Novel 3-cyclopentylidene-5-(methylsulfonyl)indolin-2-one derivatives as Anti-tubercular Agents: Design, Synthesis, Docking, Molecular Dynamic Simulation, and Biological Evaluation

Abstract Nearly 3 million people die from tuberculosis (TB), which affects the lungs and other regions of the body. It is the most common bacterial infectious agent. We report the molecular docking, molecular dynamic simulations, synthesis, characterization, and biological activity of indolin-2-one derivatives as a novel anti-mycobacterial series identified from MABA (Microplate Alamar Blue Assay )method. The docking method was employed to investigate the intermolecular interactions between each compound and the enzyme Decaprenyl phosphoryl-D-ribose 2′-epimerase(DprE1). The results revealed significant binding interaction energies between these compounds and the enzyme. The stability of the interaction was evaluated using a standard 20 ns dynamic simulation study. For the protein-ligand complex's stability under the dynamic settings, parameters generated from MD simulation trajectories were computed and validated. The three compounds showed significant anti-mycobacterial activity, with MICs of 3.12 μg/ml against M. tuberculosis. All the compounds have favourable in vitroabsorption-distribution-metabolism-excretion (ADME). Evaluation of all the new compounds for in vitroanti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294) resulted in 9b, 9c, and 15a (MIC: 3.125μg/mL) as promising lead analogues.