title: Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives with potential anti-HIV activity.
abstract: BACKGROUND
  Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1.
  
  
  METHODS
  Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N(1)-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil.
  
  
  RESULTS
  These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.067 and 0.069 μM) and selective (selectivity index =685 and 661), respectively. Structure-activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase.
  
  
  CONCLUSIONS
  We discovered two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) as novel anti-HIV agents. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.
authors: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Japan.
authors: Yohei
authors: Y
authors: Isono
authors: Norikazu
authors: N
authors: Sakakibara
authors: Paula
authors: P
authors: Ordonez
authors: Takayuki
authors: T
authors: Hamasaki
authors: Masanori
authors: M
authors: Baba
authors: Masahiro
authors: M
authors: Ikejiri
authors: Tokumi
authors: T
authors: Maruyama
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C527156:3-(3,5-dimethylbenzyl)uracil; D019380:Anti-HIV Agents; D014498:Uracil