Synthesis And Antifungal Activity Of 1-(1H-1,2,4-Triazole-1-yl)-2-(2,4-Difluorophenyl)-3-Substituted-2-Propanol

The incidence of fungal infections has increased dramaticaly during the past several years. The most notable explanation for this increase is a rise in the number of immunocompromised patients due to advances in transplantation, the emergence of AIDS, and an increase in the number of invasive surgical procedures. The fungal infections that present most commonly in immunocompromised patients include Candidiasis, Aspergillosis and Cryptococcosis. Despite the availability of Amphotericin B, Fluconazole and Itraconazole antifungal therapies, morbidity and mortailty from invasive fungal infections remain unacceptably high. In addition, many of the currently available antifungal agents have limitations, including toxicity, fungal resistance and the treatment of some fungal infections, particularly Aspergillus fmigatus, is still far from satisfactory. Therefore, it is a critical need for new antifungal agents that are more potent, broader spectrum, and higher effective, yet safe and well tolerated.Azoles is an important class of antifungal agents that interfere with ergosterol biosynthesis by inhibiting a cytochrome P450 enzyme lanosterol 14αdemethylase (CYP51), an essential enzyme in this pathway. This leads to the depletion of ergosterol and accumulation of C-14 methylated sterols and hence disruption of membrane functions. Triazole antifungal agents such as Fluconazole and Itraconazole now are the most widely used for the treatment of systemic fungal infections.In an effort to search for more potent, less toxic and broader spectrum antimycotics, sixty-eight 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted -2-propanols were designed and synthesized according to the antifungal mechanisms and structure-activity relationships of the azoles antifungal compounds. All of them were first reported. All the title compounds were confirmed by means of 1H-NMR, LC-MS and IR.MICs of all title compounds were determined by the method recommended by the National Committee for Clinical Laboratory Standards(NCCLS) using RPMI1640 test medium. Eight fungi were used: Candida albicans ATCC76615, Cryptococcus neoformans ATCC32609, Candida tropicalis, Candida parapsilosis, Trichophyton rubrum, Microsp orumcani, Fonsecaea compacta and Aspergillus fumigatus. The MIC80 values indicate that compounds 9a-l, 10a-l and 12a-l exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 11a-n, 13a-f and 14a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 9d, 9j, 12a, 12b and 12g is 64 times lower than that of ?uconazole against Microsporum gypseum in vitro. And compounds 10i, 11m, 11n, 12a and 12b, 13b showed 128 times higher activity (with the MIC80 value of 0.0039μg/ml) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the shorter side chains enhanced the antifungal activity of the compounds, because it had more strong affinity with the narrow hydrophobic cleft. This conclusion was consistent with the preliminary pharmacology test in vitro. The structure-activity relationship of the title compounds were worth to discuss.