Design, Synthesis, and Molecular Docking of Novel Benzothiazinone Derivatives as DprE1 Inhibitors with Potential Antitubercular Activities

Abstract

Objective: As a possible antitubercular agent, we disclose in this study the design and synthesis of a novel series of benzothiazinone derivatives (Va–Vi), contributing to the worldwide fight to eradicate TB, one of the deadliest infectious killers in the world. Methods: The newly synthesized benzothiazinone derivatives were characterized using various spectroscopic and elemental analysis techniques. The antituberculosis activity of the synthesized benzothiazinone derivatives was evaluated against drug-sensitive Mtb H37Rv and MDR-TB strains. To explain their inhibitory qualities, potent compounds underwent molecular docking studies. The synthetic molecules’ ability to function as lead-like molecules and the drug-likeness of the compounds were computed using the SwissADME online tool. Results and Discussion: With a MIC of 0.01 and 0.21 µM, respectively, compound (Vi) showed the most promising antitubercular efficacy against drug-sensitive Mtb H37Rv and MDR-TB strains. Four of the nine studied compounds had strong DprE1 inhibitory action, with IC₅₀ values ranging from 0.02 to 0.79 μM. The molecular docking findings indicated that these compounds had a high docking score and a strong binding affinity to the target DprE1 protein’s active pocket. Conclusions: The current study demonstrated the potential significance of novel benzothiazinone derivatives as antitubercular prospects, and further investigation into optimization may lead to the creation of new antitubercular medication candidates.