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  • Author: Karam Ahmed El-Sharkawy x
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Mohammed Albratty, Karam Ahmed El-Sharkawy and Hassan Ahmed Alhazmi

Abstract

In an attempt to produce heterocyclic compounds based on 1,3,4-oxadiazole derivatives with potential antiviral activity, synthesis of compound 1 [2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile] was performed through the reaction of cyanoacetic acid hydrazide with carbon disulfide in alcoholic potassium hydroxide. Compound 1 has an activating methylene group, so it was directed toward some specific reactions. Thus, aryldiazonium chlorides reacted with compound 1 affording hydrazono derivatives 2a-c. Also, aromatic aldehydes reacted with compound 1 to produce compounds 3a,b. Furthermore, cyclic ketones were subjected to the synthesis of fused thiophene derivatives 4a,b via reaction with compound 1 in the presence of elemental sulfur. In addition, 1,3,4-oxadiazole derivative 1, when reacted with isothiocyanates, salicylaldehyde or 1,3-dicarbonyl compounds, formed thiazole derivatives 5a,b, coumarin derivative 6 and alkenyl derivatives 7a,b resp. Compound 7b underwent cyclization to afford pyridine derivative 8. Arylhydrazono derivatives 9a,b were produced through the reaction of compound 7a with aryldiazonium chlorides. Products 9a,b underwent cyclization to produce pyridazine derivatives 10a,b. Finally, 1,3,4-oxadiazole derivative 1 was directed toward reaction with hydrazine derivatives, bromoacetophenone and ethylchloroacetate affording compounds 11a,b, 12 and 13, resp. Fused thiophene derivatives 14a,b were produced via reaction of compounds 4a,b with a mixture of malononitrile and ethylorthoformate. Antiviral activity of the synthesized products showed that 5-(4-amino-3-ethyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5a) and 5-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-yl)-1,3,4-oxadiazole-2(3H)-thione (5b) acted as the most active agents against Feline herpes virus, Feline corona virus, Herpes simplex virus-1 and Herpes simplex virus-2, whereas compound 2-(5-(2-phenylhydrazono)-4,5-dihydro-1,3,4-oxadiazol-2-yl)acetonitrile (11b) was the most effective against Vaccinia virus, Herpes simplex virus (TK-KOS-ACVr), Coxsackie virus B4 and Vesicular stomatitis virus.

Open access

Mohammed Albratty, Karam Ahmed El-Sharkawy and Shamsher Alam

Abstract

2-Cyano-N-(thiazol-2-yl) acetamide (2a) and 2-cyano-N-(oxazol- 2-yl) acetamide (2b) were obtained via the reaction of ethyl cyanoacetate with either 2-aminothiazole (1a) or 2-aminooxazole (1b). The formed products were directed toward the reaction with cyclopentanone and elemental sulfur in the presence of triethylamine to give cyclopenta[b]thiophene derivatives (3a,b). The latter products were reacted with either ethyl cyanoacetate or malononitrile to form compounds 4a,b and 5a,b, respectively. Compounds 4a,b were aimed at synthesizing some heterocyclic compounds; thus internal cyclization reactions were introduced to form compounds 6a,b. Also, compounds 4a,b reacted with salicylaldehyde, hydrazine derivatives and either urea or thiourea to produce coumarin derivatives (7a,b), pyrazole derivatives (8a-d) and pyrimidine derivatives (9a-d), respectively. Reaction of either benzaldehyde or benzene diazonium chloride (11) with compounds 4a,b afforded compounds 10a,b and 12a,b, respectively. On the other hand, compounds 5a,b underwent internal cyclization to form pyrimidine derivatives 13a,b. Also, when compounds 5a,b reacted with either ethyl cyanoacetate or malononitrile, they gave pyridine derivatives (15a-d) through the formation of intermediates (14a-d). Finally, formation of fused pyrimidine derivatives (17a,b) was achieved through the reaction of compounds 5a,b and salicylaldehyde applying two different pathways. The first pathway used a catalytic amount of piperidine to form compounds 16a,b; the latter products underwent cyclization to give compounds 17a,b. The second pathway, using a catalytic amount of sodium ethoxide solution directly in one step, afforded compounds 17a,b. Structures of the newly synthesized compounds were established using IR, 1H NMR, 13C NMR and mass spectrometry and their antitumor activity was investigated. Some of these compounds showed promising inhibitory effects on three different cell lines. However, fused pyrimidine acetonitrile derivatives 6a and 6b exerted the highest inhibitory effect, comparable to that of doxorubicin.