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.
Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy, Campus Torribera, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Santa Coloma de Gramenet, 08921 Barcelona, Spain.
J Med Chem. 2021 Sep 23;64(18):13604-13621. doi: 10.1021/acs.jmedchem.1c00987. Epub 2021 Sep 9.
Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as , , , , , and , were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds , , , and in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.
设计了两类新的含吡啶并带有稠合双环类似物，旨在针对非核苷类逆转录酶抑制剂（NNRTI）结合口袋的双重耐受区域。合成了这些化合物并评估了它们的抗 HIV 活性。结果发现，化合物 、 、 、 、 和 等对野生型（WT）HIV-1 株或多种 NNRTI 耐药株具有较强的抑制作用，其抑制活性在纳摩尔水平。通过改变相应药效团内的部分结构，获得了详细的构效关系。评估了选定化合物的体外代谢稳定性谱和一些类药性特征，提供了初步的结构-代谢稳定性关系。此外，分子建模研究阐明了化合物 、 、 、 与 WT、E138K、K103N 或 Y181C HIV-1 RT 结合口袋的结合模式。这些有前途的化合物可用作先导化合物，并需要进一步的结构优化以产生更有效的 HIV-1 抑制剂。
