DESIGN, SYNTHESIS AND ANTIINFLAMMATORY ACTIVITY OF SOME 1,3,4-OXADIAZOLE DERIVATIVES

A series of substituted 1,3,4-oxadiazole derivatives 19-34 were synthe sized as antiinflammatory agents. The target compounds were obtained b y cyclodesulfurization of the corresponding thiosemicarbazides 3-18 us ing either dicyclohexylcarbodiimide DCC, or I-2/NaOH. Intermediates 3- 18 are readily accessible through conversion of the carboxylic acids 1 a-d to the respective hydrazides 2a-d followed by treatment with appro priate isothiocyanate derivatives. The structures of the synthesized c ompounds were confirmed by elemental as well as spectroscopic analyses . The antiinflammatory activity was investigated by determination of t he inhibitory effects of the oxadiazole derivatives 19-34 on histamine -induced edema in rat abdomen. Compounds 19a, 21a, 23b, 28c and 32d pr oved to be more potent antiinflammatory agents at 200 mg/kg po than ib uprofen, the standard reference drug. Other compounds such as 20a, 25b , 27c, 29c, and 33d showed significant antiinflammatory activity but l ess than ibuprofen at the same dose level. The low toxicity of the mos t potent compounds was reflected by their higher LD(50) value, ranging from similar to 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)-i nduced writhing test in mice.