Studies on Antifungal Agents. Part 25. 1‐[(3,5‐Bisaryl‐2‐methylisoxazolidin‐3‐yl)methyl]‐1H‐1,2,4‐triazoles

The synthesis and antifungal activity of a novel series of 1‐[(3,5‐bisaryl‐2‐methylisoxazolidin‐3‐yl)methyl]‐1H‐1,2,4‐triazoles 6 and 7 (i.e. 8–19) are discussed. The preparation of 8–19 was straightforward and highlighted by a regiospecific 1,3‐dipolar cycloaddition of α‐substituted (E)‐ketonitrones 4 with appropriate atyrene derivatives 5 that led to a cis/trans‐diastereoisomeric mixture of the corresponding triazoles (Scheme). The title compounds were evaluated for in vitro antifungal activity in solid agar cultures against a broad array of yeast and systemic mycoses and dermatophytes. The in vivo activity was determined in an immune‐compromised mouse model of systemic candidiasis. While the in vitro activity was evident throughout the series, it was moderate in potency. However, some of the triazole derivatives demonstrated a potent in vivo activity comparable to that of the standard drug ketoconazole. Analogue 12 (PR 988‐399) emerged as the best overall compound demonstrating potent antifungal activity in both in vitro and in vivo assays.