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

ABSTRACT: 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.

SUBMITTER: Wu ZY 

PROVIDER: S-EPMC4085996 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature