title: Synthesis, biological evaluation and in silico molecular modeling of pyrrolyl benzohydrazide derivatives as enoyl ACP reductase inhibitors.
abstract: In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD+that fitted well within the binding pocket of InhA. All the synthesized compounds were screened for preliminary antibacterial activities against Gram-positive S. aureus and Gram-negative E. coli and M. tuberculosis H37Rv to evaluate their antitubercular activities. Some representative compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic. These compounds exhibited moderate inhibition activities against InhA.
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: Sheshagiri R
authors.initials: SR
authors.lastname: Dixit
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: Venkatarao H
authors.initials: VH
authors.lastname: Kulkarni
authors.affiliation: Universite de Toulouse, UPS, Laboratoire de Synthese et Physico-chimie de Molecules d'Interet Biologique, LSPCMIB, 118 Roote de Narbonne, F-31062, Toulouse Cedex 9, France; ITAV-USR3505, Université de Toulouse, CNRS, UPS, F-31106 Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Lherbet
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: Tejraj M
authors.initials: TM
authors.lastname: Aminabhavi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D001665:Binding Sites; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Antitubercular activity; Enzyme inhibition studies; GALAHAD; Pharmacophore hypothesis; Pyrrolyl benzohydrazide derivatives; Surflex docking