Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Curr Comput Aided Drug Des. 2021;17(2):235-243. doi: 10.2174/1573409916666200217090855.
Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are Nsubstituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to the importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both nitrogen are un-substituted was reported.
Designed compounds were synthesized by the reaction of imidazole-4- carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae was done using a broth micro-dilution assay. Docking studies were done using AutoDock.
Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compounds 3, 7, and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azoleheme coordination played the main role in drug-receptor interaction.
Our results offer some useful references for molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.
唑类抗真菌药物作为广泛使用的抗真菌抗生素，抑制细胞色素 P450 甾醇 14α-去甲基酶（CYP51）。几乎所有的唑类抗真菌药物都是 N-取代唑类化合物。此外，所有唑类抗真菌药物都具有独特的唑基苯烷基药效团。由于唑类化合物的氮原子（咪唑的 N-3 和三唑的 N-4）在酶结合部位与血红素配位的重要性，这里报道了一组 N-未取代的唑类化合物，其中两个氮原子都未取代。
设计的化合物通过咪唑-4-甲醛与适当的芳胺反应合成，然后还原为所需的胺衍生物。使用肉汤微量稀释法测定对白色念珠菌和酿酒酵母的抗真菌活性。使用 AutoDock 进行对接研究。
抗菌评估显示，其中一些化合物对测试的致病性真菌表现出中等的抗菌活性，其中化合物 3、7 和 8 具有较强的活性。对接研究表明，所有制备的唑类化合物都与 14α-DM 相互作用，其中唑类血红素配位在药物受体相互作用中起主要作用。
我们的结果为这一系列化合物的分子设计性能或修饰提供了一些有用的参考，作为发现新的有效抗菌剂的先导化合物。
