Synthesis of some new substituted 2-mercaptoquinazoline analogs as potential antimicrobial agents

Article abstract of DOI:10.1080/10426500600919207

A new series of substituted 2-mercapto-3-(4-chlorophenyl)-6-iodo-3H- quinazolin-4-ones was prepared and screened for antimicrobial activity. Compounds 11, 13, 17, and 18 showed a remarkably broad spectrum of antimicrobial activity and could be useful as t

Full text of DOI:10.1080/10426500600919207

This article was downloaded by: [Temple University Libraries]
On: 16 November 2014, At: 04:29
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of Some
New Substituted 2-
Mercaptoquinazoline Analogs
as Potential Antimicrobial
Agents
Adel S. El-Azab a
a Department of Pharmaceutical Chemistry , King
Saud University , Riyadh, Saudi Arabia
Published online: 18 Feb 2007.
To cite this article: Adel S. El-Azab (2007) Synthesis of Some New Substituted
2-Mercaptoquinazoline Analogs as Potential Antimicrobial Agents, Phosphorus,
Sulfur, and Silicon and the Related Elements, 182:2, 333-348, DOI:
10.1080/10426500600919207
To link to this article: http://dx.doi.org/10.1080/10426500600919207
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,

and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 182:333–348, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600919207
Synthesis of Some New Substituted
2-Mercaptoquinazoline Analogs as Potential
Antimicrobial Agents
Adel S. El-Azab
Department of Pharmaceutical Chemistry, King Saud University,
Riyadh, Saudi Arabia
A new series of substituted 2-mercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-
ones was prepared and screened for antimicrobial activity. Compounds 11, 13, 17,
and 18 showed a remarkably broad spectrum of antimicrobial activity and could
be useful as templates for further development through modification or derivati-
zation to design more potent antimicrobial agents. A detailed synthesis of new 2-
mercaptoquinazolinones and their antimicrobial screening are reported.
Keywords Synthetic chemistry; 2-quinazolines; 1,3,4-oxadiazoles; 1,3,4-thiadiazoles;
condensations; antimicrobial agent
INTRODUCTION
It was established that quinazolinones have a powerful and broad an-
timicrobial activity against different species of pathogenic gram neg-
ative and positive bacteria. In the present investigation, thioquina-
zoline analogs were designed to contain some moieties, which are
believed to contribute to antimicrobial activity, such as CH2CN ,
CO CH CH Ar, CH2CO Ar, and CH2 CONH Ar, in addition to
a series of heterocycles connected to the quinazoline ring, such as
1,3,4-oxadiazole and thiadiazole.1−4 The new compounds were screened
against Gram negative bacteria (Escherichia coli), Gram positive bac-
teria (Staphylococcus aureus, Bacillus subitilis), and fungi (Saccha-
romyces cerevisiae, Candida albicans).
Received April 22, 2006; accepted July 9, 2006.
The author would like to express his special thanks to Dr. Soliman I. Fouda,
Department of Microbiology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt,
for performing antimicrobial testing of the synthesized compounds.
Address correspondence to Adel S. El-Azab, King Saud University, Department
of Pharmaceutical Chemistry, College of Pharmacy, P.O. Box 245, Riyadh, 11451
Saudi Arabia. E-mail: adelazaba@hotmail.com
333

334
A. S. El-Azab
MATERIALS AND METHODS
All melting points were determined in open Barnistead Electrother-
mal capillaries and are uncorrected. Microanalyses were performed
on a Heraeus instrument: results are within 0.4% of the theoreti-
cal values. TLC was performed on Merck (Darmsta¨dt, Germany) 5 ×
10 cm plates, which were precoated with silica gel GF254 using short
wavelength UV light for visualization (CHCl3, methanol 10:1) (Upland,
USA). All of the fine chemicals and reagents used were purchased from
Aldrich (Wisconsin, USA). 1H NMR spectra were recorded on a Varian
Gemini 200 spectrometer. Chemical shifts are given in δ (ppm) values
downfield from Me4Si as an internal standard. IR spectra were recorded
on a Pye Unicam SP 100 instrument using KBr pellets. Mass spectra
were recorded using an HP MS-5988 apparatus. The following organ-
isms were used in the antimicrobial screening: E. coli ATCC 10536,
Staphylococcus aureus ATCC 06538, Bacillus subitilis ATCC 6633, Sac-
charomyces cerevisiae ATCC 9763, and Candida albicans ATCC 1023.
SYNTHESIS
2-Thioxo-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-one (1)
A mixture of iodoanthranilic acid (2.63 g, 0.01 mol) and p-
chlorophenylisothiocyanate (2.03 g, 0.012 mol) in ethanol (50 mL) was
heated under reflux for 4 h. The reaction mixture was then cooled to r.t.,
and the solvent was evaporated under vacuum. The obtained residue
was washed with petroleum ether (40:60), filtered, dried, and recrys-
tallized from ethanol to give 1 (Table I, II). 1H NMR (DMSO-d6), δ 7.41
(d, J = 7.5 Hz, 1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.65 (d, J =
8.5 Hz, 2H, Ar-H), 8.11 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J =
2.0 Hz, 1H, Quin-H), 12.88 (br s, 1H, NH).
2-Alkylmercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-
4-ones (2a–d)
To a solution of 2-mercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-
one (1) (4.14 g, 0.01 mol) in dry acetone (50 mL), anhydrous potas-
sium carbonate (2.0 g) was added, followed by the addition of either
methyl iodide, ethyl iodide, propyl iodide, or butyl iodide (0.015 mol).
The reaction mixture was heated under reflux for 20 h, filtered
while hot, and the filtrate was concentrated in vacuo to give the
crude product, which was recrystallized from the respective solvent
(Table I, II).

