Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Treatment.

Pks13 was identified as a key enzyme involved in the final step of mycolic acid biosynthesis. We previously identified antitubercular coumestans that targeted Pks13-TE, and these compounds exhibited high potency both in vitro and in vivo. However, lead compound presented potential safety concerns because it inhibits the hERG potassium channel in electrophysiology patch-clamp assays (IC = 0.52 μM). By comparing the Pks13-TE-compound complex and the ligand-binding pocket of the hERG ion channel, fluoro-substituted and oxazine-containing coumestans were designed and synthesized. Fluoro-substituted compound and oxazine-containing coumestan showed excellent antitubercular activity against both drug-susceptible and drug-resistant strains (MIC = 0.0039-0.0078 μg/mL) and exhibited limited hERG inhibition (IC ≥ 25 μM). Moreover, exhibited improved metabolic stability relative to parent compound while showing favorable bioavailability in mouse models via serum inhibition titration assays.