Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N '-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistanthuman immunodeficiency virus

The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromo pyridyl)]-thiourea (HI-236) targeting the non-nucleoside inhibitor (NNI) bi nding pocket of HIV-1 reverse transcriptase (RT) was rationally designed us ing a computer model of the NNI binding pocket. The Nh? binding pocket mode l takes into consideration changes in binding pocket size, shape, and chang es in residue character that result from clinically-observed NNI resistance -associated mutations of HIV RT. RT assays revealed that HI-236 was not onl y more potent than trovirdine, MKC-442, and AZT against the drug-sensitive HIV-1 strain HTLVIIIB it was also 50-100 times more effective than delavird ine or nevirapine and twice as effective as our recently reported lead comp ound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) ag ainst the NNI-resistant Y181C mutant HIV-1 strain A17. Most importantly, HI -236 was highly effective against the multidrug-resistant HIV-1 strain RT-M DR with multiple mutations involving the RT residues 74V, 41L, 106A, and 21 5Y. The activity of HI-236 against RT-MDR was superior to that of other ant i-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: 300 nM) > nevirapine (IC50: 5 mu M), (C) 1999 Elsevier Science Ltd. All rights reserved.