Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.

Journal Article (Journal Article)

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10 nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.

Full Text

Duke Authors

Cited Authors

  • Wu, Z-Y; Liu, N; Qin, B; Huang, L; Yu, F; Qian, K; Morris-Natschke, SL; Jiang, S; Chen, CH; Lee, K-H; Xie, L

Published Date

  • July 2014

Published In

Volume / Issue

  • 9 / 7

Start / End Page

  • 1546 - 1555

PubMed ID

  • 24895029

Pubmed Central ID

  • PMC4085996

Electronic International Standard Serial Number (EISSN)

  • 1860-7187

Digital Object Identifier (DOI)

  • 10.1002/cmdc.201400075


  • eng

Conference Location

  • Germany