Sakakibara Norikazu, Balboni Gianfranco, Congiu Cenzo, Onnis Valentina, Demizu Yosuke, Misawa Takashi, Kurihara Masaaki, Kato Yoshihisa, Maruyama Tokumi, Toyama Masaaki, Okamoto Mika, Baba Masanori
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Kagawa, Japan
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy.
Antivir Chem Chemother. 2015 Apr;24(2):62-71. doi: 10.1177/2040206615612208. Epub 2015 Oct 28.
The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure-activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors.
A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells.
Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents.
The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.
人类免疫缺陷病毒1型（HIV-1）的逆转录酶（RT）是开发用于治疗HIV-1感染和获得性免疫缺陷综合征（AIDS）药物的一个有吸引力的靶点。我们利用成功的1,3-二取代和1,3,6-三取代尿嘧啶型HIV-1 RT抑制剂的构效关系，继续寻找新型抗HIV-1药物。
采用既定方法合成了一系列新的三嗪类似物。根据这些化合物对MT-4细胞中病毒诱导的细胞病变效应的抑制作用来测定其抗HIV-1活性。通过评估未感染病毒细胞的活力来评价化合物的细胞毒性。
一些化合物对HIV-1表现出良好至中等的活性，半数最大有效浓度（EC50）在亚微摩尔范围内。特别是，一种二氢-1-（4-氨基苄基）三嗪类似物表现出令人满意的抗HIV-1活性，EC50为0.110µM，选择性指数（SI）为909。此外，还进行了分子模拟分析，以探索HIV-1 RT与强效抑制剂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药物可能很重要。
三嗪类似物令人满意的抗HIV-1活性可为进一步研究这类化合物对耐药突变体的作用提供依据。
