Synthesis of antifungal 2-anilino-4-phenylthiazoles and their inhibitory activities on sterol biosynthesis

We previously reported that 1,2,4-thiadiazole derivatives such as 5-(4-chlo roanilino)-3-(2,6-dichlorophenyl)-1,2,4-thiadiazole showed high antifungal activities in vitro against Trychophyton mentagrophytes and Botrytis cinere a, and accumulated squalene remarkably. In view of the Nussbaumer's model o f squalene epoxidase inhibitors, we synthesized the corresponding thiazole derivatives in which 2-nitrogen atom of 1,2,4-thiadiazole was replaced by c arbon in order to explore the structural requirement of the heteroaromatic moiety for fungicidal activity. We further synthesized the related thiazole s having various substituents to investigate the structure-activity relatio nships. Antifungal activities and squalene accumulation of the thiazole com pounds were well correlated. Among the compounds synthesized, 2-(4-chloroph enylamino)-4-(2,6-dichlorophenyl)thiazole (5) showed the highest antifungal activity against T. mentagrophytes and B. cinerea, and was more active tha n tolnaftate, a clinically used thiocarbamate. The compound (5) inhibited s qualene epoxidase remarkably in a cell free assay using S. These experiment al results indicate that the primary mode of action of the thiazole derivat ives is the inhibition of squalene epoxidase in the sterol biosynthesis.