H-NMR in (DMSO-d6) d: 3.7 [s,
3H, OCH3], 6.7–8.0 [m, 13H, Ar–H ? CH pyrimidine], 8.7
[s, 2H, 2N=CH pyrimidine], 9.0 [s, 1H, NH, D2O
exchangeable], 9.8 [s, 1H, N=CH], 11.7 [s, 1H, SO2NH,
D2O exchangeable]. Anal. Calcd. For C26H21N7O4S: C,
59.19; H, 4.01; N, 18.59. Found: C, 59.40; H, 4.22; N, 18.25.
4-(2-(4-(Dimethylamino)phenyl)-9-oxo-[1,2,4]triazolo[5,1-
b]quinazolin-3(9H)-yl)-N-(4-methylpyrimidin-2-yl)benzene
sulfonamide (13) Yield, 84 %; m.p. 139–141 ꢁC; IR
(KBr, cm-1): 3402 (NH), 2920, 2850 (CH-aliph.), 1688
1
(C=O), 1311, 1176(SO2). H-NMR in (DMSO-d6) d: 2.2
[s, 3H, CH3], 2.9 [s, 6H, N(CH3)2], 6.7–8.2 [m, 14H, Ar–
H ? 2CH pyrimidine], 11.4 [s, 1H, SO2NH, D2O
exchangeable]. Anal. Calcd. For C28H24N8O3S: C, 60.86;
H, 4.38; N, 20.28. Found: C, 60.59; H, 4.16; N, 20.01.
(E)-4-(3-(4-(Dimethylamino)benzylideneamino)-4-oxo-3,4-
dihydroquinazolin-2-ylamino)-N-(pyrimidin-2-yl) benzene-
sulfonamide (10) Yield, 66 %; m.p. 250–252 ꢁC; IR
(KBr, cm-1): 3225, 3175 (2NH), 2980, 2860 (CH-aliph.),
4-(9-Oxo-[1,2,4]triazolo[5,1-b]quinazolin-3(9H)-yl)-N-
(pyrimidin-2-yl)benzenesulfonamide (14)
1
1685(C=O), 1620(C=N), 1310, 1150 (SO2). H-NMR in
A solution of 5 (4.09 g, 0.01 mol) in formic acid (50 mL) was
heated, under reflux for 8 h.; the solvent was concentrated
and the residue was recrystallized from ethanol to give 14.
Yield, 66 %; m.p. 188–190 ꢁC; IR (KBr, cm-1): 3340 (NH),
(DMSO-d6) d: 2.8 [s, 6H, 2CH3], 6.7–8.1 [m, 13H, Ar–
H ? CH pyrimidine], 8.6 [s, 2H, 2N=CH pyrimidine], 9.1
[s, 1H, NH, D2O exchangeable], 9.6 [s, 1H, N=CH], 11.0
[s, 1H, SO2NH, D2O exchangeable]. Anal. Calcd. For
C27H24N8O3S: C, 59.99; H, 4.47; N, 20.73. Found: C,
59.63; H, 4.21; N, 20.85.
1
3100 (CH-arom.), 1685 (C=O), 1319, 1145(SO2). H-NMR
in (DMSO-d6) d: 6.7–8.0 [m, 10H, Ar–H ? CH tria-
zole ? CH pyrimidine], 8.4 [s, 2H, 2N=CH pyrimidine],
11.6 [s, 1H, SO2NH, D2O exchangeable]. Ms (m/z): 419
[M?] (13.43), 315(100). Anal. Calcd. For C19H13N7O3S: C,
54.41; H, 3.12; N, 23.38. Found: C, 54.15; H, 3.02; N, 23.19.
N-(4-Methylpyrimidin-2-yl)-4-(9-oxo-2-(substitutedphenyl)
-[1,2,4]triazolo[5,1-b]quinazolin-3(9H)-yl)benzenesul
fonamides (11–13)
A mixture of 6 (4.23 g, 0.01 mol) and the corresponding
aromatic aldehydes (0.01 mol) in glacial acetic acid
(30 mL) containing fused sodium acetate (0.5 g) was
heated under reflux for 4 h. The solvent was concentrated
and the residue was recrystallized from ethanol to give 11–
13, respectively.
4-(2-Methyl-9-oxo-[1,2,4]triazolo[5,1-b]quinazolin-3(9H)-
yl)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide (15)
A solution of 6 (4.23 g, 0.01 mol) in acetic anhydride
(50 mL) was heated, under reflux for 8 h.; the solvent was
concentrated and the residue was recrystallized from eth-
anol to give 15. Yield, 64 %; m.p. 194–196 ꢁC; IR (KBr,
cm-1): 3382 (NH), 3016(CH-arom.), 2932, 2781 (CH-
aliph.), 1676 (C=O), 1315, 1176 (SO2). 1H-NMR in
(DMSO-d6) d: 1.3 [s, 3H, CH3 triazole], 2.4 [s, 3H, CH3],
6.7–8.2 [m, 10H, Ar–H ? 2N=CH pyrimidine], 11.0 [s,
1H, SO2NH, D2O exchangeable]. MS (m/z): 447 [M?]
(0.2), 257(100). Anal. Calcd. For C21H17N7O3S: C, 56.37;
H, 3.83; N, 21.91. Found: C, 56.15; H, 3.63; N, 21.75.
N-(4-Methylpyrimidin-2-yl)-4-(9-oxo-2-phenyl-[1,2,4]triazolo
[5,1-b]quinazolin-3(9H)-yl)benzenesulfonamide (11) Yield,
69 %; m.p. 150–152 ꢁC; IR (KBr, cm-1): 3432(NH),
1
1685(C=O), 1592(C=N), 1318, 1148 (SO2). H-NMR in
(DMSO-d6) d: 2.4 [s, 3H, CH3], 6.7–8.2 [m, 15H, Ar–
H ? 2CH pyrimidine], 11.1 [s, 1H, SO2NH, D2O
exchangeable]. MS (m/z): 509 [M?] (1.67), 60 (100). Anal.
123

M. M. Ghorab et al.
4-(2-(2-Chlorophenyl)-9-oxo-[1,2,4]triazolo[5,1-b]quinaz-
olin-3(9H)-yl)-N-(substitutedpyrimidin-2-yl)benzenesulf-
onamides (16, 17)
sodium methoxide (0.54 g, 0.01 mol), was refluxed for 8 h.
After cooling the reaction mixture was poured onto ice
water and the solid obtained was recrystallized from
dioxane to give 22. Yield, 81 %; m.p. 80–82 ꢁC; IR (KBr,
cm-1): 3433 (NH), 2940, 2862 (CH aliph.), 1710, 1677
(2 C=O), 1558 (C=N), 1342, 1157(SO2). 1H-NMR in
(DMSO-d6) d: 1.3 [t, 3H, CH3], 4.3 [q, 2H, CH2], 6.7–8.1
[m, 9H, Ar–H ? CH pyrimidine], 8.5 [s, 2H, 2N=CH
pyrimidine], 11.2 [s, 1H, SO2NH, D2O exchangeable]. MS
(m/z): 491 [M?] (2.3), 341(100). Anal. Calcd. For
C22H17N7O5S: C, 53.76; H, 3.49; N, 19.95. Found C,
53.52; H, 3.32; N, 19.75.
A mixture of 5 or 6 (0.01 mol) and 2-chlorobenzoylchlo-
ride (1.75 g, 0.01 mol) in benzene (20 mL) was refluxed
for 10 h. The reaction mixture was cooled, then was con-
centrated and the obtained solid was recrystallized from
ethanol to give 16, 17, respectively.
4-(2-(2-Chlorophenyl)-9-oxo-[1,2,4]triazolo[5,1-b]quinaz-
olin-3(9H)-yl)-N-(pyrimidin-2-yl)benzenesulfonamide
(16) Yield, 83 %; m.p. 111–113 ꢁC; IR (KBr, cm-1):
3150 (NH), 3050 (CH-arom.), 1680 (C=O), 1604 (C=N),
Antimicrobial screening
1
1350, 1156 (SO2), 768 (C–Cl). H-NMR in (DMSO-d6) d:
6.7–8.0 [m, 13H, Ar–H ? CH pyrimidine], 8.7 [s, 2H,
2N=CH pyrimidine], 11.4 [s, 1H, SO2NH, D2O
exchangeable]. MS (m/z): 529 [M?] (0.3), 139 (100).
Anal. Calcd. For C25H16ClN7O3S: C, 56.66; H, 3.04; N,
18.50. Found: C, 56.42; H, 3.18; N, 18.36.
The antimicrobial activity screening of the newly synthe-
sized compounds was undertaken using the agar cup dif-
fusion (8 mm diameter) assay against the microbial
organisms, listed in Table 1 (Singh and Wahi 2011). The
agar media were inoculated with the test organism, and a
solution of test compound 2 and 1 lmol/mL in DMSO.
Ampicillin (2 lmol/mL and 1 lmol/mL), in addition to
fluconazole (2 lmol/mL and 1 lmol/mL), were used as a
reference for antibacterial and antifungal activity, respec-
tively. The zones of inhibition were measured after 24 h
incubation.
4-(2-(2-Chlorophenyl)-9-oxo-[1,2,4]triazolo[5,1-b]quinaz-
olin-3(9H)-yl)-N-(4-methylpyrimidin-2-yl) benzenesulfon-
amide (17) Yield, 75 %; m.p. 121–123 ꢁC; IR (KBr,
cm-1): 3424(NH), 3076 (CH-arom.), 2950, 2858 (CH-
1
aliph.), 1690 (C=O), 1312, 1105 (SO2), 750 (C–Cl). H-
NMR in (DMSO-d6) d: 2.4 [s, 3H, CH3], 6.7–8.1 [m, 14H,
Ar–H ? 2CH pyrimidine], 10.9 [s, 1H, SO2NH, D2O
exchangeable]. Anal. Calcd. For C26H18ClN7O3S: C, 57.41;
H, 3.34; N, 18.02. Found: C, 57.21; H, 3.13; N, 18.31.
For determination of MIC value (Singh and Wahi 2011),
by a serial plate dilution method, five milligrams of each
test compounds were dissolved in 1 mL of dimethylsulf-
oxide (DMSO), separately, to prepare the stock solution.
From the stock solution, serial dilutions were prepared.
Thus, proper amounts of the different concentrations of
compounds were pipetted on the blank disks, which were
placed on the plates. The plates were incubated at 37 ꢁC for
24 h. The minimum inhibitory concentrations (MICs), the
lowest concentration (lmol/mL) of the test compound that
resulted in no visible growth on the plates were recorded.
DMSO was used as a solvent control to ensure that the
solvent had no effect on the bacterial growth. The results of
the antimicrobial activities are summarized in Table 1.
4-(2,10-Dioxo-2,3-dihydro-1H-[1,2,4]triazino[3,2-b]quinazolin
-4(10H)-yl)-N-(pyrimidin-2-yl)benzenesulfonamide (19)
A mixture of 5 (4.09 g, 0.01 mol) and ethyl chloroacetate
(1.23 g, 0.01 mol) in methanol, containing sodium meth-
oxide (0.054 g, 0.01 mol), was refluxed for 10 h. After
cooling the reaction mixture was poured onto ice water,
and the solid obtained was recrystallized from dioxane to
give 19. Yield, 68 %; m.p. 201–203 ꢁC; IR (KBr, cm-1):
3410(NH)), 3039 (CH-arom.), 1681 (C=O), 1310, 1156
(SO2). 1H-NMR in (DMSO-d6) d: 4.3 [s, 2H, CH2], 6.7–8.2
[m, 9H, Ar–H ? CH pyrimidine], 8.6 [s, 2H, 2N=CH
pyrimidine], 8.9 [s, 1H, NH, D2O exchangeable], 11.6 [s, 1H,
SO2NH, D2O exchangeable]. MS (m/z): 449 [M?] (5.10),
200 (100). Anal. Calcd. For C20H15N7O4S: C, 53.45; H, 3.36;
N, 21.82. Found: C, 53.31; H, 3.14; N, 21.60.
