C. Richard Kinsolving

In vitro antifungal activity of novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives.

To further investigate the role of the C-5 substituent on the isoxazolidine ring on antifungal activity, a number of novel substituted 3,5-diphenyl-3-( lH-imidazol1 -ylmethyl)-2-methylisoxazoiidine derivatives (1) were prepared and assayed in vitro using broth and agar cultures. The synthesis of the title compounds involved a 1,3-dipolar cycloaddition reaction of substituted phenyl1H-imidazol1-ylmethyl nitrones with appropriate styrene precursors. The resulting cis/trans mixtures of the corresponding isoxazolidines were separated by flash chromatography on silica gel (TABLE 1):

Comparisons of ketoconazole, PR 969-566, PR 967-234, and PR 967-248 as antifungals in vitro and in the rat model of candidal vaginitis based on efficacy/safety profiles.

Critical factors in the rational development of new antifungal drugs are standardized, quantitative, and coordinated approaches involving chemical discovery, preclinical evaluations, and comparisons of novel antifungal candidates with positive reference compounds. The reference compound ketoconazole has been found to be effective clinically against vaginal candidiasis as well as in the rat model of candidal vaginitis. A new chemical series of isoxazolidine compounds was targeted for preclinical evaluations involving 1) in vitro testing; 2 ) in vivo analysis in the rat model of candidal vaginitis; and 3 ) safety considerations involving hormonal, central nervous system (CNS), and cardiovascular (CV) effects. The following antifungal candidates were first compared to ketoconazole for in vitro activity: 1) PR 969-566 or cis-3-(4-chlorophenyl) 3 [ ( 1Himidazol1 yl) methyl] 2 -methyl 5 { [ ( 4 methylphenyl) thiolmethyl) isoxazolidine; 2) PR 967-234 or cis-3,5-bis(4-chlorophenyl)-3-[ ( ltl-imidazoll-yl)methyl]-2-methylisoxazolidine; and 3) PR 967-248 or cis-5-[ (4-chlorophenoxy ) methy1]-3-(4-~hlorophenyl)-3-[( lH-imidazol1 -yl)methyl]-2-methylisoxazolidine. In the in vitro evaluations, minimum inhibitory concentration (MIC) values were used for comparing antifungal activity of all four compounds against two strains of Candida