Design, development, and insilico study of pyrazoline based mycobactin analogs as anti-tubercular agents

The pathogenicity and virulence of Mycobacterium tuberculosis have further potentiated its infectiousness thereby making it a killer disease as evident from the WHO database. Eradicating the TB epidemic by 2030 is amongst the major health targets of the United Nations Sustainable Development Goals (SDGs). The increase in multidrug-resistant TB (MDR-TB) cases has challenged and prompted the scientific community to develop novel chemotherapeutic agents with novel mechanisms of action. This can be achieved by the concept of “conditionally essential target” (CET)-based drug design. The research pertaining to the Mycobactin biosynthesis pathway (MBP) relating to iron acquisition is at a nascent stage and serves as a promising endogenous target for novel lead compounds discovery (non-specific MBP inhibitors). In continuation to our previous research work reported by Stirret et al, 2008 and Ferreras et al., 2011; here we further aim to explore the structural diversity of the previously identified active molecules which could lead to the discovery of a more potent analog. Eventually, we designed a small library of mycobactin analogs retaining the basic scaffold as diaryl-substituted pyrazoline (DAP) and tested their insilico stability by molecular docking (AutoDock 4.2.6). Docking of the designed molecules was performed in the active site of the receptor (PDB: 5KEI; by analogy with the related structure PDB: 1MDB) to evaluate the binding modes and inhibitory profile. The lowest energy conformation of each docked ligand was analyzed in BIOVIA Discovery Studio Visualizer. Docking results showed that the designed compound GS was found to be more potent and could serve as a lead compound. The ADMET profile also revealed satisfactory results. Further, these results can be validated using MD simulation and intracellular activity.