Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

• Published in: Antiviral chemistry & chemotherapy 2011-11, Vol.22 (2), p.57-65
• Main Authors: Isono, Yohei, Sakakibara, Norikazu, Ordonez, Paula, Hamasaki, Takayuki, Baba, Masanori, Ikejiri, Masahiro, Maruyama, Tokumi
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Alkylation; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antiretroviral drugs; Antiviral activity; Cell Line, Tumor; Drug Evaluation, Preclinical - methods; HIV; HIV-1 - drug effects; Human immunodeficiency virus; Humans; Hydrogen Bonding; Non-nucleoside reverse transcriptase inhibitors; Pharmacokinetics; RNA-directed DNA polymerase; Structure-Activity Relationship; Toxicity; Uracil; Uracil - analogs & derivatives; Uracil - chemistry
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.3851/IMP1844

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 N1-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.