Discovery of Potent Benzoselenazinone-Based DprE1 Inhibitors: A Novel Selenium-Containing Scaffold with Superior Anti-TB Activity and Pharmacokinetic Properties

Tuberculosis remains one of the world’s most devastating infectious diseases. Targeting the essential cell wall enzyme, DprE1 has emerged as a promising therapeutic strategy. In this study, we report the discovery of a novel selenium-containing scaffold, benzoselenazinones (BSZs), which was designed through selenium-for-sulfur replacement in benzothiazinones (BTZs) to combine DprE1 inhibition with the pharmacological benefits of organoselenium compounds. Most BSZ derivatives exhibited exceptional anti-TB activity (MICs < 0.03 μM), low cytotoxicity (Vero IC 50 s > 100 μM), and potent DprE1 inhibition (IC 50 s < 0.1 μM). Moreover, compound 11c demonstrated superior oral bioavailability ( F % = 31.9%) compared to the representative PBTZ169 of BTZs in CD-1 mice, positioning it as a promising preclinical candidate. This study highlights the potential of selenium-based bioisosteres in anti-TB drug discovery and offers a novel benzoselenazinone scaffold with enhanced efficacy and safety for further development.