Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 +/- 0.94 mu M) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 mu g/ mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Automated summary

Tuberculosis is a global problem due to drug-resistant strains, and this study focuses on developing new antitubercular drugs by inhibiting a specific enzyme. The synthesized isatin derivatives, especially compound 4l, have shown promising potential in treating TB by inhibiting the target enzyme. Molecular docking and dynamics studies provide insights into the mechanism of action and stability of the compound. This research sets the foundation for the design and synthesis of novel antitubercular drugs.