title: Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus.
abstract: The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) targeting the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT) was rationally designed using a computer model of the NNI binding pocket. The NNI binding pocket model takes into consideration changes in binding pocket size, shape, and changes in residue character that result from clinically-observed NNI resistance-associated mutations of HIV RT. RT assays revealed that HI-236 was not only more potent than trovirdine, MKC-442, and AZT against the drug-sensitive HIV-1 strain HTLV(IIIB), it was also 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. Most importantly, HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR with multiple mutations involving the RT residues 74V, 41L, 106A, and 215Y. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, which are listed in the following order: HI-236 (IC50: 5 nM) > HI-240 (IC50: 6 nM) > trovirdine (IC50: 20 nM) > AZT (IC50: 150 nM) > MKC-442 (IC50: 300 nM) > delavirdine (IC50: 400 nM) > nevirapine (IC50: 5 microM).
authors.affiliation: Department of Structural Biology, Hughes Institute, St. Paul, MN 55113, USA.
authors.forename: C
authors.initials: C
authors.lastname: Mao
authors.forename: E A
authors.initials: EA
authors.lastname: Sudbeck
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D020008:Delavirdine / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D019829:Nevirapine / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; C121245:HI 236; C119306:HI 240; D011725:Pyridines; D019829:Nevirapine; D020008:Delavirdine; D013890:Thiourea