Design, synthesis and biological evaluation of 1,3,4-oxadiazoles as promising anti-inflammatory agents

Abstract

A series of 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for radical scavenging and anti-inflammatory properties. Molecular docking simulation studies onto the proteins cyclooxygenase-1 (PDB: 1CQE) and cyclooxygenase-2 (PDB: 3LN1) to visualize the probable binding affinity towards anti-inflammatory importance and in silico studies, towards their appreciable ADME & probable toxicity property were screened. The best-ranked molecules; N-((5-substituted-1,3, 4-oxadiazol-2-yl)methyl) benzo[d]thiazol-2-amine (5a–5j) were synthesized from 2-(benzo[d]thiazol-2-ylamino)acetohydrazide (4) on reaction with aryl/heteroaryl/aliphatic carboxylic acid derivatives via acid catalyzed dehydrative cyclization. N-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl) benzo[d]thiazol-2-amine (5k) was synthesized by base catalyzed condensation of hydrazide derivative 4 and with carbon disulfide. The newly synthesized compounds were characterized and established on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass studies. The 1,3,4-oxadiazoles were evaluated for in vitro antioxidant property by 2,2′-diphenyl-1-picryl hydrazyl radical scavenging assay method and in vivo anti-inflammatory activity by carrageenan induced paw edema method. The radical scavenging activity indicated that the 1,3,4-oxadiazoles at 25 µM test concentration exhibited significant radical scavenging property ranging from 32.0 to 87.3 % in comparison to 76.0 % radical scavenging activity obtained for the reference drug, ascorbic acid. The results of the in vivo anti-inflammatory activity highlighted that the 1,3,4-oxadiazoles at 25 mg Kg−1 test dose exhibited significant edema inhibition with a mean value ranging from 23.6 to 82.3 % in comparison to 48.3 % edema inhibition obtained for the reference drug, indomethacin. The compound 5h with mean edema inhibition value of 82.3 % and potent among the series was further evaluated for in vitro COX inhibition and was found to more selective towards COX-2. The acute ulcerogenic evaluation of compound 5h indicated it to be safe at the dose of 50 mg Kg−1.