Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment.
Wei ZhangShichun LunShuang-Shuang WangYan-Peng CaiFan YangJie TangWilliam R BishaiLi-Fang YuPublished in: Journal of medicinal chemistry (2022)
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 (IC 50 = 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 (IC 50 ≥ 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.
Keyphrases
- drug resistant
- mycobacterium tuberculosis
- multidrug resistant
- positron emission tomography
- acinetobacter baumannii
- high throughput
- molecular docking
- mouse model
- pulmonary tuberculosis
- escherichia coli
- emergency department
- computed tomography
- drug delivery
- pseudomonas aeruginosa
- risk assessment
- replacement therapy
- electronic health record