Synthesis and antimicrobial activity of some new benzimidazole derivatives

Article abstract of DOI:10.3390/51201429

Reaction of 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide (1) with CS₂/KOH gave oxadiazole 2 which underwent Mannich reaction to give 3. Compound 2 was treated with hydrazine hydrate to give triazole 4 which was treated with both aldehydes and acetic anhydride to give 5 and 6, respectively. Carbohydrazide 1 was reacted with ethyl acetoacetate, acetylacetone and aldehydes to give 7, 8 and 9, respectively. Cyclocondensation of 9 with thioglycolic and thiolactic acids gave 10 and 11, respectively. Some of these compounds showed potential antimicrobial activities.

Full text of DOI:10.3390/51201429

Molecules 2000, 5, 1429–1438
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis and Antimicrobial Activity of Some New
Benzimidazole Derivatives
Afaf H. El-masry, H. H. Fahmy and S. H. Ali Abdelwahed
Therapeutical Chemistry Department. National Research Centre, Dokki, Cairo, Egypt.
Fax: 00202 3370931. E-mail: elmasry_afaf@hotmail.com.
Received: 10 January 2000; in revised form 5 August 2000 / Accepted: / Published: 22 December 2000
Abstract: Reaction of 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide (1) with
CS2/KOH gave oxadiazole 2 which underwent Mannich reaction to give 3. Compound 2 was
treated with hydrazine hydrate to give triazole 4 which was treated with both aldehydes and
acetic anhydride to give 5 and 6, respectively. Carbohydrazide 1 was reacted with ethyl
acetoacetate, acetylacetone and aldehydes to give 7, 8 and 9, respectively.
Cyclocondensation of 9 with thioglycolic and thiolactic acids gave 10 and 11, respectively.
Some of these compounds showed potential antimicrobial activities.
Keywords: Methylbenzimidazole, oxadiazole, thioglycolic, thiolactic, triazole, pyrazole,
antimicrobial.
Introduction
A wide variety of benzimidazole derivatives have been described for their chemotherapeutic
importance [1-6]. Oxadiazole compounds have shown biological activity against parasites [7] and
bacteria [8]. Also, the presence of basic Mannich side chains in a drug may overcome the water
insolubility problem through the formation of hydrochlorides [9]. Also, some heterocyclic moieties
such as triazole nucleus are known to possess antibacterial [10] and fungicidal [11] properties.
Furthermore, Schiff’s bases possess anticancer [12,13] activity in animal screening, and pyrazoles,
pyrazolones and alkylpyrazoles have shown wide ranging pharmacological applications [14]. We
© 2000 MDPI. All rights reserved.

Molecules 2000, 5
1430
report here the synthesis of some derivatives of the title structure type containing the above mentioned
moieties for evaluation of their antimicrobial activity.
Results and Discussion
In the present work, 3-(2-methylbenzimidazol-1-yl)propanoic acid hydrazide (1), which was
previously prepared by one of us [15], was used as the key intermediate for further synthesis. Thus,
when compound 1 was treated with carbon disulphide and potassium hydroxide according to a reported
method of Young and Wood [8,16], 5-[2-(2-methylbenzimidazol-1-yl)ethyl]-[1,3,4]-oxadiazole-2(3H)-
thione (2) was obtained, (Scheme 1, Tables 2 and 3). One of the earliest discoveries concerning the
utility of Mannich bases as intermediates in drug synthesis was made by Burckhalter and co-workers
[17]. Similarly, compound 2 was allowed to undergo the Mannich reaction with different secondary
amines namely, diethylamine, morpholine or N-methylpiprazine and paraformaldehyde in absolute
ethanol to give compounds 3a-c respectively. (Scheme 1, Tables 2 and 3).
A benzimidazole incorporated into a triazole moiety was synthesized by the reaction of 2 with
hydrazine hydrate (99%) in absolute ethanol which afforded 1-[(1-amino-2-mercapto-1,3,4-triazol-5-
yl)ethyl]-2-methylbenzimidazole (4). (Scheme 1, Tables 2 and 3).
A number of arylidine hydrazones incorporated into the parent benzimidazole were also
synthesized. Thus condensation of compound 4 with aromatic aldehydes, namely, p-methoxy
benzaldehyde and o-chlorobenzaldehyde in absolute ethanol afforded the corresponding Schiff’s bases
5a,b respectively. (Scheme 1, Tables 2 and 3).
Scheme 1.

Molecules 2000, 5
1431
On the other hand, reaction of 4 with acetic anhydride in the presence of glacial acetic acid leads to
the formation of monoacetyl derivative 6. (Scheme 1, Tables 2 and 3).
Carbohydrazide 1 was also allowed to react with ethyl acetoacetate and acetylacetone to give the
corresponding methylpyrazolone derivative 7 and dimethylpyrazole derivative 8 respectively. (Scheme
2, Tables 1 and 3). Condensation of compound 1 with aromatic and heterocyclic aldehydes in absolute
ethanol afforded the corresponding Schiff’s bases 9a-f. (Scheme 2, Tables 2 and 3).
Also, the cyclocondensation of some substituted Schiff’s bases with thioglycolic acid and thiolactic
acid afforded the corresponding thiazolidinone 10a-c and methylthiazolidines 11a-c respectively.
(Scheme 2, Tables 2 and 3). This result is in accordance with previous reported results [18, 19].
Scheme 2.
Biological Screening. Antimicrobial activity test
The test was performed according to the disk diffusion method [20] adopted with some
modifications for the prepared compounds using Gentamycine and Ampicelline as references. The
prepared compounds were tested against one strain of Gram +ve bacteria (Bacillus cereus), Gram –ve
bacteria (Escherichia coli), Yeast (Saccharomyces cerevisae) and Fungi (Aspergillus niger). Whatman
No. 1 filter paper disk of 5mm diameter were sterilized by autoclaving for 15 min at 121°C . The

Molecules 2000, 5
1432
sterile disks were impregnated with different compounds (600 µg / disk). Agar plates were surface
inoculated uniformly from the broth culture of the tested microorganisms. The impregnated disks were
placed on the medium suitably spaced apart and the plates were incubated at 5 °C for 1 h. to permit
good diffusion and then transferred to an incubator at 37 °C for 24 h. for bacteria, and at 28 °C for 72
h. for yeast and fungi. The inhibition zones caused by the various compounds on the microorganisms
were examined. The results of the preliminary screening test are listed in Table 1. The antibacterial and
antifungal activity of compounds 1, 2, 3a, 4, 5b, 8, 9a, 10a,c and 11a,c were tested. From the data
obtained in Table 1, it is clear that compound 2 was found to be highly active against Bacillus cereus
but, slightly active against Escherichia coli. Compounds 4 and 9a were found to be moderately active
against Bacillus cereus while compounds 3a and 10c were found to be slightly active against Bacillus
cereus. But all the tested compounds were found to be inactive against Saccharomyces cerevisae and
Aspergillus niger. Also, compounds 1, 5b, 8, 10a and 11a were found to be inactive against all
microorganisms used.
Table 1. Results of antimicrobial activity of the tested compounds.
Compound No.
B. cereus .
E. coli .
S. cerevisae .
A. niger .
+++
+++
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Gentamycine
+++
+++
Ampicelline
-
+++
+
-
+
-
1
2
3a
4
++
-
-
-
5b
8
-
-
++
-
-
9a
10a
10c
11a
11c
-
+
-
-
-
-
+
Key to symbols:
Highly active
= +++ (inhibition zone > 12 mm)
Moderately active = ++ (inhibition zone 9 - 12 mm)
Slightly active
Inactive
= + (inhibition zone 6 - 9 mm)
= - (inhibition zone < 6 mm)

Molecules 2000, 5
1433
Experimental
Materials and Methods
All melting points are uncorrected and were taken in open capillaries on a Gallenkamp apparatus.
