Molecular Insight into the Discrepancy of Antitubercular Activity between 8-Nitro and 8-Cyano Benzothiazinones

Benzothiazinones with 8-NO₂ group is a novel class of compounds with potent antitubercular activity, especially BTZ043 and PBTZ169, which covalently inhibit DprE1. 8-CN benzothiazinones is reported as another type of benzothiazinones with potent antitubercular activity. Taking this as the starting point, a series of 8-CN benzothiazinones are synthesized and evaluated for their antitubercular activity. To better understand the antitubercular activity of this series of benzothiazinones, the difference between the molecular structures of CN01 and PBTZ169 in crystal are analyzed. CN01 and PBTZ169 show completely different conformations of the piperazine ring. Density functional theory analysis (DFT) and molecular dynamics (MD) simulation are performed to provide more details to explain the different antitubercular activity. All the analysis based on crystallography, quantum chemistry, and molecular modeling lay a foundation for the subsequent structural optimization of 8-CN benzothiazinones.