Acta Pharm. 69 (2019) 261-276
Original research paper
Synthesis and evaluation
of some new 1,3,4-oxadiazoles bearing thiophene, thiazole, coumarin, pyridine
and pyridazine derivatives as antiviral agents
MOHAMMED ALBRATTY, KARAM AHMED EL-SHARKAWY and HASSAN AHMED ALHAZMI
1 Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
2 Department of Organic Chemistry,
Faculty of Biotechnology, October University for Modern Sciences and Arts(MSA),
El-Wahat Road, 6 October City, Egypt
Accepted November 5, 2018
Published online November 25, 2018
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-phenyl-
hydrazono)-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.
Keywords: 1,3,4-oxadiazole
derivatives, thiophene, coumarin,
thiazole, pyridine, pyridazine,
antiviral activity