Maruyama Tokumi, Kozai Shigetada, Demizu Yosuke, Witvrouw Myriam, Pannecouque Christophe, Balzarini Jan, Snoecks Robert, Andrei Graciella, De Clercq Erik
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Samuki, Japan.
Chem Pharm Bull (Tokyo). 2006 Mar;54(3):325-33. doi: 10.1248/cpb.54.325.
3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated according to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2- and 4-picolyl derivatives was particularly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group.
3-(3,5-二甲基苄基)尿嘧啶(3)在碱存在下与卤代烷反应，得到1-取代的同系物。使用 Mitsunobu 反应使3与醇缩合也被用作另一种方法。根据先前建立的程序评估了3-(3,5-二甲基苄基)尿嘧啶的1-取代类似物的抗HIV-1活性。结果表明，1-氰基甲基的氮对于抗HIV-1活性很重要，这表明它与HIV-1逆转录酶的氨基酸残基相互作用。1-芳基甲基衍生物也显示出良好的抗HIV-1活性；2-和4-吡啶甲基衍生物的活性尤其出色。使用Glide配体对接程序进行的对接研究证实了这些结果，该研究表明Lys 101的酰胺N-H与氰基甲基和吡啶甲基的氮之间存在氢键。
