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

被引:75
作者
Mao, C
Sudbeck, EA
Venkatachalam, TK
Uckun, FM [1 ]
机构
[1] Howard Hughes Med Inst, Drug Discovery Program, Dept Biol Struct, St Paul, MN 55113 USA
[2] Howard Hughes Med Inst, Dept Chem, St Paul, MN 55113 USA
[3] Howard Hughes Med Inst, Dept Virol, St Paul, MN 55113 USA
关键词
D O I
10.1016/S0960-894X(99)00235-8
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 Nh? 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 HTLVIIIB 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: 300 nM) > nevirapine (IC50: 5 mu M), (C) 1999 Elsevier Science Ltd. All rights reserved.
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收藏
页码:1593 / 1598
页数:6
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