Anti-inflammatory activity of substituted 1,3,4-oxadiazoles.
Various 2-(4-biphenoxymethyl)-5-arylamino-1,3,4-oxadiazoles were synthesized by cyclization of the corresponding 1-(4-biphenoxyacetyl)-4-substituted thiosemicarbazides. These compounds were characterized by their elemental analyses and infrared, mass, and nuclear magnetic resonance spectral data. All substituted thiosemicarbazides (100 mg/kg, ip) and cyclized substituted oxadiazoles (100 mg/kg, ip) possessed anti-inflammatory activity, as reflected by their ability to provide protection against carrageenin-induced edema in the rat paw which ranged from 28 to 68% and 36 to 76%, respectively. Cyclization of the substituted thiosemicarbazides, in general, resulted in an increase in the anti-inflammatory activity of their corresponding substituted oxadiazoles, with the exception of those containing 2,4-dimethyl and 3,4-dimethyl substituents in their molecular structure. Hydrocortisone (10 mg/kg, ip) and oxyphenbutazone (40 mg/kg, ip) were used as the standard reference drugs and these provided 45 and 53% protection, respectively. All compounds (1 mM) possessed antiproteolytic activity and the in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin ranged from 13 to 75% for substituted thiosemicarbazides and 39 to 70% for substituted oxadiazoles. There was no relationship between the anti-inflammatory activity of substituted thiosemicarbazides and substituted oxadiazoles and their antiproteolytic effectiveness. The low toxicity of these compounds was reflected by their high approximate LD50 values, ranging from 500 to 1000 mg/kg.
Raman
K
K
Division of Medical Sciences, Alfred I. duPont Institute of the Nemours Foundation, Wilmington, DE 19899.
Parmar
S S
SS
Salzman
S K
SK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D005260:Female; D007928:Lethal Dose 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology* / Q000633:toxicity; D011480:Protease Inhibitors; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010069:Oxadiazoles; D011480:Protease Inhibitors