Analog-based Design and Development of Novel Molecules as Anti-tubercular Agents

Abstract:

Background: The burden of tuberculosis is immense as most of the drugs developed resistance to Mycobacterium tuberculosis (Mtb). This issue shall be addressed by developing new drugs acting through novel mechanisms. GSK 2556286 (GSK-286) is a phase 1 clinical candidate with a novel mechanism of action related to cholesterol catabolism, hence it was selected as template/ parent molecules for our analogue-based drug design strategy. Materials and Methods: The novel-designed molecules were initially checked to be drug-like using ‘Lipinski’s rule of five and synthesized with good yields. The obtained compounds were evaluated for anti-tubercular activity against Mtb H37Rv, antibacterial activity against S. aureus and E. coli, cytotoxicity screening against mammalian VERO cells and BBB permeability against Porcine Brain Lipid. Docking was also performed against HsaA monooxygenase (PDB ID: 3AFF) to understand the possible mechanism of action. Results and Conclusion: The compounds 3a and 7a exhibited promising anti-tubercular activity at MIC of 3.13 μg/mL. Further, the compounds proved to be effective towards S. aureus at 0.98 μg/mL and E. coli at 7.81 μg/mL. The molecules 3a and 7a produced good docking scores of -9.2 and -9.3 kcal/mole respectively. The association between docking results and anti-tubercular activity has postulated that the molecules could act through novel mechanisms by inhibiting HsaA monooxygenase. Moreover, all the compounds in the study produced very less cytotoxicity at CC₅₀ > 190 μg/mL against mammalian VERO cells and also showed minimal BBB permeability in PAMPA assay. The effective anti-tubercular activity of the lead molecules with additional safety against mammalian VERO cells with reduced BBB permeability could provide a new standpoint in anti-tubercular drug discovery.

Keywords: Analog-based Design, Anti-tubercular activity, BBB permeability, GSK 2556286, VERO cells.