Ligand based pharmacophore modeling
LigandScout program (version 3.0) was used to derive
the 3D chemical feature-based pharmacophores from the
structural data of the synthesized compounds
(Schemes 1, 2, 3,4), using the default settings (Friederike
et al. 2002). Compounds (5, 7, 10, 12, 13–15, 19, 22) as
training set were included in the modeling method. Prior
to the generation of pharmacophore hypotheses, the
training set compounds, which were converted to 3D
structure, were used to generate diverse conformations.
LigandScout program was used to generate the
Ethyl 9-oxo-3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)-3,9-
dihydro-[1,2,4]triazolo[5,1-b]quinazoline-2-carboxylate (22)
A mixture of 5 (4.09 g, 0.01 mol) and diethyloxalate
(1.46 g, 0.01 mol) in methanol (20 mL), containing
123

Quinazolinones: synthesis and pharmacophore studies
Table 1 Minimal inhibitory
Compounds S. marcescens
(IMRU-70)
P. mirabilis
(NTC-289)
S. aureus
(NCTC-7447)
B. cereus
(ATCC-14579)
A. ochraceus
Wilhelm
(AUCC-230)
concentration (MIC lM/mL) of
the newly synthesized
compounds
3
0.50
0.82
0.31
0.73
0.42
NA
0.25
0.27
0.23
0.37
0.56
0.89
NA
0.75
0.55
0.92
0.97
0.28
0.30
NA
0.19
0.21
0.31
0.97
0.85
0.59
0.95
0.46
0.34
0.24
NA
0.50
0.27
0.43
0.97
0.56
0.30
0.47
0.17
0.25
NA
4
5
6
7
8
9
0.47
0.23
0.49
0.33
0.34
0.30
0.84
0.95
0.46
0.39
0.25
0.25
–
10
0.23
0.37
0.48
0.91
0.60
1.12
0.71
0.35
1.11
0.19
0.25
–
0.35
0.49
0.24
0.45
0.60
0.39
NA
11
12
13
0.45
0.22
1.12
0.24
0.46
0.21
NA
14
NA
15
0.56
0.24
0.17
0.42
0.51
0.25
–
16
17
0.23
0.84
0.36
0.25
–
19
22
Ampicillin
Fluconazole
NA
NA compounds having MIC
value [1.5 lM
0.050
conformations, using the BEST conformation model
generation method. Other parameters, like the maximum
number of 250 conformers and an energy threshold value
of 20 kcal/mol above the global energy minimum, were
chosen during conformation generation. During the
pharmacophore hypothesis generation, three pharmaco-
phoric features, like hydrogen bond acceptor (HBA),
hydrogen bond donor (HBD) and hydrophobic feature
(HY) were selected to produce reliable pharmacophore
model for our experimental results.
associated with their conformations were subsequently
carried out for pharmacophore mapping (Friederike et al.
2002).
O
C
O
C
OCH3
OCH3
CSCl2
NH2
NCS
1
2
NH2
O
O
S
DMF
NHR
Pharmacophore validation
O
O
NH2
NH
N
The generated pharmacophore hypothesis was validated
using a test set, and leave-one-out methods.
H3CO
HN
RHN
O
S
O
N
N2H4.H2O
EtOH
N
S
Pharmacophore validation using test set
H
O
O
S
NHR
Compounds (3, 4, 6, 8, 11, 17) were selected as a test set.
This method is used to elucidate whether the generated
pharmacophore hypothesis is proficient to predict the
activities of compounds other than the training set and
classify them correctly in their activity scale. The confor-
mation generation for the test set compounds was carried
out in a similar way, like the training set compounds using
BEST conformation analysis algorithm, implemented
within the LigandScout program with setting values, as
same as those used with the training set. The compounds
N
N
N
N
3, R =
5, R =
6, R =
N
N
N
4, R =
N
CH3
CH3
Scheme 1 Synthetic pathway of 3-aminoquinazolines bearing sul-
fonamide moiety
123

M. M. Ghorab et al.
5
Results
6
Ar-CHO
Anhyd. NaOAc
Ar-CHO
EtOH
Chemistry
As a part of a program aimed at the synthesis of novel
quinazolines, triazoloquinazolines and triazinoquinazoline,
bearing a biologically active sulfonamide moiety, which
could be useful for biological screening, we have investi-
gated the possible utility of methyl 2-isothiocyanatobenzo-
ate 2 (Guccion et al. 1995) to react with sulfadiazine or
sulfamerazine in dimethylformamide, at room temperature,
to give thioureido derivatives 3, 4, respectively, in high yield
Scheme 1. Structure of compounds 3, 4 was established
based on the elemental and spectral data.
