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

• Published in: Bioorganic & medicinal chemistry letters 1999-06, Vol.9 (11), p.1593-1598
• Main Authors: Mao, Chen, Sudbeck, Elise A., Venkatachalam, T.K., Uckun, Fatih M.
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Delavirdine - chemistry; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Medical sciences; Models, Molecular; Nevirapine - chemistry; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - pharmacology; Thiourea - analogs & derivatives; Thiourea - chemical synthesis; Thiourea - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00235-8

The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea ( 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 (IC 50: 5 nM) > HI-240 (IC 50: 6 nM) > trovirdine (IC 50: 20 nM) > AZT (IC 50: 150 nM) > MKC-442 (IC 50: 300 nM) > delavirdine (IC 50: 400 nM) > nevirapine (IC 50: 5 μM) . The anti-HIV potency of designed inhibitors HI-236 and HI-240 against HIV RT mutants was predicted and confirmed.