335

336
A. S. El-Azab
1
2a: H NMR (DMSO-d6): δ 2.61 (s, 3H, CH3-S), 7.41 (d, J = 7.5 Hz,
1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.65 (d, J = 8.5 Hz, 2H,
Ar-H), 8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.32 (d, J = 2.0 Hz, 1H,
Quin-H).
1
2b: H NMR (DMSO-d6): δ 1.17 (t, J = 7.0 Hz, 3H, S-CH2-CH3), 3.25
(q, J = 7.0 Hz, 2H, S-CH2-CH3), 7.40 (d, J = 7.5 Hz, 1H, Quin-H), 7.51
(d, J = 8.5 Hz, 2H, Ar-H), 7.64 (d, J = 8.5 Hz, 2H, Ar-H), 8.12 (dd, J =
2.0, 7.5 Hz, 1H, Quin-H), 8.32 (d, J = 2.0 Hz, 1H, Quin-H).
1
2c: H NMR (DMSO-d6): δ 0.94 (t, J = 7.0 Hz, 3H, S-CH2CH2CH3),
1.62–1.69 (m, 2H, S-CH2CH2CH3), 3.21 (t, J = 7.0 Hz, 2H, S-CH2-
CH2CH3), 7.41 (d, J = 7.5 Hz, 1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H,
Ar-H), 7.65 (d, J = 8.5 Hz, 2H, Ar-H), 8.18 (dd, J = 2.0, 7.5 Hz, 1H,
Quin-H), 8.33 (d, J = 2.0 Hz, 1H, Quin-H).
2d: 1H NMR (DMSO-d6): δ 0.89 (t, J = 7.0 Hz, 3H, S-CH2CH2CH2CH3),
1.32–1.38 (m, 2H, S-CH2CH2CH2CH3), 1.58–1.67 (m, 2H, S-
CH2CH2CH2CH3), 3.14 (t, J = 7.0 Hz, 2H, S-CH2CH2CH2CH3), 7.41
(d, J = 7.5 Hz, 1H, Quin-H), 7.53 (d, J = 8.5 Hz, 2H, Ar-H), 7.60 (d, J =
8.5 Hz, 2H, Ar-H), 8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J =
2.0 Hz, 1H, Quin-H).
3-(4-Chlorophenyl)-6-iodo-2-(arylmethylthio)-
4-(3H)quinazolines (3a–c)
A mixture of 1 (4.14 g, 0.01 mol), benzyl bromide, or 4-substituted
benzyl bromide (0.015 mol), and anhydrous K2CO3 (2.0 g) in ace-
tone (50 mL) was heated under reflux for 12 h. The reaction mix-
ture was filtered while hot, the filtrate was evaporated in vacuo,
and the obtained solid was recrystallized from the respective solvent
(Table I, II).
3a: 1H NMR (DMSO-d6): δ 4.41 (s, 2H, CH2Ph), 7.28–7.64(m, 10H, Ar-H
and Quin-H), 8.14 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.34 (d, J = 2.0 Hz,
1H, Quin-H).
3b: 1H NMR (DMSO-d6): δ 4.44 (s, 2H, CH2Ph), 7.16–7.69 (m, 9H, Ar-H
and Quin-H), 8.14 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.34 (d, J = 2.0 Hz,
1H, Quin-H).
3c: 1H NMR (DMSO-d6): δ 4.46 (s, 2H, CH2-Ph), 7.25–8.04 (m, 9H, Ar-H
and Quin-H), 8.13 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.34 (d, J = 2.0 Hz,
1H, Quin-H).

New Substituted 2-Mercaptoquinazoline Analogs
337
TABLE II IR and Mass Spectral Data of the New Synthesized
Compounds
Compound
IR Data, ν (cm−1
)
MS Data, m/z
1
3160 (NH), 1685 (C O)
414 (M+, 6.97%), 416 (M + 2, 2.36%),
345 (25.55%), 347 (9.52%)
2a
2b
2c
3030 (Ar-CH), 2950 (aliph. CH),
1690 (C O), 1050 (C S)
428 (M+, 38.85), 430 (M + 2, 15.61%),
413 (1.17%), 381(14.58%), 383
(6.38%), 317 (17.34%), 216 (23.97%)
442 (M+, 41.81%), 444 (M + 2,
15.13%), 381 (16.71%), 383 (6.71%),
317 (15.61%), 216 (21.81%)
3020 (Ar-CH), 2976 (aliph-CH),
1690 (C O), 1060 (C S)
3050 (Ar-CH), 2980 (aliph-CH),
1688 (C O), 1055 (C S)
456 (M+, 36.85%), 458 (M + 2,
14.21%), 381 (29.61%), 383
(13.61%), 317 (14.61%), 216
(29.30%)
2d
3a
3b
4a
4b
4c
3060 (Ar-CH), 2995, (aliph-CH),
1690 (C O), 1050 (C S)
470 (M+ 34.81), 4.72 (M + 2, 14.81%),
413 (2.21%), 381 (19.81%), 383
(8.21%), 317 (19.65%), 216 (25.61%)
504 (M+, 4.44%), 406 (M + 2, 2.81%),
413 (9.31%), 415 (3.14%), 91 (100%)
3050 (Ar-CH), 2996 (aliph-CH),
1685 (C O), 1640 (C N),
1050 (C S)
3060 (Ar-CH), 2995 (aliph-CH),
1690 (C O), 1645 (C + N),
1050 (C S)
3050 (Ar-CH), 2995 (aliph-CH),
1715, 1690 (2C O), 1640
(C N), 1075 (C S)
3050 (Ar-CH), 2990 (aliph-CH),
1710, 1685 (2C O), 1630
(C N), 1070 (C S)
538 (M+, 26.25%), 540 (M + 2,
15.72%), 542 (M + 4, 2.91%), 413
(1.03%), 125 (39.03%), 127 (13.01%)
532 (M+, 13.61%), 534 (M + 2, 4.61%),
455 (26.51%), 457 (8.71%), 427
(32.21%), 429 (11.03%), 413 (4.07%)
577 (M+, 9.91%), 579 ((M + 2), 3.31%),
455 (4.21%), 457 (1.52%), 427
(8.21%), 429 (2.915), 413 (1.01%)
610 (M+, 26.925), 612 (M + 2,
37.61%), 614 (M + 4, 9.4%), 557
(6.35%), 579 (2.21%), 427 (18.61%),
429 (6.3%), 413 (11.32%)
3040 (Ar-CH), 2985
(ALIPH-CH), 1685 (C O),
1650 (C N), 1050 (C S)
5
6
7
3060 (Ar-CH), 2992 (aliph-CH),
1685 (C O), 2250 (C N),
1640 (C N), 1060 (C S)
3050 (Ar-CH), 2900 (aliph-CH),
1745, 1695 (2C O)
453 (M+, 15.61%), 455 (M + 2, 6.91%),
427 (7.61%), 429 (2.57%), 413
(19.21%)
500 (M+, 18.74%), 502 (M + 2, 7.34%)
455 (21.23%), 457 (8.21%), 427
(10.21%), 413 (21.2%)
3400, 3290 (NH2), 3200 (NH),
3050 (Ar-CH), 2990
(aliph-CH), 1735, 1695
(2C O)
3500 (OH), 3210 (NH), 3040
(Ar-CH), 2990 (aliph-CH),
1700, 1685 (2C O), 1060
(C S)
486 (M+, 15.31%), 488 (M + 2, 6.1%),
413 (3.62%)
8
515 (M+, 9.71%), 517 (M + 2, 3.21%),
455 (79.12%), 427 (31.04%), 413
(30.38)
(Continued on next page)

338
A. S. El-Azab
TABLE II IR and Mass Spectral Data of the New Synthesized
Compounds (Continued)
Compound
IR Data, ν (cm−1
)
MS Data, m/z
9
3150 (NH), 3040 (Ar-CH), 2995
(aliph-CH), 1700, 1690
(2C O), 1620 (C N), 1070
(C S)
3250 (2NH), 3040 (Ar-CH),
2990 (aliph-CH), 1700, 1690,
1620 (3C O), 1620 (C N),
1080 (C-5)
3460, 3320 (2NH), 3060
(ar-CH), 2990 (aliph-CH),
1700, 1685 (2C O)
3250 (NH), 3050 (Ar-CH), 2995
(aliph-CH), 1700–1685
(4C O), 1640 (C N)
3060 (Ar-CH), 2990 (aliph-CH),
1700, 1685 (2C O), 1645
(C N), 1070 (C S)
3050 (Ar-CH), 2995 (aliph-CH),
1700, 1690 (2C O), 1650
(C N), 1055 (C S)
3250 (NH), 3060 (Ar-CH), 2995
(aliph-CH), 1700, 1690
(2C O), 1650 (C N), 1055
(C S)
3390, 3250 (2NH), 3055
(Ar-CH), 2995 (aliph-CH),
1725–1700, 1690 (3C O),
2800–2700 (aldehydic-H),
1655 (C N), 1060 (C S)
3050 (ar-CH), 2995 (aliph-CH),
1690 (C O), 1640 (C N),
1070 (C S)
497 (M+, 39.61%), 599 (M + 2, 13.61),
413 (1.2%)
10
593 (M+, 15.61%), 597 (M + 2,
20.61%), 599 (4.92%), 455 (3.61%),
457 (1.21%), 427 (9.33%), 429
(3.21%), 413 (6.01%)
11
12
13
14
15
621 (M+, 31.32%), 623 (M + 2,
15.11%), 455 (68.32%), 427
(29.09%), 413 (23.38%)
554 (M+, 34.321%), 556 (M + 2,
12.12%), 455 (35.21%), 427
(12.03%), 413 (1.32%)
550 (M+, 29.56%), 552 (M + 2, 9.51%);
455 (21.31%), 457 (7.07%), 427
(19.61%), 429 (6.52%), 413 (3.10%)
536 (M+, 18.36%), 538 (M + 2, 6.4%),
455 (33.21%), 457 (10.90%), 427
(13.21%), 429 (4.40%), 413 (13.21%)
542 (M+, 39.12%), 544 (M + 2,
12.91%), 413 (23.21%)
16
514 (M+, 21.34%), 516 (M + 2,
7.21%), 413 (1.21%)
17
18
496 (H+, 31.34%), 498 (M + 2,
12.31%), 427 (19.25%), 429 (6.41%),
413 (1.91%)
3060 (Ar-CH), 2990 (aliph-CH),
1685 (C O), 1640 (C N),
1050 (C S)
512 (M+, 36.24%), 514 (M + 2,
14.69%), 413 (19.21%)
3-(4-Chlorophenyl)-6-iodo-2-(arylcarbonylmethylthio)-
4(3H)-quinazolinones (4a–c)
A mixture of 1 (4.14 g, 0.01 mol), the appropriate 4-substituted phenacyl
bromide (0.01 mol), and anhydrous K2CO3 (2.0 g) in acetone (50 mL) was
heated under reflux for 24 h. The reaction mixture was filtered while
hot, and the filtrate was concentrated under reduced pressure and then

New Substituted 2-Mercaptoquinazoline Analogs
339
cooled to r.t. The obtained solid was filtered, dried, and recrystallized
from the respective solvent (Table I, II).
1
4a: H NMR (DMSO-d6): δ 4.71 (s, 2H, CH2CO), 7.37–7.86 (m, 10H,
Ar-H and Quin-H), 8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.33 (d, J =
2.0 Hz, 1H, Quin-H).
1
4d: H NMR (DMSO-d6): δ 3.73 (s, 3H, OCH3), 4.68 (s, 2H, CH2CO),
7.31–7.75 (m, 9H, Ar-H and Quin-H), 8.10 (dd, J = 2.0, 8.5 Hz, 1H,
Quin-H), 8.32 (d, J = 2.0 Hz, 1H, Quin-H).
2-Cyanomethylthio-3-(4-chlorophenyl)-4-oxo-6-iodo-
3H-quinazoline (5)
To a solution of 2-mercapto-3-(4-chlorophenyl)-6-iodo-3H-quinazolin-4-
one (1) (4.14 g, 0.01 mol) in dry acetone (40 mL), anhydrous potas-
sium carbonate (2.0 g) was added followed by the addition of 2-
chloroacetonitrile (1.1 g, 0.015 mol) The reaction mixture was refluxed
for 8 h, and filtered while hot, and the filtrate was concentrated in vacuo
to give the crude product, which was recrystallized from methanol. 1H
NMR (DMSO-d6): δ 4.25 (s, 2H, CH2CN), 7.43 (d, J = 7.5 Hz, 1H, Quin-
H), 7.53 (d, J = 8.5 Hz, 2H, Ar-H), 7.66 (d, J = 8.5 Hz, 2H, Ar-H), 8.12
(dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J = 2.0 Hz, 1H, Quin-H).
2-(Ethoxycarbonylmethyl)thio-3-(4-chlorophenyl)-4-oxo-
6-iodo-3H-quinazoline (6)
A mixture of 2-mercapto-3-(4-chlorophenyl)-4-oxo-6-iodo-3H-quinazo-
line 1 (4.14 g, 0.01 mol), ethylbromoacetate (0.015 mol), and anhydrous
potassium carbonate (2.0 g) in dry acetone (50 mL) was heated under
reflux for 8 h. The solvent was evaporated, and the obtained residue
1
was recrystallized from ethanol. H NMR (DMSO-d6): δ 1.30 (t, J =
10.0 Hz, 3H, CH3CH2-), 4.14 (s, 2H, CH2CO), 4.39 (q, J = 10.0 Hz, 2H,
CH3CH2-), 7.41 (d, J = 7.5 Hz, 1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H,
Ar-H), 7.66 (d, J = 8.5 Hz, 2H, Ar-H), 8.11 (dd, J = 2.0, 7.5 Hz, 1H,
Quin-H), 8.31 (d, J = 2.0 Hz, 1H, Quin-H).
2-[(3-(4-Chlorophenyl)-4-oxo-6-iodo-3H-quinazoline-
2-yl)thio]acetylhydrazine (7)
A solution of the ester 6 (5 g, 0.01 mol) and hydrazine (85%,
5 mL) in ethanol (50 mL) was heated under reflux for 3 h. The sol-
vent was evaporated, the obtained residue was washed with water

