Isono Yohei, Sakakibara Norikazu, Ordonez Paula, Hamasaki Takayuki, Baba Masanori, Ikejiri Masahiro, Maruyama Tokumi
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Japan.
Antivir Chem Chemother. 2011 Oct 7;22(2):57-65. doi: 10.3851/IMP1844.
Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1.
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.
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.
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.
合成了九种新型尿嘧啶类似物，并评估了它们作为HIV-1抑制剂的活性。
关键的结构修饰包括用其他官能团取代1-苄基-6-氯-3-(3,5-二甲基苄基)尿嘧啶的6-氯基团，或对3-(3,5-二甲基苄基)-5-氟尿嘧啶进行N(1)-烷基化。
这些化合物在MT-4细胞中对HIV-1仅表现出微摩尔级别的活性，不过其中两种化合物，即6-叠氮基-1-苄基-3-(3,5-二甲基苄基)尿嘧啶和6-氨基-1-苄基-3-(3,5-二甲基苄基)尿嘧啶具有高效活性（半数最大效应浓度分别为0.067和0.069 μM）和选择性（选择性指数分别为685和661）。新合成的尿嘧啶类似物之间的构效关系表明，6-氨基-1-苄基-3-(3,5-二甲基苄基)尿嘧啶的6-氨基与HIV-1逆转录酶的酰胺基团之间形成的氢键很重要。
我们发现了两种6-取代的1-苄基-3-(3,5-二甲基苄基)尿嘧啶（6-叠氮基-1-苄基-3-(3,5-二甲基苄基)尿嘧啶和6-氨基-1-苄基-3-(3,5-二甲基苄基)尿嘧啶）作为新型抗HIV药物。应进一步研究这些化合物的体内毒性、药代动力学以及对非核苷逆转录酶抑制剂耐药菌株的抗病毒活性。
