Design, Development, and In Silico Study of Pyrazoline-Based Mycobactin Analogs as Anti-Tubercular Agents

Abstract

The pathogenicity and virulence of Mycobacterium tuberculosis has further potentiated its infectiousness, making it a killer disease, as is 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. The goal can be achieved by “conditionally essential target” (CET)-based drug design. The research pertaining to the mycobactin biosynthesis pathway (MBP) relating to iron acquisition is in a nascent stage; the pathway serves as a promising endogenous target for novel lead compound discoveries (non-specific MBP inhibitors). As a continuation of our previous research, reported by Stirret et al., 2008 and Ferreras et al., 2011, in this study we further aim to explore the structural diversity of the previously identified active molecules as this could lead to the discovery of a more potent analog. Eventually, we designed a small library of mycobactin analogs retaining diaryl-substituted pyrazoline (DAP) as the basic scaffold and tested their in silico stabilities by molecular docking (AutoDock 4.2.6). Docking of the designed molecules was performed in the active site of the MbtA receptor (by analogy with the related structure, PDB: 1MDB) to evaluate the binding modes and inhibitory profiles. The lowest energy conformation of each docked ligand was analyzed with the BIOVIA Discovery Studio Visualizer. The docking results identified GM08 and GM09 as potent inhibitors which could therefore serve as good leads. The ADMET profile also revealed satisfactory results. Furthermore, what remains to be seen is the stability of each molecule by employing MD simulation along with intracellular activity.

Keywords

• tuberculosis drug discovery
• target-based screening
• mycobactins
• siderophores
• pyrazoline
• molecular docking