Design,Synthesis And Biological Evaluation Of Novel Antifungal Compounds

In the past four decades,the morbidity of invasive fungal infections（IFIs）has been increasing rapidly,which has seriously threatened human health.However,the types of existing drugs are insufficient,and serious drug resistance is common clinically.It is urgent and crucial to develop antifungal drugs with new structures and new mechanisms.This thesis consisted of two parts:First,a serious of albaconazole analogs containing benzotriazinone,isoquinolinone and phenolphthaleone were designed and synthesized in order to obtain novel triazole lead compounds with high antifungal activity,broad antifungal spectrum,low toxicity and in vivo efficacy.Secondly,based on the berberine analogs with synergistic antifungal effects reported in our previous works,molecule structure was modified to improve water solubility and metabolic stability,which was aimed to discover novel lead compounds with in vivo synergistic antifungal activity with fluconazole.1.Design,Synthesis and Antifungal Activity of Novel Triazole CompoundsTriazole antifungal drugs are currently first-line drugs in the treatment of IFIs with good efficacy and safety.In this study,48 albaconazole analogs（four series）were designed and synthesized based on bioisosterism.Most compounds of A,B and C series have excellent antifungal activities against Candida albicans(MIC₈₀:0.5-0.0156μg/m L),Cryptococcus neoformans(MIC₈₀:2.0-0.0313μg/m L)and Aspergillus fumigatus(MIC₈₀:8.0-0.25μg/m L),and a clear structure-activity relationship was obtained.The preferred compounds A13,B2and C2 have low cytotoxicity and were stable in liver microsomes.Further research showed that compound B2（1.0 mg/kg）can significantly prolong the survival period of mice infected by Candida albicans in vivo.These provide theoretical guidances and lead compounds for the further discovery of novel triazole antifungal drugs.2.Design,Synthesis and Preliminary Mechanism Research of Pepper Propionic Acid Derivatives with Synergistic Antifungal Activity against Fluconazole Resistance Candida albicansDrug combination therapy is a worldwide treatment strategy that can improve drug efficacy and reduce drug resistance.Especially,the combination with antifungal drugs and non-antifungal small molecules has drawn extensive attention.In this study,26 new pepper propionic acid derivatives（three series）were designed and synthesized based on lead 3e.In vitro evaluation showed that most compounds had synergistic antifungal activity against fluconazole resistance Candida albicans with fluconazole.Moreover,the synergistic effects of preferred compounds E4,E7,F1 and G8 were equivalent to that of lead 3e（FICI:0.063-0.005）,and they also have high water solubility and metabolic stability in liver microsome.Further mechanism study clarified that G8 can restore the sensitivity of fluconazole in drug-resistant Candida albicans,and can synergistically inhibit the formation of biofilm and the growth of hyphae.Interestingly,the combination of the two drugs has fungicidal effect.These compounds have strong synergistic effects with fluconazole in vitro,and the structure-activity relationship was clear,which was worthy of further exploration and research.