Sakakibara Norikazu, Baba Masanori, Okamoto Mika, Toyama Masaaki, Demizu Yosuke, Misawa Takashi, Kurihara Masaaki, Irie Kohji, Kato Yoshihisa, Maruyama Tokumi
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Kagawa, Japan
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Antivir Chem Chemother. 2015 Feb;24(1):3-18. doi: 10.1177/2040206614566584.
A new series of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors.
A series of new 6-azido and 6-amino derivatives of 1-substituted-3-(3,5-dimethylbenzyl)uracils were synthesized using our previously reported method, and three acyclic derivatives were synthesized from urea. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicities of the compounds were evaluated using the viability of mock-infected cells.
Some of these compounds showed good-to-moderate activities against HIV-1 with half maximal effective concentration (EC50) values in the submicromolar or subnanomolar range. Compared with emivirine, compound 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil showed significant anti-HIV-1 activity with an EC50 value of 10 nM and a high selectivity index of 1923. Preliminary structure-activity relationship studies and molecular modeling analyses were carried out to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil; these results may be important for further development of this class of compounds as anti-HIV-1 agents.
The excellent activity of 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil (EC50: 0.010 ± 0.006 µM, SI: >1923) may serve as the basis for conducting further investigations on the behavior of this class of compounds against drug-resistant mutants.
合成了一系列新的1-芳基甲基取代的3-(3,5-二甲基苄基)尿嘧啶和N-3,5-二甲基苄基取代的脲衍生物，并将其作为非核苷类HIV-1逆转录酶抑制剂进行评估。
采用我们之前报道的方法合成了一系列新的1-取代-3-(3,5-二甲基苄基)尿嘧啶的6-叠氮基和6-氨基衍生物，并由脲合成了三种无环衍生物。基于对MT-4细胞中病毒诱导的细胞病变效应的抑制作用，测定了这些化合物的抗HIV-1活性。使用未感染细胞的活力评估了化合物的细胞毒性。
其中一些化合物对HIV-1显示出良好至中等的活性，半数最大有效浓度（EC50）值在亚微摩尔或亚纳摩尔范围内。与依米韦仑相比，化合物6-氨基-3-(3,5-二甲基苄基)-1-(4-氨基苄基)尿嘧啶显示出显著的抗HIV-1活性，EC50值为10 nM，选择性指数高达1923。进行了初步的构效关系研究和分子模拟分析，以探索HIV-1逆转录酶与强效抑制剂6-氨基-3-(3,5-二甲基苄基)-1-(4-氨基苄基)尿嘧啶之间的主要相互作用；这些结果对于进一步开发这类化合物作为抗HIV-1药物可能具有重要意义。
6-氨基-3-(3,5-二甲基苄基)-1-(4-氨基苄基)尿嘧啶的优异活性（EC50：0.010 ± 0.006 μM，SI：>1923）可为进一步研究这类化合物对耐药突变体的作用提供基础。
