Elucidating structural basis of benzofuran pyrrolidine pyrazole derivatives for enhancing potency against both the InhA enzyme and intact M. tuberculosis cells: a combined MD simulations and 3D-QSAR study

A 2-trans enoyl-acyl carrier protein (ACP) reductase or InhA of M. tuberculosis is a drug target of isoniazid (INH), the first-line drug for tuberculosis treatment. Many series of compounds have been developed as novel inhibitors of this enzyme. However, they lack good potency against purified InhA and activity against intact M. tuberculosis cells. Benzofuran pyrrolidin pyrazole derivatives are potent direct InhA inhibitors. These compounds show high potency for InhA inhibition with IC50 values at nanomolar levels. However, their activities against M. tuberculosis cells in terms of MIC90 were about one-thousand fold than IC50. Accordingly, in this work, IC50 and MIC90 values of benzofuran pyrrolidin pyrazole derivatives were subjected to CoMFA and CoMSIA studies in order to investigate the structural basis required for good activity against both purified InhA and M. tuberculosis cells. Moreover, MD simulations were employed to evaluate key interactions for binding benzofuran pyrrolidin pyrazole derivatives in InhA. Based on MD results, the core structure of these compounds is the key portion for binding in the InhA pocket. Alternatively, R substituents showed weak interactions with the InhA pockets. Interpretation of IC50 and MIC90 CoMSIA contour maps revealed the structural requirements in terms of steric, electrostatic, hydrophobic and hydrogen donor and acceptor for IC50 and MIC90 values of InhA inhibitors. Finally, the integrated results obtained from MD simulations and graphic interpretation of CoMSIA models provided a structural concept for rational design of novel InhA inhibitors with better potency against both the InhA enzyme and intact M. tuberculosis cells.