Infrared spectra were determined in KBr on a Perkin Elmer Model-137 Infracord. The 1H-NMR spectra
were measured in DMSO-d6 or CDCl3 solutions using a JEOL EX-270MHz spectrometer. The mass
spectra were recorded on a GCMS-QP 1000 EX Shimadzu Gas Chromatography-MS apparatus.
Spectroscopic and physical data is listed in Tables 2 and 3.
Synthesis of compounds
5-[2-(2-Methylbenzimidazol-1-yl) ethyl][1,3,4]oxadiazole-2(3H)-thione (2)
To a mixture of carbohydrazide 1 (2.18 g, 0.01 mole) in ethanol (200 mL) was added a solution of
KOH (0.84 gm , 0.015 mole) in ethanol (20 mL), followed by CS2 (20mL). The reaction mixture was
heated under reflux for 8 hr. Then it was concentrated, acidified with dilute hydrochloric acid and the
resulting solid was collected, washed with water and recrystallized to give compound 2.
5-[2-(2-Methylbenzimidazol-1-yl) ethyl]-3-diethylaminomethyl (or 3-N-morpholinylmethyl, or 3-N-
piprazinylmethyl)[1,3,4]oxadiazole-2(3H)-thione (3a-c).
General method
A mixture of paraformaldehyde (0.9 g, 0.001mole) and the appropriate secondary amine, namely,
diethylamine, morpholine or N-methylpiprazine (0.015 mole) was refluxed for 30 minutes in
absolute ethanol (10 mL) until complete solubilization of the paraformaldehyde was observed.
Compound 2 (1.04g, 0.004mole) was heated in absolute ethanol (10 mL), then added to the reaction
mixture which was refluxed for 2 h. The reaction mixture was concentrated and the separated product
was filtered off and recrystallized form chloroform/petroleum ether to give compounds 3a-c,
respectively.
5-[2-(2-Methylbenzimidazol-1-yl) ethyl]-4-amino[1,2,4]triazole-3-thiol (4)
A mixture of compound 2 (2.6 g, 0.01 mole) and 99% hydrazine hydrate (2 mL, 0.03 mole) in
absolute ethanol (20 mL) was refluxed for 6 h. The solvent and the excess hydrazine hydrate were
removed under reduced pressure, the residue washed with ether, then recrystallized to give the product
4.

Molecules 2000, 5
1434
5-[2-(2-Methylbenzimidazol-1-yl)ethyl]-4-arylidenimino-[1,2,4]triazole-3-thiol (5a,b)
General method
To a solution of compound 4 (2.74 g, 0.01 mole) in absolute ethanol (30 mL), the appropriate
aromatic aldehyde, namely, p−methoxybenzaldehyde or ο-chlorobenzaldehyde (0.012 mole) was
added. The reaction mixture was refluxed for 4 h. The formed solid after cooling was filtered off and
recrystallized to give the title compounds 5a,b, respectively.
5-[2-(2-Methylbenzimidazol-1-yl)ethyl]-4-actamido-[1,2,4]triazole-3-thiol (6)
Acetic anhydride (0.19 mL, 0.002 mole) was added to a boiling solution of 5-[2-(2-methyl-
benzimidazol-1-yl) ethyl]-4amino[1,2,4]triazole-3-thiol (4) (0.28 g, 0.001 mole) in glacial acetic acid
(3 mL). After refluxing for 2 h., the reaction mixture was cooled and poured into ice/cold water. The
formed precipitate was filtered off and recrystallized from ethanol to give the title compound 6 .
1-[3-(2-Methylbenzimidazol-1-yl)propanoyl]-4,5-dihydro-3-methylpyrazol-5-one (7)
A mixture of carbohydrazide 1 (0.6 g, 0.0028 mole) and ethyl acetoacetate (0.364 g, 0.0028 mole)
in absolute ethanol (20 mL) was heated at reflux temperature for 3 h. The reaction mixture was cooled
and the formed precipitate was filtered off and recrystallized to give the title compound 7.
1-[3-(2-Methylbenzimidazol-1-yl)propanoyl]-3,5-dimethylpyrazole (8)
A mixture of compound I (0.6 g, 0.0028 mole) and acetylacetone (0.28 g, 0.0028 mole) in absolute
ethanol (20 mL) was treated according to the procedure described above to give compound 8.
3-(2-Methylbenzimidazol-1-yl)propanoic acid hydrazide Schiff’s bases (9a-f )
General method
A mixture of compound 1 (2.2 g, 0.01 mole) and the appropriate aromatic or heterocyclic aldehyde,
namely, o-chlorobenzaldehyde, p-nitrobenzaldehyde,
p-methoxybenzaldehyde, 4-hydroxy-3-
methoxybenzaldehyde, p-N,N-dimethylaminobenzaldehyde or 2-thiophenecarboxaldehyde (0.012
mole) was refluxed in absolute ethanol (20 mL) for 5 h. The reaction mixture was concentrated, cooled
and the formed precipitate was filtered off, dried and then recrystallized to give the title compounds 9a-
f respectively.

Molecules 2000, 5
1435
3-(2-Methylbenzimidazol-1-yl)-N-(2-aryl-4-oxo[1,3]thiazolidin-3-yl)propionamide (10a-c)
General method
A mixture of compound 9a,e,f (0.005 mole) and thioglycolic acid (0.55 g, 0.006 mole) was refluxed
in dry benzene (50 mL) for 6 hr. The solvent was evaporated and the reaction mixture was neutralized
with cold dilute sodium bicarbonate solution, the formed product was filtered off and recrystallized to
give the title compounds 10a-c respectively.
3-(2-Methylbenzimidazol-1-yl)-N-(2-aryl-5-methyl-4-oxo[1,3]thiazolidin-3-yl)propionamide (11a-c)
General method
A mixture of compound 9a,b,f (0.005 mole) and thiolactic acid (0.65 g, 0.006 mole) was heated to
fusion at 110-120 °C in an oil bath for 8 hr. The reaction mixture was neutralized with sodium
bicarbonate solution, the formed product was filtered off and recrystallized to give the title compounds
11a-c respectively.
Table 2. Spectral data for the newly synthesized compounds.
Compd. No
2
Spectral data
IR (KBr, cm-1): 3300 (NH), 2923 (CH), 2600 (SH), 1624 (C=N) and 1136.0 (C=S), [(SH) and (C=S)
absorptions indicate thiol-thione tautomers].
1H-NMR (DMSO-d6, δ ppm): 2.55 (3H, s, CH3 at C-2 of benzimidazole), 3.25 (2H, t, J = 7 Hz, NCH2CH2), 4.6
(2H, t, J = 7 Hz, NCH2CH2) and 7.25-7.6 (5H, m, aromatic protons, and SH).
MS, m/z (%): 260 (M+, 57.72), 145 (100).
IR (KBr, cm-1): 2991 (CH), 1180 (C-O), 1654 (C=N) and 1150 (C=S).
1H-NMR (CDCl3, δ ppm): 1.2 (6H, t, J = 7 Hz, 2 CH2CH3), 2.55 (3H, s, CH3 at C-2 of benzimidazole), 2.75
(2H, t, J = 7 Hz, NCH2CH2), 3.6 (4H, q, J = 6 Hz, 2 CH2 CH3), 4.45 (2H, t, J = 7 Hz, NCH2CH2), 4.9 (2H, s,
NCH2N) and 7.15-7.6 (4H, m, aromatic protons).
3a
IR: (KBr, cm-1), 2985 (CH), 1177 (C-O), 1660 (C=N) and 1147 (C=S).
1H-NMR (CDCl3, δ ppm): 2.55 (4H, t, J = 7 Hz, N(CH2)2 of morpholine ring), 2.6 (3H, s, CH3 at C-2 of
benzimidazole), 3.2 (2H, t, NCH2CH2), 3.65 (4H, t, J = 7 Hz, O(CH2)2 of morpholine ring), 4.5 (2H, t, J = 7
Hz, NCH2CH2) 4.85 (2H, s, NCH2N) and 7.15-7.7 (4H, m, aromatic protons).
