Author:

Keywords:

uracil derivative, anti-human immunodeficiency virus (hiv) activity, docking study, reverse-transcriptase inhibitors, immunodeficiency-virus type-1, drug-resistance, hiv-1 infections, highly potent, wild-type, design, strategies, complexes, analogs, Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Chemistry, Medicinal, Chemistry, Multidisciplinary, Pharmacology & Pharmacy, Chemistry, anti-human immunodeficiency virus (HIV) activity, REVERSE-TRANSCRIPTASE INHIBITORS, IMMUNODEFICIENCY-VIRUS TYPE-1, HIGHLY POTENT, WILD-TYPE, HIV-1, DESIGN, ANALOGS, NNRTIS, Anti-HIV Agents, Cytomegalovirus, HIV Reverse Transcriptase, Indicators and Reagents, Ligands, Models, Molecular, Molecular Conformation, Protein Binding, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Uracil, 0304 Medicinal and Biomolecular Chemistry, 0306 Physical Chemistry (incl. Structural), 1115 Pharmacology and Pharmaceutical Sciences, General Chemistry, 3214 Pharmacology and pharmaceutical sciences

Abstract:

3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give I-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.