title: Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties.
abstract: We report here the synthesis, antibacterial and antitubercular evaluation of 61 novel pyrrolyl derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Molecular docking was carried out on enoyl ACP reductase from Mycobacterium tuberculsosis using Surflex-Dock, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of Mycobacterium tuberculosis, an attractive target for designing novel antitubercular agents. Docking analysis of the crystal structure of ENR performed using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of substituted pyrrolyl derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 μg/mL) with a MIC value of 0.8 μg/mL. All other compounds showed the good activity with a MIC value of 6.25-100 μg/mL. The compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) and were nontoxic. Some compounds exhibited 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: M N
authors.initials: MN
authors.lastname: Kirankumar
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: Division of Polymers and Functional Materials, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India.
authors.forename: K V S N
authors.initials: KV
authors.lastname: Raju
authors.affiliation: Division of Polymers and Functional Materials, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 607, India.
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Narayan
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.
authors.forename: Christian
authors.initials: C
authors.lastname: Lherbet
authors.affiliation: Department of Polymer and Fiber System Engineering, Chonnam National University, 300 Yongbong-Dong, Bukgu, Gwangju, 500 757, South Korea.
authors.forename: Kap Seung
authors.initials: KS
authors.lastname: Yang
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry; D008024:Ligands; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects; D013890:Thiourea / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008024:Ligands; D011758:Pyrroles; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D013890:Thiourea
keywords: Anti-tubercular activity; Cytotoxicity activity; Enzyme inhibition studies; Pyrrolyl chalcones; Pyrrolyl isoxazoles; Pyrrolyl pyrazolines; Surflex docking