340
A. S. El-Azab
(50 mL), dried, and recrystallized from ethanol/dioxane (1:1). 1H NMR
(DMSO-d6): δ 3.96 (s, 2H, CH2CO), 4.30 (br s, 2H, NH2), 7.40 (d, J =
7.5 Hz, 1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.65 (d, J = 8.5 Hz,
2H, Ar-H), 8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.32 (d, J = 2.0 Hz,
1H, Quin-H), 9.4 (br s, 1H, NH).
N-(2-Hydroxyethyl)-2-[(3-(4-chloro)phenyl-4-oxo-6-iodo-
3H-quinazolin-2-yl)thio]acetamide (8)
A solution of ester 6 (5 g, 0.01 mol) and 2-aminoethanol (1.2 g, 0.02 mol)
in ethanol (50 mL) was heated under reflux for 3 h. The precipitated
solid was filtered while hot, dried, and recrystallized from methanol. 1H
NMR (DMSO-d6): δ 2.71 (m, 2H, CH2CH2-), 3.45 (m, 2H, CH2CH2), 3.76
(br s, 1H, OH), 4.01 (s, 2H, CH2CO), 7.40 (d, J = 7.5 Hz, 1H, Quin-H),
7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.66 (d, J = 8.5 Hz, 2H, Ar-H), 8.11 (dd,
J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J = 2.0 Hz, 1H, Quin-H), 9.27 (br
s, 1H, NH).
2-[(2-Oxopyrrolidin-3-yl)thio]-3-(4-chlorophenyl)-4-oxo-
6-iodo-3H-quinazoline (9)
A suspension of compound 8 (0.51 g, 0.001 mol) in conc. H2SO4 (10
mL) was stirred at r.t. for 6 h. The reaction mixture was poured onto
ice, stirred for 15 min, and neutralized with 30% aqueous NaOH. The
solid was filtered off, washed with water, dried, and recrystallized from
1
dioxane. H NMR (DMSO-d6): δ 1.96 (m, 2H, pyrrolidine-H), 2.56 (m,
2H, pyrrolidine-H), 3.41 (m, 1H, pyrrolidine-H), 7.41 (d, J = 7.5 Hz, 1H,
Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.65 (d, J = 8.5 Hz, 2H, Ar-H),
8.11 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J = 2.0 Hz, 1H, Quin-H),
8.9 (br s, 1H, NH).
(E )-N ’-(5-Bromo-2-oxoindolin-3-ylidene)-2-[3-
(4-chlorophenyl)-6-iodo-4-oxo-3,4-dihydroquinazolin-
2-ylthio]acetohydrazide (10)
A mixture of compound 7 (2.43 g, 0.005 mol) and 4-bromoisatin (1.16 g,
0.005 mol) in 20 mL of glacial acetic acid was heated under reflux for
18 h. The reaction mixture was cooled to r.t., poured onto crushed ice,
and the separated solid was filtered off and recrystallized from dioxane.
1H NMR (DMSO-d6): δ 3.89 (s, 2H, S-CH2CO), 7.20–7.71 (m, 9H, Ar-H

New Substituted 2-Mercaptoquinazoline Analogs
341
and Quin-H), 8.32 (d, J = 2.0 Hz, 1H, Quin-H), 8.91 (s, 1H, NH), 9.61
(s, 1H, NHCO).
N1-[(3-(4-chlorophenyl)-4-oxo-6-iodo-3H-quinazolin-2-yl)-
thioacetyl]-N3-phenylthiosemicarbazide (11)
A mixture of 2-[(3-(4-chlorophenyl)-4-oxo-6-iodo-3H-quinazoline-2-yl)-
thio]acetylhydrazine 7 (4.86 g, 0.01 mol) and phenylisothiocyanate
(1.62 g, 0.012 mol) in dioxane (30 mL) was heated under reflux for
18 h. The solid was filtered, dried, and recrystallized to give 11.
1H NMR (DMSO-d6): δ 4.21 (s, 2H, CH2CO), 7.21–7.67 (m, 10H,
Ar-H and Quin-H), 8.11 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.33
(d, J = 2.0 Hz, 1H, Quin-H), 8.62 (br s, 1H, NH), 9.51 (b rs, 2H,
NH).
2-[3,5-Dioxopyrazolidin-1-yl)carbonylmethyl-thio]-4-
(3-chlorophenyl)-4-oxo-6-iodo-3H-quinazoline (12)
To a solution of sodium ethoxide (made of 0.198 g sodium and 20
mL absolute ethanol) was added freshly distilled diethylmalonate
(0.68 g, 0.004 mol) followed by the addition of compound 7 (1.36
g, 0.003 mol). The reaction mixture was heated for 5 h, the sol-
vent was evaporated under reduced pressure, and the crude was
acidified with 10% hydrochloric acid. The precipitate formed was
filtered off, washed with cold water, and then recrystallized from
methanol/dioxane (1:1). 1H NMR (DMSO-d6): δ 3.47 (s, 2H, COCH2CO),
3.95 (s, 2H, S-CH2CO), 7.41 (d, J = 7.5 Hz, 1H, Quin-H), 7.52 (d,
J = 8.5 Hz, 2H, Ar-H), 7.66 (d, J = 8.5 Hz, 2H, Ar-H), 8.11 (dd,
J = 2.0, 7.5 Hz, 1H, Quin-H), 8.33 (d, J = 2.0 Hz, 1H, Quin-H), 9.7
(s, 1H, NHCO-).
2-[(3,5-Dimethylpyrazol-yl)carbonylmethylthio]-3-
(4-chlorophenyl)-4-oxo-3H-quinazoline (13)
Acetylacetone (1.5 g, 0.015 mol) was added to a solution of com-
pound 7 (4.86 g, 0.01 mol) in ethanol (30 mL). The reaction mix-
ture was heated under reflux for 10 h. The solvent was then re-
moved under reduced pressure, and the residue was recrystallized from
ethanol/chloroform (1:1). 1H NMR (DMSO-d6): δ 2.79 (s, 6H, CH3),
4.11 (s, 2H, SCH2CO), 7.21–707 (m, 6H, Ar-H, Quin-H and pyrazole-
H), 8.11 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J = 2.0 Hz, 1H,
Quin-H).

