Le Van Kiet, Cauvin Christine, de Walque Stéphane, Georges Benoît, Boland Sandro, Martinelli Valérie, Demonté Dominique, Durant François, Hevesi László, Van Lint Carine
Laboratoire de Chimie des Materiaux Organiques and Laboratoire de Chimie Moleculaire Structurale, Facultes Universitaires Notre-Dame de la Paix, B-5000 Namur, Belgium.
J Med Chem. 2009 Jun 25;52(12):3636-43. doi: 10.1021/jm801438e.
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 EC(50). 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.
合成了几种5-乙基-6-甲基-4-环烷氧基吡啶-2(1H)-酮，并评估了它们对野生型病毒和临床相关突变株的抗HIV-1活性。在环己氧基部分的3位和5位带有甲基取代基的外消旋混合物(10)对野生型HIV-1具有强效抗病毒活性。随后立体选择性合成的一种在赤道位置显示两个甲基的立体异构体具有最佳的半数有效浓度(EC50)。对吡啶酮环3位的进一步修饰提高了对突变病毒株的抗病毒活性。带有3-乙基(22)或3-异丙基(23)的化合物对野生型HIV-1具有最高活性，并且对几种临床相关突变株显示出低纳摩尔效力。