IR (KBr, cm-1): 2988 (CH), 1176 (C-O), 1658 (C=N) and 1148 (C=S).
3b
3c
MS: (M+.,C18H24N6OS), m/z 372.5 (0.09, unstable) and the base peak at m/z 145 (100).
IR (KBr, cm-1): 3420, 3300, 3145 (NH2 sym., asym-stretch and NH), 2600 (SH), 1155 (C=S) (thiol-thione
tautomers) and 1620 (C=N).
1H-NMR (DMSO-d6, δ ppm): 2.5 (3H, s, CH3 at C-2 of benzimidazole), 3.2 (2H, t, J = 7 Hz, NCH2CH2), 4.55
(2H, t, J = 7 Hz, NCH2CH2 ), 5.6 (2H, s, NH2) and 7.25-7.6 (5H, m, aromatic protons and SH).
MS, m/z (%):274 (M+ , 76.46), 145 (100).
4
IR (KBr, cm-1): 3047 (NH), 2993 (CH), 2580 (SH), 1267 (C=S) and 1153 (C-O).
1H-NMR (DMSO-d6, δ ppm): 2.5 (3H, s, CH3 at C-2 of benzimidazole), 3.2 (2H, t, J = 7 Hz, NCH2CH2), 3.85
(3H, s, OCH3), 4.55 (2H, t, J = 7 Hz, NCH2CH2) and 7.1-7.8 (8H, m, aromatic protons), 9.4 (1H, s, CH=N)
and 13.8 (1H, s, NH).
5a
MS, m/z (%): 392 (M+ , 14.05), 132 (100).
IR (KBr, cm-1): 3162 (NH), 2986 (CH), 2593 (SH), 1282 (C=S) and 746 (C-Cl).
MS, m/z (%): 398 (M+, 37Cl, 0.29), 396 (M+, 35Cl, 0.60), 132 (100).
IR (KBr, cm-1): 3157 (NH), 2964 (CH), 2486 (SH) and 1697 (C=O).
MS, m/z (%): 316 (M+ , 16.1), 145 (100).
5b
6

Molecules 2000, 5
1436
Compd. No
7
Spectral data
IR (KBr, cm-1): 3210 (NH), 3005, 2995 (CH), 1732 (C=O, of pyrazolone), 1682 (C=O) and 1663 (C=N).
1H-NMR (CDCl3, δ ppm): 2.2 (3H, s, CH3 at C-3 of pyrazolone), 2.5 (3H, s, CH3 at C-2 of benzimidazole), 2.75
(2H, t, J = 7 Hz, NCH2CH2), 3.1 (2H, s, CH2 of pyrazolone), 4.5 (2H, t, J = 7 Hz, NCH2CH2), and 7.15-7.6 (4H,
m, aromatic protons).
MS, m/z (%): 284 (M+ , 0.33), 145 (100).
IR (KBr, cm-1): 2990 (CH) and 1668 (C=O).
1H-NMR (CDCl3, δ ppm): 1.55, 1.75 (6H, 2s, 2CH3 of pyrazoline), 2.5 (3H, s, CH3 at C-2 of benzimidazole),
2.95 (2H, t, J = 7 Hz,NCH2CH2), 4.45 (2H, t, J = 7 Hz, NCH2CH2) and 7.0-7.6 (5H, m, 4 aromatic protons and
1H of pyrazoline).
8
IR (KBr, cm-1): 3100 (NH), 2990 (CH), 1671 (C=O).
9a
9b
MS, m/z (%): 342 (M+, 37Cl, 20.7), 340 (M+, 35Cl, 58.3), 145 (100).
IR (KBr, cm-1): 3045 (NH), 2964 (CH), 1671 (C=O), 1514, 1327 (NO2).
IR (KBr, cm-1): 3190 (NH), 3000 (CH), 1670 (C=O).
1H-NMR (CDCl3, δ ppm): 2.45 (3H, s, CH3 at C-2 of benzimidazole), 3.0 (2H, t, J = 7 Hz, NCH2CH2), 3.6 (3H,
s, OCH3), 4.35 (2H, t, J = 7 Hz, NCH2CH2), 6.65-7.7 (9H, m, 8 aromatic protons and 1H of N=CH) and 10.3
(1H, s, NH).
