The synthesis and antifungal activity of a novel series of l-[(3,5-bisaryl-2-methylisoxazolidin-3-yl)methyl]-IH-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 a -substituted (E)-ketonitrones 4 with appropriate styrene derivatives 5 that led to a &/trans-diastereoisomeric mixture of the corresponding triazoles (Scheme). The title compounds were evaluated for in uitro antifungal activity in solid agar cultures against a broad array of yeast and systemic mycoses and dermatophytes. The in uiuo activity was determined in an immune-compromised mouse model of systemic candidiasis. While the in uitru activity was evident throughout the series, it was moderate in potency. However, some of the triazole derivatives demonstrated a potent in uiuo 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 uitro and in uiuo assays.
Recently [ 11, we have reported the synthesis and biological activity of a novel class of antifungal 3-aryl-5-[(aryloxy)alkyl]-3-[( 1 H-imidazol-1 -yl)methyl]-2-methylisoxazolidines 1. The preparation of compounds 1 involved a 1,3-dipolar cycloaddition of CI -substituted (E)-ketonitrones with 1-alkenyl phenyl ethers. Previous reports [24] by a number of research laboratories indicated that substituting the 1H-imidazole ring with a 1H-1,2,4triazole ring provided compounds having a more potent in oioo antifungal activity. This, coupled with a better pharmacokinetic profile made the lH-l,2,4-triazole-containing azoles attractive and promising targets because of their lesser toxicity and better activity as systemic antifungal agents [5].