EDASA Scientific srls, Via Stingi 37, 66050, San Salvo (CH), Italy.
Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th Street, New York, NY 10065, USA.
ChemMedChem. 2022 Nov 18;17(22):e202200344. doi: 10.1002/cmdc.202200344. Epub 2022 Sep 29.
The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small-molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule's flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD-14270 by retrosynthetic analysis approach, their anti-HIV-1 activity, cellular toxicity, and structure-activity relationships. The study revealed that Scaffold A provided the best HIV-1 inhibitors with higher potency and better selectivity index (SI).
人类免疫缺陷病毒 1 型（HIV-1）的包膜糖蛋白 gp120 通过与宿主细胞蛋白 CD4 结合在病毒进入细胞中发挥关键作用。此前，我们报道了一系列含有噻唑环的高活性小分子进入抑制剂的设计和发现（支架 A）。由于噻唑环通过乙基酰胺键连接，代表了分子的柔性部分，我们决定用噻唑环的另外两个位置异构体（支架 B 和 C）来取代支架 A，以评估它们对抗病毒活性和细胞毒性的影响。在这里，我们通过反合成分析方法报告了 NBD-14270 的两个位置噻唑异构体的新型合成，以及它们的抗 HIV-1 活性、细胞毒性和构效关系。研究表明，支架 A 提供了最好的 HIV-1 抑制剂，具有更高的效力和更好的选择性指数（SI）。