342
A. S. El-Azab
2-[(3-Methyl-5-oxo-4,5-dihydropyrazol-1-
yl)carbonylmethylthio]-3-(4-chlorophenyl)-4-oxo-
6-iodo-3H-quinazoline (14)
Ethylacetoacetate (2.0 g, 0.015 mol) was added to a solution of com-
pound 7 (4.86 g, 0.01 mol) in ethanol (30 mL). The reaction mix-
ture was heated under reflux for 8 h. The solvent was then re-
moved under reduced pressure, and the residue was recrystallized
1
from dioxane. H NMR (DMSO-d6): δ 2.56 (s, 3H, CH3), 4.13 (s, 2H,
S-CH2CO), 4.47 (s, 2H, CH2CO), 7.42 (d, J = 7.5 Hz, 1H, Quin-
H), 7.53 (d, J = 8.5 Hz, 2H, Ar-H), 7.68 (d, J = 8.5 Hz, 2H, Ar-H),
8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J = 2.0 Hz, 1H,
Quin-H).
N-Ethoxymethine-N ’-[2(3-(4-chlorophenyl)-4-oxo-6-iodo-
3H-quinazolin-2-yl)thioacetyl]hydrazine (15)
A mixture of 7 (2.43 g, 0.005 mol) and triethylorthoformate (10 mL)
was heated under reflux for 30 min. The reaction mixture was filtered
while hot and then cooled to r.t. The solid formed was filtered off, dried,
1
and recrystallized from ethanol/dioxane (1:1). H NMR (DMSO-d6): δ
1.31 (t, J = 7.0 Hz, 3H, CH3), 3.96 (q, J = 7.0 Hz, 2H, CH2), 4.16 (s,
2H, S-CH2CO), 7.41 (d, J = 7.5 Hz, 1H, Quin-H), 7.54 (d, J = 8.5 Hz,
2H, Ar-H), 7.67 (d, J = 8.5 Hz, 2H, Ar-H), 8.13 (dd, J = 2.0, 7.5 Hz, 1H,
Quin-H), 8.31 (d, J = 2.0 Hz, 1H, Quin-H), 9.96 (s, 1H, CH=N), 10.08
(br s, 1H, NH).
N-Formyl-N-(2-(3-(4-chlorophenyl)-4-oxo-6-iodo-
3H-quinazolin-2-yl)-thioacetyl]-hydrazine (16)
A solution of compound 7 (1.22, 0.003 mol) in formic acid (15 mL) was
heated under reflux for 30 min. The solid separated upon cooling to r.t.
was filtered off, washed with petroleum ether (50 mL), dried, and recrys-
1
tallized from acetic acid. H NMR (CDCl3): δ 4.17 (s, 2H, -S-CH2CO),
7.41 (d, J = 7.5 Hz, 1H, Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.64
(d, J = 8.5 Hz, 2H, Ar-H), 8.10 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.33
(d, J = 2.0 Hz, 1H, Quin-H), 8.21 (br s, 1H, NH), 9.13 (br s, 1H, NH),
9.82 (s, 1H, CHO).

