Design, Synthesis And Antifungal Evaluation In Vitro Of New Triazole Antifungal Compounds

During past few years, with the widely use of broad-spectrum antibiotics, anticancerdrugs in clinic, the morbidity and mortality of fungal infections have soared in theimmuno-compromised hosts suffering from tuberculosis, cancer, AIDS and organtransplant cases. Currently, azoles are the first choice in clinic, such as fluconazole,itraconazole. However, their clinical application value is hampered by their relatively highrisk of toxicity, the emergence of drug resistance, pharmacokinetic deficiencies and/orinsufficiencies in their antifungal activities, what created an urgent need for the discoveryof new antifungal compounds that have broader spectrum and lower toxicity.Azole antifungals curb the growth of fungi by competitive inhibition of the lanosterol14α-demethylase(CYP51), the enzyme that catalyzes the oxidative removal of the14α-methyl group of lanosterol to giveΔ^{14, 15}-desaturated intermediates in ergosterolbiosynthesis. Selective inhibition of CYP51 would cause depletion of ergosterol andaccumulation of lanosterol and other 14-methyl sterols leading to the growth inhibition offungal cells.In an effort to search for more potent, less toxic and broader spectrum antimycotics,eighty-one 1-(2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1- yl)propyl)-1H-1,2,4-triazol-5(4H)-one of fluconazole analogs were designed and synthesized according to theantifungal mechanisms and structure-activity relationships of the azoles antifungalcompounds. The title compounds were confirmed by means of ¹H-NMR, ¹³C NMR,LC-MS and IR.MICs of all title compounds were determined by the method recommended by theNational Committee for Clinical Laboratory Standards (NCCLS) using RPMI1640 testmedium. Eight fungi were used: Candida albicans Y0109 and Candida albicans SC5314,Cryptococcus neoformans BLS108, Candida parapsilosis, Candida tropicalis, Trichophytonrubrum, Candida kefyr and Aspergillus fumigatus. Computational docking experimentsindicated 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-activityrelationship of the title compounds were worth to discuss.