Design, synthesis and antiinflammatory activity of some 1,3,4-oxadiazole derivatives.
A series of substituted 1,3,4-oxadiazole derivatives 19-34 were synthesized as antiinflammatory agents. The target compounds were obtained by cyclodesulfurization of the corresponding thiosemicarbazides 3-18 using either dicyclohexylcarbodiimide DCC, or I(2)/NaOH. Intermediates 3-18 are readily accessible through conversion of the carboxylic acids 1a-d to the respective hydrazides 2a-d followed by treatment with appropriate isothiocyanate derivatives. The structures of the synthesized compounds were confirmed by elemental as well as spectroscopic analyses. The antiinflammatory activity was investigated by determination of the inhibitory effects of the oxadiazole derivatives 19-34 on histamine-induced edema in rat abdomen. Compounds 19a, 21a, 23b, 28c and 32d proved to be more potent antiinflammatory agents at 200 mg/kg po than ibuprofen, the standard reference drug. Other compounds such as 20a, 25b, 27c, 29c, and 33d showed significant antiinflammatory activity but less than ibuprofen at the same dose level. The low toxicity of the most potent compounds was reflected by their higher LD(50) value, ranging from ~1000 to 1500 mg/kg, as well as the lower ulcerogenic liability at 200 mg/kg po. Furthermore, some of the newly synthesized derivatives were better analgesics than the reference drug as observed from the percentage writhing inhibition in the p-benzoquinone (PBQ)-induced writhing test in mice.