New Pyridinone Derivatives as Potent HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

被引：25

作者：

Le Van, Kiet ^{[2
]}

Cauvin, Christine ^{[1
]}

de Walque, Stephane

Georges, Benoit ^{[2
]}

Boland, Sandro ^{[1
]}

Martinelli, Valerie

Demonte, Dominique

Durant, Francois ^{[1
,3
]}

Hevesi, Laszlo ^{[2
,3
]}

Van Lint, Carine ^{[3
]}

机构：

[1] Fac Univ Notre Dame Paix, Lab Chim Mol Struct, B-5000 Namur, Belgium

[2] Fac Univ Notre Dame Paix, Lab Chim Mat Organ, B-5000 Namur, Belgium

[3] Univ Libre Bruxelles, Mol Virol Lab, Inst Biol & Med Mol, B-6041 Gosselies, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 12期

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; DRUG-RESISTANT STRAINS; SOCIETY-USA PANEL; ANTIVIRAL ACTIVITY; TYPE-1; RECOMMENDATIONS; COMPLEXES; 4-BENZYL; MUTATION; ANALOGS;

D O I：

10.1021/jm801438e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC50. Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.

引用

页码：3636 / 3643

页数：8

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