O
N
O
N
N
Ar
N
O
N
O
N
NH
N
S
Ar
S
HN
O
O
N
N
HN
N
N
CH3
7-10
Compounds 3, 4 allowed a fruitful, one step synthesis of
several heterocyclic rings via their reaction with hydrazine
hydrate. The formation of N-amino derivatives 5 and 6
proceeded via the elimination of one molecule of H2S,
followed by intramolecular cyclization. IR spectra exhib-
ited the presence of characteristic bands for N-amino
11-13
7 , Ar = C6H5
8 , Ar = C6H4-OH-2
9 , Ar = C6H4-OCH3-2
10, Ar = C6H4-N(CH3)2-4
11 , Ar = C6H5
12 , Ar = C6H4-OH-2
13, Ar = C6H4-N(CH3)2-4
Scheme 2 Synthetic pathway of 3-benzylidinylaminoquinazolines
and triazoloquinazolines having sulfonamide moiety
1
group. H NMR spectra revealed the presence of a singlet
at 5.8 and 5.6 ppm, due to N-amino group. Mass spectrum
of compound 5 revealed a molecular ion peak m/z at 409,
with a base peak m/z at 228. Schiff’s bases 7–10 were
obtained by the reaction of 5 with the corresponding aro-
matic aldehydes, Scheme 2. Upon a reaction of compound
6 with aromatic aldehydes in acetic acid containing fused
sodium acetate yielded the corresponding triazoloquinaz-
oline derivatives 11–13, respectively (Scheme 2). Triazo-
loquinazolines 14–17 were prepared by a reaction of
N-amino derivatives 5, 6 with one carbon cyclizing
reagent, namely formic acid, acetic anhydride and/or
2-chlorobenzoylchloride (Scheme 3). Reaction of com-
pound 5, with ethyl chloroacetate in presence of sodium
methoxide, furnished the triazinoquinazoline 19, rather
than its isomeric structure 18 (Scheme 4). Interaction of
compound 5 with diethyloxalate gave a triazoloquinazoline
derivative 22, which was confirmed by its elemental
analysis, 1H-NMR and mass spectral data. These results are
in agreement with the method previously reported (Fahmi
et al. 1994). 1H-NMR spectrum indicated the presence of a
triplet at 1.3 ppm and a quartet at 4.3 ppm assigned to ester
moiety. Mass spectrum revealed a molecular ion peak m/z
at 491, with a base peak at 172.
O
N
N
N
N
S
R'
i) HCOOH
5 or 6
ii) Ac2O
iii) C6H4 COCl-Cl-2
O
O
NHR
N
N
N
14; R =
15; R =
,
R' = H
16; R =
17; R =
,
,
R' = C6H4-Cl-2
R' = C6H4-Cl-2
N
N
N
,
R' = CH3
N
N
CH3
CH3
Scheme 3 Synthetic pathway of triazoloquinazolines containing
sulfonamide moiety
Pharmacophore validation using leave-one-out
The pharmacophore hypothesis is cross validated by the
leave-one-out method. In this method, one compound is
left in the generation of a new pharmacophore model, and
its affinity is predicted using that new model. The model
building and estimation cycle is repeated until each com-
pound was left out once (Inte:ligand GmbH, Vienna,
Austria) (Wolber and Langer 2005). This test is performed
to verify whether the correlation coefficient of the training
set compounds is strongly dependent on one particular
compound or not (John et al. 2011).
Antimicrobial screening
Table 1 lists the screening results of the tested compounds
against the Gram-negative bacteria, Serratia marcescens,
Proteus mirabilis, and the Gram-positive bacteria, Staph-
ylococcus aureus and Bacillus cereus, in addition to the
pathogenic fungi, Aspergillus ochraceus Wilhelm.