New Substituted 2-Mercaptoquinazoline Analogs
343
2-[(1,3,4-Oxadiazol-2-yl)methylthio]-3-(4-chlorophenyl)-
4-oxo-6-iodo-3H-quinazoline (17)
Method A
To a solution of 16 (0.514 g, 0.001 mol) in xylene (50 mL), phosphorus
pentaoxide (2.0 g) was added. The reaction mixture was refluxed for 3 h
and filtered, and the residue was recrystallized from dioxane.
Method B
Compound 15 (0.985 g, 0.002 mol) was heated at 210◦C for 30 min.
The reaction product was purified by preparative TLC on silica gel us-
1
ing chloroform/ethylacetate (90:10) as an eluent to give 17. H NMR
(DMSO-d6): δ 4.13 (s, 2H, S-CH2-), 7.42 (d, J = 7.5 Hz, 1H, Quin-H),
7.54 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 (d, J = 8.5 Hz, 2H, Ar-H), 7.88 (s,
1H, oxadiazole-H), 8.17 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.31 (d, J =
2.0 Hz, 1H, Quin-H).
2-[(1,3,4-Thiadiazol-2-yl)methylthio]-3-(4-chlorophenyl)-
4-oxo-6-iodo-3H-quinazoline (18)
To a solution of 16 (0.514 g, 0.001 mol) in xylene (50 mL), phosphorus
pentasulfide (2.0 g) was added. The reaction mixture was refluxed for
1 h and filtered. From the filtrate, the solvent was evaporated, and the
residue was treated with dimethylsulfoxide (10 mL) and filtered. The
clear filtrate was poured onto ice and stirred. The solid was filtered off,
washed with water, dried, and recrystallized from ethanol to afford 18.
1H NMR (DMSO-d6): δ 4.15 (s, 2H, S-CH2-), 7.43 (d, J = 7.5 Hz, 1H,
Quin-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 7.66 (d, J = 8.5 Hz, 2H, Ar-H),
8.16 (dd, J = 2.0, 7.5 Hz, 1H, Quin-H), 8.10 (s, 1H, thiadiazole-H), 8.33
(d, J = 2.0 Hz, 1H, Quin-H).
RESULTS AND DISCUSSION
Chemistry
The synthetic strategy to obtain target compounds 1–18 is shown
in Schemes
1 and 2. The starting material 2-mercapto-3-(4-
chlorophenyl)-4-oxo-6-iodo-3H-quinazoline was prepared by reacting
5-iodoanthranilic acid with 4-chlorophenylisothiocyanate in boiling
ethanol. The 2-sulfhydryl group of 1 was alkylated with a series
of alkylhalides, benzyl halides, phenacylhalides, and chloroacetoni-
trile to produce compounds 2a–d, 3a–c, 4a–f, and 5, respectively
(Scheme 1). Further alkylation of 1 using ethylbromoacetate in boiling

344
A. S. El-Azab
acetone containing anhydrous potassium carbonate afforded the target
ester 6 (Scheme 1).6,7
The ester group in 6 was reacted with hydrazine hydrate or
ethanolamine to produce hydrazide 7 and the corresponding amide 8,
which, upon treatment with conc. sulfuric acid, was cyclodehydrated
to produce 2-oxo-pyrrolidine 9 (Scheme 1). Acetic acid hydrazide 7
was reacted with isatin to produce -S-[2-oxo-3-indolinylidene)acetic
acid hydrazide derivative 10. Again acid hydrazide 7 was reacted
with phenylisothiocyanate to afford the phenyl thiosemicarboazide
derivative 11.8 Condensation of hydrazide 7 with diethylmalonate,
acetylacetone, or ethylacetoacetate in ethanol furnished products,
which gave analytical data compatible with 3-oxo-5-pyrazolono, 3,5-
dimethylpyrazolo, and 3-methyl-5-pyrazolono derivatives 12, 13, and
14, respectively (Scheme 2).9,10
Hydrazide 7 was reacted with triethylorthoformate or formic acid
to produce the compound 15 or N-formyl derivative 16, respectively
(Scheme 2). Heating compound 15 afforded 1,3,4-oxadiazole 17, while
N-formyl derivative 16 was cyclodehydrated using P2O5 or P2S5 to give
a compound, which proved to be identical to 17 in addition to the 1,3,4-
thiadiazole 18, respectively (Scheme 2).11,12
Antimicrobial Screening
Antimicrobial Testing. Nutrient agar plates were seeded using 0.1
mL overnight cultures. Cylindrical plugs were removed from the agar
plate using a sterile cork borer, and 100 μL of the tested compounds (1
mg/mL DMSO) were added to the well in triplicates. A blank solvent was
used as a control. Plates inoculated with tested bacteria were incubated
at 37◦C, while those of fungi were incubated at 30◦C. Results (Table III)
were taken after 24 h of incubation and were recorded as the average
diameter of the inhibition zone in mm.5
All newly synthesized compounds were subjected to antimicrobial
screening by the in vitro cup-plate technique using ampicillin, strep-
tomycin, and nystatin as positive controls. Compounds 13, 14, 17,
and 18 showed remarkable activity toward Gram negative bacteria
E. coli.
Gram positive bacteria S. aureus and B. subtilis were proven to be
sensitive toward compounds 9, 10, 12, 17, and 18. Compounds 3c,
4b, 11, and 18 showed remarkable activity toward the fungi S. cere-
visiae and C. albicans used. A close examination of the structures of
the active compounds revealed that the antimicrobial activity was con-
fined to compounds that were connected with different heterocyclic
rings.

