title: Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents.
abstract: In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA enzyme. Highly active compound 5r (MIC 0.2 μg/mL) showed hydrogen bonding interactions with Tyr158 and NAD(+) in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (r(pred)(2)) of 0.896 and 0.930, respectively.
authors.affiliation: Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India; Centre for Research and Development, Prist University, Thanjavur 613 403, Tamil Nadu, India.
authors.forename: Uttam A
authors.initials: UA
authors.lastname: More
authors.affiliation: Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India. Electronic address: shrinivasdj@rediffmail.com.
authors.forename: Shrinivas D
authors.initials: SD
authors.lastname: Joshi
authors.affiliation: Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India.
authors.forename: Tejraj M
authors.initials: TM
authors.lastname: Aminabhavi
authors.affiliation: School of Pharmacy, Faculty of Medical Sciences (The University of the West Indies, St. Augustine), Champs-Fleurs, Mount-Hope, Trinidad and Tobago.
authors.forename: Andanappa K
authors.initials: AK
authors.lastname: Gadad
authors.affiliation: Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India.
authors.forename: Mallikarjuna N
authors.initials: MN
authors.lastname: Nadagouda
authors.affiliation: Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad 580 002, India.
authors.forename: Venkatrao H
authors.initials: VH
authors.lastname: Kulkarni
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006835:Hydrazones; D008024:Ligands; D011758:Pyrroles; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: Anti-tubercular activity; CoMFA; CoMSIA; Enoyl-ACP reductase subunit A; Pyrrole hydrazones