Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.

Journal Article (Journal Article)

Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.

Full Text

Duke Authors

Cited Authors

  • Liu, N; Wei, L; Huang, L; Yu, F; Zheng, W; Qin, B; Zhu, D-Q; Morris-Natschke, SL; Jiang, S; Chen, C-H; Lee, K-H; Xie, L

Published Date

  • April 28, 2016

Published In

Volume / Issue

  • 59 / 8

Start / End Page

  • 3689 - 3704

PubMed ID

  • 27070547

Pubmed Central ID

  • PMC5206802

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.5b01827


  • eng

Conference Location

  • United States