Design, Synthesis, and Biological Evaluation of Novel 2-(Pyridin-3-yloxy)acetamide Derivatives as Potential Anti-HIV-1 Agents. 2016

Boshi Huang, and Xiao Li, and Peng Zhan, and Erik De Clercq, and Dirk Daelemans, and Christophe Pannecouque, and Xinyong Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, 250012, Shandong, China.

Through a structure-based molecular hybridization and bioisosterism approach, a series of novel 2-(pyridin-3-yloxy)acetamide derivatives were designed, synthesized, and evaluated for their anti-HIV activities in MT-4 cell cultures. Biological results showed that three compounds (Ia, Ih, and Ij) exhibited moderate inhibitory activities against wild-type (wt) HIV-1 strain (IIIB ) with EC50 values ranging from 8.18 μm to 41.52 μm. Among them, Ij was the most active analogue possessing an EC50 value of 8.18 μm. To further confirm the binding target, four compounds were selected to implement an HIV-1 RT inhibitory assay. In addition, preliminary structure-activity relationship (SAR) analysis and some predicted physicochemical properties of three active compounds Ia, Ih, and Ij were discussed in detail. Molecular docking studies were also carried out to investigate the binding modes of Ij and the lead compound GW678248 in the binding pocket of RT, which provided beneficial information for further rational design of non-nucleoside reverse transcriptase inhibitors.

UI MeSH Term Description Entries
D009570 Nitriles Organic compounds containing the -CN radical. The concept is distinguished from CYANIDES, which denotes inorganic salts of HYDROGEN CYANIDE. Nitrile
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000081 Acetamides Derivatives of acetamide that are used as solvents, as mild irritants, and in organic synthesis.
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013449 Sulfonamides A group of compounds that contain the structure SO2NH2. Sulfonamide,Sulfonamide Mixture,Sulfonamide Mixtures,Mixture, Sulfonamide,Mixtures, Sulfonamide
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human

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