新型三氮唑酰胺衍生物的设计、合成及其抗真菌活性研究OA

Triazoles are currently the most widely used drugs for treating invasive fungal infections in clinical practice.However,drug resistance is becoming increasingly serious,posing challenges for the treatment of fungal infections.To discover antifungal agents with novel structures and excellent broad-spectrum antifungal activity,a series of new triazole amide derivatives were synthesized and evaluated for their antifungal activity.Four novel triazole amide derivatives were designed and synthesized by utilizing(2S)-2-(4-isobutylphenyl)propanoic acid,(2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid,(S)-1-Boc-2-methylpiperazine,and 1-Boc-piperazine as starting materials.The structures of the triazole amide derivatives were characterized by 1 HNMR,13 CNMR and MS.Subsequently,their inhibitory effects on Candida albicans,Aspergillus fumigatus,Cryptococcus neoformans,and azole-resistant Candida were assessed through in vitro assays.The triazole amide derivatives demonstrated excellent antifungal and anti-drug-resistant fungal activities.Among them,(2S)-1-[(3S)-4-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazapentadien-1-yl)but-2-yl]-3-methylpiperazine-1-yl]-2-[4-(2-methylpropyl)phenyl]propan-1-one(3e)was the most potent antifungal agent with MIC80 values of 0.25,2.0,and 2.0 μg/mL against Candida albicans,Cryptococcus neoformans,and Aspergillus fumigatus,respectively,which are the three most common and critical priority pathogenic fungi.Compound 3e also exhibited potent activity against azole-resistant Candida.Molecular docking was used to simulate the binding mode of compound 3e with Candida albicans CYP51 and to analyze the potential amino acid residues involved in the formation of interactions between each compound and the target enzyme.These compounds have strong in vitro antifungal activity and are worthy of further exploration and research.