Design,synthesis and evaluation of HSP90 inhibitors combined with fluconazole against azole-resistant candidiasis
Using SNX-2112 as the lead compound,sixteen 2-[(trans-4-hydroxycyclohexyl)amino]benzamide HSP90 inhibitors were designed and synthesized.The target compounds A1-A7 were synthesized from 2-bromo-4-fluorobenzonitrile by nucleophilic substitution,Buchwald-Hartwig coupling and nitrile hydrolysis.The target compounds A8 and A9 were obtained from 4-(bromomethyl)-2-fluorobenzonitrile by electrophilic substitution,nucleophilic substitution and nitrile hydrolysis.The target compounds A10-A16 were obtained from 2-mercaptobenzimidazole and its derivatives by Ullmann coupling,nucleophilic substitution,Buchwald-Hartwig coupling and nitrile hydrolysis.The structures of target compounds were characterized by 1H-NMR and ESI-MS.The inhibitory activities of target compounds combined with fluconazole against fluconazole-resistant strain of C.albicans as strain 901,strain 904,strain 632,strain 100,strain 103 and strain 311 were determined by double dilution method.SNX-2112 combined with fluconazole was used as positive control and fluconazole alone was used as negative control.In vitro antifungal activity test showed that most of target compounds presented different degrees of inhibition against various azole-resistant candidiasis.The antifungal activity of compound A11 combined with fluconazole was superior to the positive control.In this paper,the combined use of fluconazole and HSP90 inhibitors against azole-resistant candidiasis was preliminarily explored,which has further research value and provides experience for further research.
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