Design, synthesis, and antiviral activity of a series of CD4-mimetic small-molecule HIV-1 entry inhibitors

• DOI: 10.1016/j.bmc.2021.116000
• Publication Date: 2021-01-09T09:56:57Z
• Authors: Francesca Curreli; Shahad Ahmed; Sofia M. Benedict...; Ildar R. Iusupov; Evgeny A. Spiridonov; Dmitry S. Belov; Andrea Altieri; Alexander V. Kurkin; Asim K. Debnath
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; Anti-HIV Agents; Microbial Sensitivity Tests; HIV Envelope Protein gp120; 3. Good health; Small Molecule Libraries; Structure-Activity Relationship; 03 medical and health sciences; HIV Fusion Inhibitors; Drug Design; CD4 Antigens; HIV-1

We presented our continuing stride to optimize the second-generation NBD entry antagonist targeted to the Phe43 cavity of HIV-1 gp120. We have synthesized thirty-eight new and novel analogs of NBD-14136, earlier designed based on a CH2OH "positional switch" hypothesis, and derived a comprehensive SAR. The antiviral data confirmed that the linear alcohol towards the "N" (C4) of the thiazole ring yielded more active inhibitors than those towards the "S" (C5) of the thiazole ring. The best inhibitor, NBD-14273 (compound 13), showed both improved antiviral activity and selectivity index (SI) against HIV-1HXB2 compared to NBD-14136. We also tested NBD-14273 against a large panel of 50 HIV-1 Env-pseudotyped viruses representing clinical isolates of diverse subtypes. The overall mean data indicate that antiviral potency against these isolates improved by ~3-fold, and SI also improved ~3-fold compared to NBD-14136. This new and novel inhibitor is expected to pave the way for further optimization to a more potent and clinically relevant inhibitor against HIV-1.