51. Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies.
- Author
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Huang B, Ginex T, Luque FJ, Jiang X, Gao P, Zhang J, Kang D, Daelemans D, De Clercq E, Pannecouque C, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents metabolism, Cell Line, Drug Design, HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase genetics, HIV Reverse Transcriptase metabolism, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring metabolism, Humans, Microsomes, Liver metabolism, Molecular Dynamics Simulation, Molecular Structure, Mutation, Protein Binding, Pyridines chemical synthesis, Pyridines metabolism, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors metabolism, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents pharmacology, HIV-1 drug effects, Heterocyclic Compounds, 2-Ring pharmacology, Pyridines pharmacology
- Abstract
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.
- Published
- 2021
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