title: Synthesis and anti-HIV-1 and anti-HCMV activity of 1-substituted 3-(3,5-dimethylbenzyl)uracil derivatives.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Shido, Samuki, Japan. maruyama@kph.bunri-u.ac.jp
authors.forename: Tokumi
authors.initials: T
authors.lastname: Maruyama
authors.forename: Shigetada
authors.initials: S
authors.lastname: Kozai
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Demizu
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Robert
authors.initials: R
authors.lastname: Snoecks
authors.forename: Graciella
authors.initials: G
authors.lastname: Andrei
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects*; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D007202:Indicators and Reagents; D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase