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

• Published in: European journal of medicinal chemistry 2016-01, Vol.107, p.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: Article
• Language: English
• 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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.10.047

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.