Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

ABSTRACT: This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics. Our endeavor involved the implementation of a bioisosterism strategy, leading to the discovery of an assemblage of halogen-containing biphenyl-diarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Notably, compound A12 demonstrated exceptional efficacy against both WT HIV-1 (EC₅₀ = 1.9 nmol/L) and seven mutant strains (EC₅₀ = 1.7-157 nmol/L), surpassing that of the lead compound 6 and comparable to etravirine. Furthermore, this analog exhibited minimal adverse effects with significantly reduced cytotoxicity (CC₅₀ = 195 μmol/L) and a high selectivity index (SI = 102,608), superio

SUBMITTER: Chen XM 

PROVIDER: S-EPMC12399242 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature