Design, synthesis, molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as potential antimycobacterial agents

• A series of pyrrole derivatives have been designed and synthesized.
• Compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral analysis.
• Compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv.
• All the compounds exhibited moderate to good antitubercular activities.

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 (rpred2) of 0.896 and 0.930, respectively.

Molecular docking and 3D-QSAR studies were done on pyrrole hydrazone derivatives as enoyl-ACP reductase inhibitors in Mycobacterium tuberculosis.Figure optionsDownload as PowerPoint slide