Development and evaluation of new oxindole derivatives as potential anti-tubercular agents

Abstract

Tuberculosis (TB), which affects the lungs and other parts of the body, claims the lives of around 3 million people. Indolin-2-one derivatives were identified as a novel anti-tubercular series from Microplate Alamar Blue Assay (MABA) method, along with its synthesis, characterisation, molecular docking, and molecular dynamic simulations. The enzyme decaprenylphosphoryl-β-D-ribose 20-oxidase (DprE1) demonstrated high binding interaction energies associated with these compounds, which were investigated through the use of the docking technique. A conventional dynamic simulation study lasting 20 ns was used to assess the interaction's stability. The parameters derived from the trajectories of molecular dynamic simulation were computed and validated with respect to the stability of the protein-ligand complex under dynamic conditions. The absorption-distribution-metabolism-excretion (ADME) values are favourable for all of the synthesized compounds. After testing each novel compound for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), the most promising lead analogues were 9e (MIC: 1.56 μg/mL), 13b (MIC: 3.125 μg/mL), and 13e (MIC: 3.125 μg/mL). In this study, we have designed and produced new 5-substituted Oxindole derivatives as anti-tubercular drugs through the application of docking and molecular dynamic modeling. Given the increasing demand for novel antibiotics and the ensuing urgent need for novel anti-TB medications, we think the currently reported oxindole derivatives of DprE1 inhibitors present an excellent possibility for future optimization.