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N-hydroxy-substituted 2-aryl acetamide analogs: A novel class of HIV-1 integrase inhibitors. 2017

Utsab Debnath, and Prachi Kumar, and Aakanksha Agarwal, and Ajay Kesharwani, and Satish K Gupta, and Seturam B Katti
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.

An in silico method has been used to discover N-hydroxy-substituted 2-aryl acetamide analogs as a new class of HIV-1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV-1 integrase inhibitors. Finally, six promising compounds (compounds 5b, 5c, 5e, 6-2c, 6-3b, and 6-5b) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti-HIV-1 activity in a reporter gene-based cell assay system, compounds 5d, 6s, and 6k were found as novel HIV-1 integrase inhibitors due to its better selectivity index. Additionally, docking study revealed the importance of H-bond as well as hydrophobic interactions with Asn155, Lys156, and Lys159 which were required for their anti-HIV-1 activity.

UI MeSH Term Description Entries
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa 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.
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
D015658 HIV Infections Includes the spectrum of human immunodeficiency virus infections that range from asymptomatic seropositivity, thru AIDS-related complex (ARC), to acquired immunodeficiency syndrome (AIDS). HTLV-III Infections,HTLV-III-LAV Infections,T-Lymphotropic Virus Type III Infections, Human,HIV Coinfection,Coinfection, HIV,Coinfections, HIV,HIV Coinfections,HIV Infection,HTLV III Infections,HTLV III LAV Infections,HTLV-III Infection,HTLV-III-LAV Infection,Infection, HIV,Infection, HTLV-III,Infection, HTLV-III-LAV,Infections, HIV,Infections, HTLV-III,Infections, HTLV-III-LAV,T Lymphotropic Virus Type III Infections, Human
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking
D019427 HIV Integrase Enzyme of the HUMAN IMMUNODEFICIENCY VIRUS that is required to integrate viral DNA into cellular DNA in the nucleus of a host cell. HIV integrase is a DNA nucleotidyltransferase encoded by the pol gene. HIV Integration Protein,p31 Integrase Protein, HIV,p31 Integrase Protein, Human Immunodeficiency Virus,p31 pol Gene Product, HIV,p31 pol Gene Product, Human Immunodeficiency Virus,Integrase, HIV,Integration Protein, HIV
D019428 HIV Integrase Inhibitors Inhibitors of HIV INTEGRASE, an enzyme required for integration of viral DNA into cellular DNA. Integrase Inhibitors, HIV,Inhibitors, HIV Integrase

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