title: N-hydroxy-substituted 2-aryl acetamide analogs: A novel class of HIV-1 integrase inhibitors.
abstract: 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.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Utsab
authors.initials: U
authors.lastname: Debnath
authors.affiliation: Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Prachi
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kesharwani
authors.affiliation: Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Seturam B
authors.identifier: http://orcid.org/0000-0001-9776-2391
authors.initials: SB
authors.lastname: Katti
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation
chemical_list: D000081:Acetamides; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: 
  AIDS
  ; HIV-1 integrase; ZINC database; molecular modeling