Novel Imidazopyridine Derivatives Targeting Cytochrome bd Oxidase: A Promising Strategy to Combat Tuberculosis

Tuberculosis (TB) treatment is time-consuming and is further worsened due to multi-drug resistance and toxicities. Hence, there is a need for the discovery of newer antituberculosis drugs. One of the important and emerging areas of discovering new drugs is by hindering the energy metabolism generator pathway like oxidative phosphorylation (OP) which helps the sustainability of both the replicating and dormant forms of the bacterium in the host. The drugs including Telacebec (Q203) and Bedaquiline target the OP pathway enzymes cytochrome bc1 complex and ATP synthase. However, the tuberculosis bacterium survives even after the inhibition of these enzymes due to the compensatory energy production by Mycobacterium tuberculosis-cytochrome bd oxidase enzyme leading to drug resistance. Additionally, this enzyme helps the survival of the organism in aerobic conditions and in the presence of stress factors including hypoxia conditions, reactive oxygen and nitrogen species. Hence, cytochrome bd oxidase is a promising target for the discovery of novel antitubercular lead candidates. Our work employed computational techniques to design and identify novel imidazopyridines that inhibit cytochrome bd oxidase for developing antitubercular drugs. SwissSimilarity screened structurally similar compounds from the ZINC database and resulted in 989 compounds containing different rings. However, we excluded all the non-bicyclic analogues and this resulted in a library of 824 drug-like candidates as most of the bicyclic compounds showed promising inhibitory action. Further, we considered the versatile nature of amine functionality in terms of synthetic feasibility and improving the antitubercular potency and selected 262 amine-modified derivatives of imidazopyridine (1 to 262). These 262 compounds along with three reported cytochrome bd oxidase inhibitors including amiloride derivative (1a), 2-(Quinolin-4-yloxy)acetamide (2a), and 2-Arylquinolone (3a) were docked against cytochrome bd oxidase (PDB ID: 7NKZ, 2.5 Å). This process identified 255 as the best lead candidate with a docking score of -8.38 than the other 268 compounds and the reported three compounds-1a (-7.47), 2a (-5.70) and 3a (-5.35). These results suggest that the imidazopyridine derivative 255 is a promising lead compound based on its docking score and favorable binding properties indicating strong potential for further development as an anti-TB agent.