2. Academic Validation
  3. Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

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

  • J Med Chem. 2021 Sep 23;64(18):13604-13621. doi: 10.1021/acs.jmedchem.1c00987.
Boshi Huang 1,  Tiziana Ginex 2,  F Javier Luque 2,  Xiangyi Jiang 1,  Ping Gao 1,  Jian Zhang 1,  Dongwei Kang 1 3,  Dirk Daelemans 4,  Erik De Clercq 4,  Christophe Pannecouque 4,  Peng Zhan 1 3,  Xinyong Liu 1 3
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
  • 4 Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
PMID: 34496571 DOI: 10.1021/acs.jmedchem.1c00987
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.

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