Abstract：
Life-threatening invasive fungal infections pose a serious threat to human health. A series of novel triazole derivatives bearing a pyrazole-methoxyl moiety were designed and synthesized in an effort to obtain antifungals with potent, broad-spectrum activity that are less susceptible to resistance. Most of these compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and 10,231, Cryptococcus neoformans 32,609, Candida glabrata 537 and Candida parapsilosis 22,019 with minimum inhibitory concentration (MIC) values of ≤0.125 μg/mL to 0.5 μg/mL. Use of recombinant Saccharomyces cerevisiae strains showed compounds 7 and 10 overcame the overexpression and resistant-related mutations in ERG11 of S. cerevisae and several pathogenic Candida spp. Despite being substrates of the C. albicans and Candida auris Cdr1 drug efflux pumps, compounds 7 and 10 showed moderate potency against five fluconazole (FCZ)-resistant fungi with MIC values from 2.0 μg/mL to 16.0 μg/mL. Growth kinetics confirmed compounds 7 and 10 had much stronger fungistatic activity than FCZ. For C. albicans, compounds 7 and 10 inhibited the yeast-to-hyphae transition, biofilm formation and destroyed mature biofilm more effectively than FCZ. Preliminary mechanism of action studies showed compounds 7 and 10 blocked the ergosterol biosynthesis pathway at Erg11, ultimately leading to cell membrane disruption. Further investigation of these novel triazole derivatives is also warranted by their predicted ADMET properties and low cytotoxicity.
摘要：
威胁生命的侵袭性真菌感染对人类健康构成严重威胁。设计并合成了一系列带有吡唑-甲氧基部分的新型三唑衍生物，以努力获得具有有效，广谱活动，不易受到抗性的影响。这些化合物中的大多数对白色念珠菌SC5314和10,231，新生隐球菌32,609，光滑念珠菌537和近扁平念珠菌22,019具有中等至优异的体外抗真菌活性，最小抑制浓度（MIC）值≤0.125μg/mL至0.5μg/mL。使用重组酿酒酵母菌株显示，化合物7和10克服了酿酒酵母和几种致病性念珠菌的ERG11中的过表达和抗性相关突变。尽管是白色念珠菌和耳念珠菌Cdr1药物外排泵的底物，化合物7和10对5种耐氟康唑（FCZ）的真菌显示中等效力，MIC值为2.0μg/mL至16.0μg/mL。生长动力学证实化合物7和10具有比FCZ强得多的抑制真菌活性。对于白色念珠菌,化合物7和10抑制了酵母到菌丝的转变，生物膜形成和破坏成熟生物膜比FCZ更有效。初步作用机制研究显示化合物7和10在Erg11阻断麦角甾醇生物合成途径,最终导致细胞膜破坏。这些新型三唑衍生物的进一步研究也因其预测的ADMET性质和低细胞毒性而得到保证。