123

Quinazolinones: synthesis and pharmacophore studies
Scheme 4 Synthetic pathway
of triazinoquinazoline carrying
sulfonamide moiety
O
N
O
H
N
H
N
O
N
N
N
N
N
O
N
N
O2S
O2S
N
H
N
H
N
N
O
Cl
C2H5 ONa
19
OEt
18
5
OEt
OEt
O
O
O
N
H
O
O
N
N
-HOEt
N
-HOEt
O
-HOEt
O
O
N
H
N
N
OEt
O
N
NH2
N
O2S
N
O
N
H
OEt
N
N
NH
O
23
O
N
OEt
N
N
N
O2S
O2S
N
N
N
N
N
H
N
O
H
-H2O
21
20
-H2O
-H2O
N
N
O2S
N
O
H
N
N
24
N
N
COOEt
N
O2S
N
H
N
22
Discussion
appearance of signals of benzylidine N=CH protons at
9.3–9.9 ppm. Their mass spectra were in agreement with
their molecular weights. The structure of 11–13 was
established on the bases of elemental analysis and spectral
Chemistry
1
IR spectra of compounds 3 and 4 revealed the absence of
NCS band and presence of characteristic bands for NH,
CH-aliphatic, SO2, C=S. 1H NMR spectra of 3 and 4
indicated the presence of a singlet at 3.9 due to the meth-
oxy group and a singlet at 10.9 and 11.0 corresponding to
SO2NH. Mass spectrum of compound 3 showed a molec-
ular ion peak m/z at 443 with a base peak m/z at 175.
The structure of compounds 7–10 was elucidated based
on the elemental analysis and spectral data. The IR spectra
of 7–10 revealed the absence of NH2 bands. 1H NMR
spectra exhibited the disappearance of signals NH2 and
data. IR spectra showed the absence of NH2 bands. H
NMR spectra revealed the disappearance of NH2 signals
and presence of signals at 10.2 ppm, corresponding to the
phenolic OH group in compound 12 and 2.9 ppm due to
dimethylamino group in compound 13. Their mass spectra
are in agreement with their molecular weights. IR spectra
1
showed the absence of NH2 bands. H NMR spectrum of
compound 15 revealed the disappearance of NH2 signal
and presence of a singlet at 1.3 ppm, due to a methyl group
at triazole ring. Mass spectra were in accordance with their
molecular weights. Structure 19 was suggested rather than
123

M. M. Ghorab et al.
structure 18, based on the assumption that the reaction
basic condition allowed it to proceed through the formation
of sodium salt on the less basic NH, and elimination of
sodium chloride, followed by cyclization (Liu et al. 1992).
In addition, the IR spectrum of isolated product showed a
(C=O) band at 1681 cm-1, which was at less frequency
than that expected for structure 18. Further evidence was
the 1H-NMR spectrum, which showed a singlet at 4.3 ppm
for the methylene protons. Its mass spectrum showed a
molecular ion peak m/z at 449, with a base peak at 200.
1H-NMR spectrum of compound 22 indicated the presence
ofatripletat1.3 ppmandaquartetat4.3 ppmassignedtoester
moiety. Mass spectrum revealed a molecular ion peak m/z at
491, with a base peak at 172. These results are in agreement
with the method previously reported (Fahmi et al. 1994).
In view of these findings and well obtained in vitro
results, it was thought worthy to search for supportive
coordination, between in silico studies with in vitro anti-
bacterial results. The antibacterial results of the synthe-
sized compounds (Table 1), against the Gram-positive
bacteria S. Aureus, were selected for pharmacophore
modelling study. The elucidation of the binding approaches
for the synthesized compounds is based on finding the
active structures. Schemes 1–4 show the structure of the
training set compounds (5, 7, 10, 12–15, 19, 22) and test set
compounds (3, 4, 6, 8, 11, 17). On the assumption that the
active compounds bind in a similar fashion at the active
site, we employed the LigandScout program (Wolber and
Langer 2005) to evaluate the common features essential for
the activity, and the hypothetical geometries adopted by
these ligands in their most active forms. Thus, these
compounds were submitted for pharmacophore model
generation based on the shared chemical features. Con-
formation generation within 20 kcal/mol energy range
were generated and submitted to the alignment procedure.
