Zhou Zhenzhen, Xie Minghui, Zhuo Zongji, Wang Yalin, Zhao Fabao, Tao Sining, Liang Zhening, De Clercq Erik, Pannecouque Christophe, Zhan Peng, Kang Dongwei, Liu Xinyong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000, Leuven, Belgium.
Eur J Med Chem. 2025 May 5;289:117464. doi: 10.1016/j.ejmech.2025.117464. Epub 2025 Feb 27.
To promote the development of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel 2,4,5-trisubstituted pyrimidine derivatives targeting the "tolerant region I″ and "tolerant region II" of NNRTI binding pocket (NNIBP) were designed through multi-site binding strategy. Among them, 13a was demonstrated with an improved potency against wild-type (WT) and a panel of mutant HIV-1 strains with EC values ranging from 0.0062 to 0.25 μM, being superior to that of efavirenz (EFV, EC = 0.0080-0.37 μM). In addition, 13a was proved to have low cytotoxicity (CC = 160.7 μM) and high SI values (SI = 25254). Further HIV-1 RT inhibition assay demonstrated that 13a is a classical NNRTI with an IC value of 0.41 μM. Molecular docking and molecular dynamics simulations results illustrated its binding mode with HIV-1 RT. Overall, these enchanting results illuminated the potential of 13a as a promising lead for the development of the new generation HIV-1 NNRTIs drugs.
为促进新一代HIV-1非核苷类逆转录酶抑制剂（NNRTIs）的开发，通过多位点结合策略设计了一系列新型2,4,5-三取代嘧啶衍生物，这些衍生物靶向NNRTI结合口袋（NNIBP）的“耐受区域I”和“耐受区域II”。其中，13a对野生型（WT）和一组突变型HIV-1毒株表现出增强的活性，其EC值范围为0.0062至0.25 μM，优于依非韦伦（EFV，EC = 0.0080 - 0.37 μM）。此外，13a被证明具有低细胞毒性（CC = 160.7 μM）和高SI值（SI = 25254）。进一步的HIV-1 RT抑制试验表明，13a是一种经典的NNRTI，IC值为0.41 μM。分子对接和分子动力学模拟结果阐明了其与HIV-1 RT的结合模式。总体而言，这些令人瞩目的结果揭示了13a作为新一代HIV-1 NNRTIs药物开发潜在先导化合物的可能性。
