2-Aryl-Benzoimidazoles as Type II NADH Dehydrogenase Inhibitors of .

The nonproton pumping type II NADH dehydrogenase in is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in , which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery. Herein, we have screened a commercially available library of drug-like molecules and have identified a hit having a benzimidazole core moiety (, H37Rv mc6230; minimum inhibitory concentration (MIC) = 16 μg/mL and ATP IC = 0.23 μg/mL) interfering with the oxidative phosphorylation pathway. Extensive medicinal chemistry optimization resulted in analogue with MIC = 4 μg/mL and ATP IC = 0.05 μg/mL against the H37Rv mc6230 strain of . Compounds and were found to be active against mono- and multidrug-resistant mycobacterium strains and demonstrated a bactericidal response. The Peredox-mCherry experiment and identification of single-nucleotide polymorphisms in mutants of (a known type II NADH dehydrogenase inhibitor) were used to confirm the molecules as inhibitors of the type II NADH dehydrogenase enzyme. The safety index >10 for the test active molecules revealed the safety of test molecules.