Design,Synthesis And Biological Activity Evaluation Of Novel Carboline Antifungal Compounds

Cryptococcus meningitis(CM),a central nervous system disease that threatens human health,is a clinically challenging therapeutic problem.Antifungal drugs for the treatment of life-threatening CMs are very limited.Moreover,severe drug resistance of Candida albicans infections have been developed,which is an urgent problem to be solved in clinical treatment.Therefore,there is an emergent need to develop novel antifungal agents with new mechanisms and novel chemical types.This dissertation focused on the novel carboline antifungal compounds mainly including two parts:(1)Structural optimization and biological activity evaluation of carboline lead compound HXM-b10;(2)Design,synthesis and biological activity evaluation of carboline antifungal compounds containing hydroxamic acid side chains.?.Structural optimization and biological activity evaluation of carboline lead compound HXM-b10Previously,our group designed and synthesized a ?-carboline antifungal compound HXM-b10 by screening the compound library and structural optimization.Compound HXM-b10 showed comparable inhibitory activity against Cryptococcus neoformans to the first-line drug fluconazole(MIC80 = 4 ?g/mL).However,the structure-activity relationship of the lead compound HXM-b10 is not clear.Thus,compound HXM-b10 was used as a lead compound for further investigation.This study performed structural optimization study of lead compound HXM-b10,rationally designed and synthesized three different types of compounds,and tested their in vitro inhibitory activity against Cryptococcus neoformans.The results showed that all the compounds exhibited moderate to good anti-Cryptococcus neoformans activity.Compound A4 revealed the best inhibitory activity against Cryptococcus neoformans,which was superior to lead compound HXM-b10.This study further enriched the structure-activity relationship of lead compound HXM-b10,laying a solid foundation for the in-depth study of this class of inhibitors.?.Design,synthesis and biological activity evaluation of carboline antifungal compounds containing hydroxamic acid side chainsIn the previous study,we found that the combination of Tubastain A and fluconazole had a synergistic antifungal effect against fluconazole-resistant Candida albicans(FICI = 0.265).By structural analysis,it was found that the scaffold of the above mentioned carbolines was similar to that of Tubastain A.Therefore,hydroxamic acid groups were introduced into the side chains,and novel carboline-based synergistic antifungal compounds with HDAC enzyme inhibitory activity were designed.As a result,13 derivatives were synthesized,which were assayed for in vitro anti-C.albicans activity.The results showed that the combination of these compounds with fluconazole showed good synergistic effects against resistance C.albicans isolates,which were superior to Tubastain A and deserved further study.