Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis 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 8 presented potential safety concerns because it inhibits the hERG
potassium channel in electrophysiology patch-clamp assays (IC50 = 0.52 μM). By comparing the Pks13-TE-compound 8 complex and the ligand-binding pocket of the hERG ion channel,
fluoro-substituted and oxazine-containing coumestans were designed
and synthesized. Fluoro-substituted compound 23 and oxazine-containing
coumestan 32 showed excellent antitubercular activity
against both drug-susceptible and drug-resistant Mtb strains (MIC = 0.0039–0.0078 μg/mL) and exhibited limited
hERG inhibition (IC50 ≥ 25 μM). Moreover, 32 exhibited improved metabolic stability relative to parent
compound 8 while showing favorable bioavailability in
mouse models via serum inhibition titration assays.