Abstract：
Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.
摘要：
基于我们先前的工作，设计并合成了31种新型的阿巴康唑衍生物。所有化合物对7种病原真菌均表现出有效的体外抗真菌活性。其中,四唑化合物D2是最有效的抗真菌药，对白色念珠菌的MIC值<0.008，<0.008和2μg/mL，新生隐球菌,和烟曲霉,分别,三种最常见和最关键的病原真菌。此外,化合物D2还表现出对氟康唑抗性的C.auris分离株的有效活性。值得注意的是,化合物D2对人CYP450酶的体外抑制活性较低，对hERGK+通道的抑制作用较低，表明药物-药物相互作用和QT延长的风险较低。此外，改善了药代动力学特征，化合物D2在减少真菌负荷和延长白色念珠菌感染小鼠的存活方面显示出比阿巴康唑更好的体内功效。一起来看,将进一步研究化合物D2作为有希望的候选物。