9c
MS, m/z (%): 336 (M+ , 100).
IR (KBr, cm-1): 3400 (OH), 3200 (NH), 2968(CH), 1664 (C=O).
1H-NMR (DMSO-d6 , δ ppm): 2.5 (3H, s, CH3 at C-2 of benzimidazole), 3.0 (2H, t, J = 7 Hz, NCH2CH2), 3.7
(3H, s, OCH3), 4.35 (2H, t, J = 7 Hz, NCH2CH2), 6.65-7.9 (8H, m, 7 aromatic protons and 1H of N=CH), 9.5
(1H, s, OH) and 11.1 (1H, s, NH).
9d
MS, m/z (%): 352 (M+ , 57), 145 (100).
IR (KBr, cm-1): 3251 (NH), 2984 (CH), 1672 (C=O).
1H-NMR (DMSO-d6 , δ ppm): 2.5 (3H, s, CH3 at C-2 of benzimidazole), 2.95 (6H, s, N(CH3)2), 3.2 (2H, t, J = 7
Hz, NCH2CH2), 4.45 (2H, t, J = 7 Hz, NCH2CH2), 6.7-7.9 (9H, m, 8 aromatic protons and 1H of N=CH) and
11.1 (1H, s, NH).
9e
9f
IR (KBr, cm-1): 3209 (NH), 2997 (CH), 1668 (C=O).
IR (KBr, cm-1): 3417 (NH), 2930 (CH), 1716 (C=O of thiazolidinone), 1673 (C=O amide) and 746 (C-Cl).
1H-NMR (DMSO-d6, δ ppm): 2.5 (3H, s, CH3 at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH2CH2), 3.75
(1H, d, J = 6 Hz, A part of an AB system, equatorial proton of thiazolidinone at C-5), 3.9 (1H, d, J = 6 Hz, B
part of an AB system, axial proton of thiazolidinone at C-5), 4.35 (2H, t, NCH2CH2), 6.00 (1H, s,CH of
thiazolidinone at C-2 ), 7.1-7.5 (8H, m, aromatic protons) and 10.4 (1H, s, NH).
10a
10b
10c
MS, m/z (%): 416 (M+, 37Cl, 3.62), 414 (M+, 35Cl, 10.70), 132 (100).
IR (KBr, cm ): 3415 (NH), 2951 (CH), 1719 (C=O of thiazolidinone), 1676 (C=O amide).
-1
IR (KBr, cm-1): 3418 (NH), 2930 (CH), 1720 (C=O of thiazolidinone), 1677 (C=O amide).
1H-NMR (DMSO-d6, δ ppm): 2.45 (3H, s, CH3 at C-2 of benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH2CH2), 3.7
(1H, d, J = 6 Hz, A part of an AB system, equatorial proton of thiazolidinone at C-5), 4.0 (1H, d, J = 6 Hz, B
part of an AB system, axial proton of thiazolidinone at C-5), 4.45 (2H, t, NCH2CH2), 5.95 (1H, s,CH of
thiazolidinone at C-2 ), 6.7-7.5 (7H, m, aromatic protons) and 10.5 (1H, s, NH).
MS, m/z (%): 386 (M+, 0.7), 132 (100).
IR (KBr, cm-1): 3400 (NH), 3000 (CH), 1715 (C=O of thiazolidinone), 1670 (C=O amide).
1H-NMR (CDCl3, δ ppm): 1.45 (3H, d, J = 6 Hz, CH3 at C-5 of thiazolidinone), 2.45 (3H, s, CH3 at C-2 of
benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH2CH2), 3.65 (1H, q, CH of thiazolidinone at C-5), 4.35 (2H, t, J = 7
Hz, NCH2CH2), 6.1 (1H, s, CH of thiazolidinone at C-2), 7.1-7.55 (8H, m, aromatic protons) and 10.4 (1H, s,
NH).