The successful pharmacophore run resulted in the gen-
eration of 10 models (model-1: model-10, Table 2). Based
on its highest rank score and its mapping into all training
set molecules, model-1 was considered to be the best
Antimicrobial screening
Antimicrobial screening revealed that compounds 5, 10, 22
were found slightly more potent or equipotent to ampicillin
against S. marcescens. Also, compounds 3, 4, 5, 10, 22
were found slightly more potent, or equipotent to ampi-
cillin against P. mirabilis. In addition, compounds 12, 17
were found slightly more potent or equipotent to ampicillin
against S. aureus.
Compared with an antimicrobial activity of ampicillin
against B. cereus, compounds 3, 4, 12, 17 were more
potent, while compounds 5–11, 15–22 were less potent,
and compounds 13, 14 were inactive. All the compounds
were found weak active against A. ochraceus Wilhelm,
compared with that of the fluconazole.
Table 2 Summary of the generated pharmacophores of the antibac-
terial activity against S. aureus
Hypothesis
Features
Rank score
Model-1
Model-2
Model-3
Model-4
Model-5
Model-6
Model-7
Model-8
Model-9
Model-10
HHHHAAAD
HHHHAAAD
HHHHAAAD
HHHHAAAD
HHHHHAAAD
HHHHHAAAD
HHHHHAAAD
HHHHHAAAD
HHHHHAAAD
HHHHHAAAD
0.9121
0.9053
0.9029
0.9009
0.8902
0.8872
0.8862
0.8680
0.8589
0.8484
Pharmacophore modeling
It was reported that there are bioisosterism between the
pharmacophoric group of ampicillin and the functional
group of the sulfonamide compounds (Fig. 1) (Chohan
et al. 2010). Also, it was hypothesized that the difference in
charges between the two heteroatoms of the same dipolar
pharmacophore site (Xd-…Yd?) may facilitate the inhi-
bition of bacteria, more than viruses.
H hydrophobic, A hydrogen bond acceptor, D hydrogen bond donor
Fig. 1 Common potential
antibacterial pharmacophores
(delineated with bold black line)
a ampicillin and
b representative compound (17)
of the synthesized analogues
H2N
O
H
N
N
H
N
S
N
N
O
O
N
N
O
OH
N
O
N
O
Cl
(a)
(b)
123

Quinazolinones: synthesis and pharmacophore studies
Fig. 3 A chart representing the negative logarithm of the minimal
inhibitor concentration in lmol (dependent value) against Ligand-
Scout program output fit value (independent value)
Fig. 2 Proposed pharmacophore model of growth inhibition activity
against S. aureus (red HBA; yellow hydrophobic; green HBD)
correlation between the fit value and the biological activity
of the screened compounds. The highly active compounds
show a range of fit value of (85.76–83.98), while the rest
compounds varied from moderate to weak activity showed
a range of fit value of 76.22–66.27. This initial correlation
encouraged us to generate a linear model, based on ‘‘fit
value’’ to predict the biological activity of the compounds
understudy. The generated model (Eq. 1) showed very
good statistics and was used successfully to calculate the
activity of the tested compounds (Fig. 3; Table 3).
Table 3 Output for model-1 mapping and predictive model S. aureus
Compounds MIC
-log MIC Fit
Pred. -log Residual
(lM) (lM)
value MIC (lM)
-log
3
0.75
0.55
0.92
0.97
0.28
0.30
0.35
0.49
0.24
0.45
0.60
0.39
0.23
0.84
0.36
0.122
0.262
0.038
0.011
0.549
0.529
0.459
0.309
0.623
0.344
0.224
0.407
0.638
0.078
0.448
66.96 0.096
66.98 0.096
0.026
0.166
4
5
68.2
68.15 0.120
85.7 0.484
0.121
-0.083
-0.109
0.065
6
7
ꢁ log MIC ðlMÞ ¼ 0:0207 fit value ꢁ 1:2908
n ¼ 15; st error ¼ 0:115; R ¼ 0:847; R2 ¼ 0:718;
8
85.76 0.485
85.62 0.482
85.68 0.483
83.98 0.448
85.36 0.477
76.22 0.287
84.32 0.455
84.24 0.453
66.27 0.081
85.16 0.472
0.044
10
11
12
13
14
15
17
19
22
-0.023
-0.174
0.175
where n is the number of compounds and R is the
multiple correlation coefficients.