New Substituted 2-Mercaptoquinazoline Analogs
345
Cl
O
Cl
I
O
N
N
Cl
I
O
N
N
N
S R
I
O
C
N
2a–d
S
CH2
R = CH3 (a), C2H5 (b)
n-C3H7 (c), n-C4H9 (d)
S
CH2
CN
5
4a–d
X = H (a), NO2 (b)
2
X
Br (c), OCH3 (d)
Cl
O
I
N
N
S
Br
H
1
X
Cl
Acetone/K CO /
Br-CH2CO2OEt3
Δ
O
N
I
X
N
S CH2
Cl
O
3a–c
I
X = H (a), Cl (b), NO2 (c)
N
N
S CH2COOEt
6
OH
H2N
EtOH
NH2NH2
Cl
Cl
O
O
N
I
I
N
N
OH
N
S CH2CONHNH2
S
CH2CONH
7
8
conc. H2SO4
EtOH Isatin/
Δ
Cl
Cl
O
N
O
I
I
N
N
O
H
Br
S
CH2
N
N
O
N
S
NH
10
N
9
O
H
SCHEME 1

346
A. S. El-Azab
Cl
O
I
N
N
S
CH2CONHNH2
7
Cl
O
N
I
S
N
S
CH2CONHNH
NHPh
11
Cl
O
N
I
H
N
O
C
O
N
N
S
12
CH2
CH2
CH2
O
Cl
O
I
N
O
CH3
N
N
N
S
Cl
O
H3C
13
I
N
Cl
N
S
CH2CONH
O
N
I
N
CH
OEt
O
N
15
N
CH3
H
N
S
H
O
14
Cl
O
N
I
Fusion/Δ
N
S
CH2CONHNHCHO
16
P S /
5 Δ
xylene
2
Cl
O
N
Cl
I
O
N
N
N
N
I
N
S
CH2
N
N
O
H
S
CH2
17
S
H
18
SCHEME 2

New Substituted 2-Mercaptoquinazoline Analogs
347
TABLE III Antimicrobial Screening Results of the Tested
Compounds at 1 mg/mL Concentration
Compound
E. coli
S. aureus B. subitilis S. cerevisica
C. albicans
1
2a
2b
2c
2d
3a
3b
3c
4a
4b
4c
4d
5
6
7
8
9
10
11
12
13
14
15
16
—
+
—
—
—
+
+
—
—
—
—
+
+
—
+
—
+ + +
+
—
—
—
—
—
—
+
+
—
—
—
—
—
+
—
—
—
—
+
+ + +
—
+ + +
++
—
+
—
—
++
—
—
—
+
+
+
—
—
—
—
—
+
+
—
—
+
—
+
++
—
++
++
—
+
—
—
—
—
+
—
—
++
—
—
+
+
+ + +
++
+
+ + +
++
+
—
—
—
—
+
++
++
+
++
++
+ + +
+ + +
+
+ + +
++
+
++
++
+
—
+
++
+
—
+
—
—
—
+
+
+
+
17
18
+ + +
+ + +
+ + +
+ + +
NT
++
++
+ + +
++
NT
++
+ + +
+ + +
+ + +
NT
+
++
++
NT
NT
+ + +
++
NT
NT
+ + +
Ampicillin
Streptomycin
Nystatin
—, Inactive (inhibition zone < 10 mm); +, moderate active (inhibition zone
10–15 mm); ++, active (inhibition zone 15–20 mm); + + +, remarkable activity
(inhibition zone >20 mm); NT = not tested.
In conclusion, the present study revealed that compounds 11, 13, 17,
and 18 could be useful as templates for further development through
modification or derivatization to design more potent antimicrobial
agents.
REFERENCES
[1] H. K. Misra and A. K. Sen Gupta, Pharmazie, 37, 254 (1982).
[2] M. A. Aziza, M. W. Nassar, S. G. Abdel-Hamide, A. E. El-Hakim, and A. S. El-Azab,
Ind. J. Heterocycl. Chem., 6, 25 (1996).

348
A. S. El-Azab
[3] S. G. Abdel-Hamide, Saudi Pharm. J., 9, 72 (2001).
[4] M. A. Aziza, M. W. Nassar, S. G. Abdel-Hamide, A. E. El-Hakim, and A. S. El-Azab,
Az. J. Pharm. Sci., 21, 65 (1989).
[5] J. G. Colle, J. P. Duguid, A. G. Fraser, and B. P. Marmion, In Practical Medical
Microbiology, T. J. Macki and J. E. McCartney, Eds., 13th ed, p. 527–596 (Churchill
Livingstone, London 1989).
[6] M. A. Al-Omar, S. G. Abdel-Hamide, H. A. Al-Khamees, and H. H. El-Subbagh,
Saudi Pharm. J., 12, 63 (2004).
[7] S. G. Abdel-Hamide, A. E. El-Hakim, and R. M. Abdel-Rahman, Ind. J. Heterocycl.
Chem., 5, 219 (1996).
[8] M. M. Ghorab, S. G. Abdel-Hamide, G. M. Ali, and H. S. El-Sayed, Pestic. Sci., 48,
31 (1996).
[9] M . S. Mohamed, M. K. Ibrahim, M. A. Ahmed, and S. G. Abdel-Hamide, J. Biol.
Sci., 4, 504 (2004).
[10] A. M. Mahmoud, H. A. El-Sherief, G. M. El-Nagger, and A. E. Abdel-Rahman, Indian
J. Chem., 22B, 491 (1983).
[11] M. A. Al-Omar, A. S. El-Azab, M. A. El-Obeid, and S. G. Abdel-Hamide; J. Saudi
Chem. Soc., 10, 113 (2006).
[12] M. A. Aziza, M. W. Nassar, S. G. Abdel-Hamide, A. E. El-Hakim, and A. S. El-Azab,
Az. J. Pharm. Sci., 16, 125 (1995).