| Literature DB >> 33461144 |
Francesca Curreli1, Shahad Ahmed1, Sofia M Benedict Victor1, Ildar R Iusupov2, Evgeny A Spiridonov2, Dmitry S Belov2, Andrea Altieri2, Alexander V Kurkin2, Asim K Debnath3.
Abstract
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.Entities:
Keywords: Broad-spectrum; Cytotoxicity; ENV-pseudovirus; Gp120 entry-antagonist; HIV-1; Structure–activity relationship (SAR); selectivity index (SI)
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Year: 2021 PMID： 33461144 PMCID： PMC7856678 DOI： 10.1016/j.bmc.2021.116000
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641