In vitro and in vivo activities of Syn2836, Syn2869, Syn2903, and Syn2921:New series of triazole antifungal agents

The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2 ,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The i n vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a pane l of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconaz ole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC(90)s) for the four test compounds f or strains of Candida spp. ranged from <0.048 to 0.78 mug/ml. All compounds were also active against FLC-resistant Candida albicans and other Candida sp. strains. Moreover, MIC(90)s for strains of Cryptococcus neoformans, Asp ergillus spp., Trichophyton spp., and Microsporum spp. were also low and ra nged from <0.048 to 0.39 mug/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated tha t all four test compounds have good efficacies against C. albicans in a mur ine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC , while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds we re similar to those for ITC. It was concluded from the data generated for t his new series of azole compounds in the studies described above that furth er pharmacokinetic and toxicologic evaluations are warranted prior to selec tion of a candidate compound for preclinical testing.