Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV‐1 Entry Inhibitor NBD‐14270

• Published in: ChemMedChem Vol. 17; no. 22; pp. e202200344 - n/a
• Main Authors: Kurkin, Alexander V., Curreli, Francesca, Iusupov, Ildar R., Spiridonov, Evgeniy A., Ahmed, Shahad, Markov, Pavel O., Manasova, Ekaterina V., Altieri, Andrea, Debnath, Asim K.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 18-11-2022
• Subjects: Antagonists; Anti-HIV Agents - chemistry; Antiviral activity; CD4 antigen; CD4 Antigens - chemistry; Cellular structure; Docking; Glycoprotein gp120; Glycoproteins; HIV; HIV Envelope Protein gp120; HIV Fusion Inhibitors - pharmacology; HIV-1; HIV-1 gp120; Human immunodeficiency virus; Humans; Isomers; NBD compounds; reverse transcriptase; Scaffolds; Selectivity; Synthesis; thiazole isomers; Thiazoles - pharmacology; Toxicity; NBD compounds; Docking; reverse transcriptase; HIV-1 gp120; thiazole isomers
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202200344

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).
The primary goal of this work was to determine whether positional isomers of the thiazole ring in one of the lead inhibitors, NBD‐14270, may lead to an improvement in antiviral potency and cytotoxicity, and to derive SAR information. Based on how the thiazole ring (Scaffold A) is bound to NBD‐14270, only two other positional isomers are possible: Scaffolds B and C. Antiviral assay data show that Scaffold A provides the best potency and a high selectivity index (SI).