Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV‑1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

• Published in: Journal of medicinal chemistry Vol. 64; no. 18; pp. 13604 - 13621
• Main Authors: Huang, Boshi, Ginex, Tiziana, Luque, F. Javier, Jiang, Xiangyi, Gao, Ping, Zhang, Jian, Kang, Dongwei, Daelemans, Dirk, De Clercq, Erik, Pannecouque, Christophe, Zhan, Peng, Liu, Xinyong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-09-2021
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Cell Line; Drug Design; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - metabolism; Heterocyclic Compounds, 2-Ring - pharmacology; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; Humans; Microsomes, Liver - metabolism; Molecular Dynamics Simulation; Molecular Structure; Mutation; Protein Binding; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - metabolism; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00987

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 6, 14, 15, 21, 30, and 33, 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 6, 15, 21, and 30 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.