11a
11b
11c
MS, m/z (%): 430 (M+, 37Cl, 8.89), 428 (M+, 35Cl, 25.78), 160 (100).
IR (KBr, cm-1): 3440 (NH), 2930 (CH), 1720 (C=O of thiazolidinone), 1677 (C=O amide) and 1520, 1325
(NO2).
IR (KBr, cm-1): 3341 (NH), 3008 (CH), 1711 (C=O of thiazolidinone), 1675 (C=O amide).
1H-NMR (DMSO-d6, δ ppm): 1.43 (3H, d, J = 6 Hz, CH3 at C-5 of thiazolidinone), 2.42 (3H, s, CH3 at C-2 of
benzimidazole), 2.65 (2H, t, J = 7 Hz, NCH2CH2), 3.65 (1H, q, CH of thiazolidinone at C-5), 4.4 (2H, t, J = 7
Hz, NCH2CH2), 6.2 (1H, s, CH of thiazolidinone at C-2), 6.9-7.5 (7H, m, aromatic protons) and 10.4 (1H, s,
NH).
MS, m/z (%): 400 (M+, 0.6), 132 (100).

Molecules 2000, 5
Table 3. Yields, physical and analytical data of the prepared compounds.
1437
Comp M.P. oC (Recryst. Yield
Formulae
(M.Wt.)
Analysis % ,Calculated / Found
No.
Solvents)
%
C
H
4.65
4.63
6.71
6.77
5.89
5.93
6.49
6.51
5.14
5.12
5.15
5.17
4.32
4.37
5.11
5.20
5.68
5.67
6.43
6.47
5.04
5.01
4.88
4.82
6.00
6.12
5.73
5.69
6.65
6.60
5.17
5.20
4.62
4.65
5.96
5.98
4.70
4.69
4.94
4.96
4.83
4.82
5.04
5.11
N
21.52
21.45
20.27
20.32
19.48
19.51
22.56
22.62
30.63
30.54
21.42
21.43
21.18
21.21
26.56
26.54
19.71
19.69
19.85
19.90
16.44
16.40
19.93
19.99
16.66
16.69
15.90
15.96
20.04
20.12
17.93
17.99
13.51
13.48
16.54
16.58
14.49
14.46
13.06
13.11
15.94
15.91
13.99
14.13
S
208-210
(AcOH/H2O)
89-91
C12H12N4OS
(260.28)
C17H23N5OS
(345.51)
C17H21N5O2S
(359.49)
C18H24N6OS
(372.54)
C12H14N6S
(274.35)
C20H20N6OS
(392.48)
C19H17ClN6S
(396.93)
C14H16N6OS
(316.43)
C15 H16 N4 O2 63.36
(284.35)
C16 H18 N4
(282.38)
C18H17ClN4O
(340.84)
C18H17N5O3
(351.36)
C19H20N4O2
(336.43)
C19H20N4O3
(352.43)
C20H23N5O
(349.48)
55.37
55.29
59.10
59.18
56.80
56.85
58.04
58.15
52.53
52.45
61.20
61.27
57.49
57.53
53.14
53.09
12.32
12.28
86
2
65
60
63
85
80
85
68
65
75
87.5
82.6
88
90
91
85
71
64
40
74
53
44
-
3a
3b
3c
(CHCl /Pet.ether)
3
183-185
-
-
(CHCl /Pet.ether)
3
149-150
(CHCl /Pet.ether)
3
304-306
11.68
11.65
4
(AcOH/H2O)
261-263
(AcOH/H2O)
249-251
(AcOH/H2O)
282-284
(Ethanol)
123-124
(Ethanol)
139-141
(Ethanol)
187-189
(Ethanol/H2O)
199-201
(Ethanol/H2O)
167-169
(Ethanol/H2O)
229-231
(Ethanol/H2O)
179-181
(Ethanol/H2O)
89-91
(Ethanol/H2O)
249-251
(Ethanol/H2O)
264-266
-
-
-
-
-
-
-
-
-
-
-
5a
5b
6
7
63.32
68.06
68.09
63.43
63.41
61.53
61.59
67.84
67.87
64.74
64.71
68.73
68.68
61.51
61.56
O
8
9a
9b
9c
9d
9e
C16H16N4OS
(312.42)
C20H19ClN4O2S 57.89
(414.94)
C22H25N5O2S
(423.58)
C18H18N4O2S2
(386.52)
C21H21ClN4O2S 58.80
(428.97)
