Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Department of Medical Mycology/Invasive Fungi Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
Bioorg Chem. 2019 Sep;90:103060. doi: 10.1016/j.bioorg.2019.103060. Epub 2019 Jun 12.
A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063-0.5 µg/mL had the best profile of activity, being 4-32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.
设计并合成了一系列含 N-(卤代苄基)哌嗪碳二硫代酸酯部分的 1H-1,2,4-三唑醇类化合物，作为有效的抗真菌药物。对不同的念珠菌属物种（包括白色念珠菌、光滑念珠菌、近平滑念珠菌、克柔念珠菌和热带念珠菌）的体外生物测定表明，具有 MIC 值为 0.063-0.5μg/mL 的 N-(4-氯苄基)衍生物（6b）具有最佳的活性谱，其活性比氟康唑高 4-32 倍。对接模拟研究证实，化合物 6b 在羊毛甾醇 14α-去甲基酶（CYP51）酶的活性部位的结合更好，该酶是唑类抗真菌药物的主要靶标。特别是，化合物 6b 对氟康唑耐药分离株的潜力及其对人红细胞和 HepG2 细胞的最小毒性，使该原型化合物成为发现有效且安全的抗真菌药物的良好先导化合物。
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