-0.133
-0.063
-0.048
0.185
Figure 4a, b shows as an example of the alignment of
the hypothesis model with the most active compounds 12
and 17, respectively, and Fig. 5a–c shows an example as
the alignment of the hypothesis model with the weakly
active compounds 3, 4 and 19 respectively. A closer look at
the mapped structures (Fig. 5a, b) reveals the importance
of certain structural features for activity. The aryl-substi-
tuted triazoloquinazolinone scaffold is thought to be criti-
cal for activity where the opening of the triazine ring or
unsubstituted triazine affect badly on the fit value of the
compounds to the pharmacophore model, which is also
reflected on its experimental weak activity. Also, the slight
displacement of the benzene ring of sulfanilamide moiety
away from the hydrophobic pharmacophore center, in
addition to the absence of hydrophobic substituent on the
fused triazine ring (Fig. 5c) can partially explain their
weak activity. The rest feature that is common for all
compounds is the two sulfonyl HBA feature and the NH
HBD of sulfonamide moiety.
-0.003
-0.024
hypothesis, statistically. Such model was selected for fur-
ther investigation and analysis. The top-ranked chemical
feature-based pharmacophore model (model-1), identified
in this study, is shown in Fig. 2. This pharmacophore
model contains eight chemical features: four hydrophobes,
three HBA and one HBD.
All synthesized compounds were mapped onto model-1,
with scoring the orientation of a mapped compound within
the hypothesis features, using a ‘‘fit value’’ score. As a
quick and primary validation of model-1, mapping of the
compounds found to show a good agreement between the
fit value and the biological activity (Table 3). Initial
investigation of the results shown in Table 3 reveals a good
123

M. M. Ghorab et al.
Fig. 4 a Best aligned pose of
compound 12 (MIC 0.24 lmol)
superposed with the query
(model-1). b Best aligned pose
of compound 17 (MIC
0.23 lmol) fitted inadequately
with the query (model-1)
Fig. 5 a Best aligned pose of the less active compound 5 (MIC
0.92 lmol) overlaid onto the pharmacophore model (model-1). b Best
aligned pose of the less active compound 6 (MIC 0.97 lmol) overlaid
onto the pharmacophore model (model-1). c Best aligned pose of the
less active compound 19 (MIC 0.84 lmol) overlaid onto the
pharmacophore model (model-1)
Further structural modifications need to be tried at the
sulfadiazine moiety before we can discuss the importance
of such feature for activity. Aromatic ring found to be
oriented into the HY, and its plane is perpendicular to that
of the triazoloquinazoline ring. However, there is no evi-
dence that the size of such group has a determinant effect
on the antibacterial activity. Further studies are in progress
in our laboratory, and are focused on the study of the
modification effect of the benzene ring of the sulfadiazine
group by replacement with substituted or fused benzene
ring or even its replacement with heterocyclic ring or
aliphatic chain of different lengths, in addition to the
modification of the sulfonamide group by replacement by
other carbonyl moieties.
biologically evaluated. Compounds 4, 7, 8, 10–13, 15, 17, 19
and 22 showed promising antibacterial activities, compared
with the reference drug. Pharmacophore modelling study of
the antibacterial effect of the synthesized compounds against
S. aureus strains revealed that compounds 12 and 17, slightly
more potent than ampicillin, were able to effectively satisfy
the proposed common feature sites using the energy acces-
sible conformers (Econf \ 20 kcal/mol).
Acknowledgments The authors are grateful to the sponsorship of
the Research Centre, College of Pharmacy and the Deanship of Sci-
entific Research, King Saud University, Riyadh 11451, Saudi Arabia.
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