C21H21N5O4S
(439.53)
9f
7.73
7.69
7.55
7.60
16.59
16.55
7.47
7.50
7.29
7.25
16.00
16.10
10a
10b
10c
11a
11b
11c
57.84
62.39
62.45
55.94
55.98
(Ethanol/H2O)
120-122
(Ethanol/H2O)
193-195
(CHCl /Pet.ether)
58.87
57.38
57.35
56.97
57.12
3
159-161
(Ethanol/H2O)
131-133
C19H20N4O2S2
(400.5)
(CHCl /Pet.ether)
3

Molecules 2000, 5
1438
Acknowledgements
The authors wish to express their thanks to Prof. Dr. Abdalhamid Ali Hamdy, Associate Professor,
Department of Natural and Microbial Products Chemistry, National Research Centre, for his help with
the biological testing .
References
1. Boruah, C. R.; Skibo, E. B., J. Med. Chem. 1994, 37, 1625.
2. Srivastava, R. P.; Sharma, S.; Die Pharmazie 1990, 45, 34.
3. Kubo, K.; Inoda, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.; Furukawa, Y.; Nishikawa, K.;
Naka, T. J. Med. Chem.. 1993, 36, 1772.
4. Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.; Nishikawa, K.; Naka, T.
J. Med. Chem., 1993, 36, 2182.
5. Kubo, K.; Kohara, Y.; Yoshmora, Y.; Inada, .; Shibouta, Y.; Furukawa, Y.; Kato, T.; Nishikawa,
K.; Naka, T. J. Med. Chem., 1993, 36, 2343.
6. Ito, K.; Kagawa, H.; Fududa, T.; Yoshino, K.; Nose, T. Arzneim-Forsch. 1982, 31, 49-55.
7. Rizk, M., Egypt. J. Pharm. Sci. 1993, 34, 243.
8. Kassem, Emad, M. M. El-masry, Afaf, Proceedings of The First International Scientific
Conference (Science and Deveopment) Cairo, 1995, 20-23 March, 119.
9. Kamel, M. M.; Naser, M. E. Die Pharmazie 1979, 34(7), 440.
10. Chiyomara, E. Y.; Dohke, G. Japan Pat. 460, 7339 (1973)., Chem. Abstr., (1974), 81, 73392.
11. Greenfield, S. A.; Michael, C. S.; Von Meyer, W, C. (Rohm and Hass Co.) Ger. Offen., 1, 966,806,
1974, Chem. Abstr. 1975, 82, 150485.
12. Popp, F. D. J. Org. Chem. 1961, 26, 1566.
13. Popp, F. D. J. Med. Chem. 1964, 7, 210.
14. Clinton, R. O.; Manson, A. J.; Stonner, F. W.; Beyler, A. L.; Potts, G. O. J. Amer. Chem. Soc.
1959, 81, 1513.
15. Abdelwahed Sameh Hassan, M. Sc.Thesis, Faculty of Science, Cairo University, 1999.
16. Young, R. W.; Wood, K. H. J. Am. Chem. Soc. 1955, 77, 400.
17. Burckhalter, J. H., Wells, J. N.; Mayer, W. J. Tetrahedron Letts. 1964, 1353.
18. Kamdar, G. C.; Chavda, A. C.; Parikh, A. R. J. Indian Chem. Soc. 1987, 64, 298.
19. El-Bannany, A. A.; Abdel-Azim, H. I. Pharmazie 1986, 41, 144.
20. Abou-Zeid, Abou-Zeid A.; Shehata, Youssef., Indian J. Pharm. 1969, 31(3), 72.
Samples Availability: Available from the authors.
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