Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Med Chem. 2021;17(9):1060-1071. doi: 10.2174/1573406416666200909104616.
HIV-1 integrase (IN) has been considered as an important target for the development of novel anti-HIV-1 drugs.
The aim of this study was to design novel groups of HIV IN inhibitors.
In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2- a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole β-diketoacids as a well-known group of IN inhibitors.
Based on in-vitro anti-HIV-1 activity in a cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC values of 4.14, 1.68 and 0.8 μM, respectively. However, integrase inhibition assay showed that most of the analogues did not have significant effects against integrase enzyme except compound 5 with an IC50 value of 45 μM. Our results indicated that compound 6k was the best one among synthesized compounds with an EC of 0.8 μM and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into the probable mechanism of tested compounds.
These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3- carboxylic acid derivatives may consider as promising lead compounds for the development of new anti-HIV-1 drugs.
HIV-1 整合酶（IN）已被认为是开发新型抗 HIV-1 药物的重要靶点。
本研究旨在设计新型 HIV IN 抑制剂。
在这项研究中，我们通过对 N-芳基吲哚β-二酮酸进行结构修饰，设计了一系列新型 4-氧代-4,10-二氢苯并[4,5]咪唑并[1,2-a]嘧啶-3-羧酸衍生物，作为一类已知的 IN 抑制剂。
基于细胞水平的抗 HIV-1 活性测定，化合物 5、6a 和 6k 表现出中等至良好的抑制活性，EC 值分别为 4.14、1.68 和 0.8 μM。然而，整合酶抑制试验表明，除化合物 5 外，大多数类似物对整合酶酶没有明显的抑制作用，IC50 值为 45 μM。我们的结果表明，化合物 6k 是合成化合物中最好的一个，EC 值为 0.8 μM，SI 值为 175。对接和分子动力学模拟研究也进行了，以提供一些关于测试化合物可能的机制的见解。
这些发现表明，4-氧代-4,10-二氢苯并[4,5]咪唑并[1,2-a]嘧啶-3-羧酸衍生物可能被认为是开发新型抗 HIV-1 药物的有前途的先导化合物。
