Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties

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...

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Bibliographic Details
Published in:	European journal of medicinal chemistry Vol. 107; pp. 133 - 152
Main Authors:	Joshi, Shrinivas D., Dixit, Sheshagiri R., Kirankumar, M.N., Aminabhavi, Tejraj M., Raju, K.V.S.N., Narayan, Ramanuj, Lherbet, Christian, Yang, Kap Seung
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-01-2016 Elsevier
Subjects:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Anti-tubercular activity Antitubercular Agents - chemical synthesis Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - antagonists & inhibitors Chemical Sciences Chemistry Techniques, Synthetic Cytotoxicity activity Drug Evaluation, Preclinical - methods Enzyme inhibition studies Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Escherichia coli - drug effects Humans Isoxazoles - chemistry Ligands Microbial Sensitivity Tests Molecular Docking Simulation Mycobacterium tuberculosis - drug effects Oxidoreductases - antagonists & inhibitors Pyrroles - chemistry Pyrrolyl chalcones Pyrrolyl isoxazoles Pyrrolyl pyrazolines Staphylococcus aureus - drug effects Surflex docking Thiourea - chemistry Anti-tubercular activity Pyrrolyl chalcones Surflex docking Pyrrolyl pyrazolines Cytotoxicity activity Pyrrolyl isoxazoles Enzyme inhibition studies
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Summary:	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. Antitubercular activity of novel series of pyrrolyl chalcone, pyrazline, isoxazole and phenyl urea derivatives was analyzed. Molecular modeling constructed using Surflex-Dock study using enoyl ACP reductase from Mycobacterium tuberculosis. [Display omitted] •Inhibitors of mycobacterial Enoyl ACP reductase were designed using in silico approach.•Synthesis of a range of these pyrrolyl chalcones, pyrazoles, isoxazoles and phenyl thiourea derivatives is described.•Surflex docking studies were carried out to understand the binding affinity of the compounds.•Inhibitors were active against Mycobacterium tuberculosis, Staphylococcus aureus, Eschrichia coli, Cell-line (A549) and InhA.
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2015.10.047