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

  • J Med Chem. 2022 Oct 13;65(19):13240-13252. doi: 10.1021/acs.jmedchem.2c01064.
Wei Zhang  1 ,  Shichun Lun  2 ,  Shuang-Shuang Wang  1 ,  Yan-Peng Cai  1 ,  Fan Yang  1 ,  Jie Tang  3 ,  William R Bishai  2 ,  Li-Fang Yu  1
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
  • 2. Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, Maryland 21231-1044, United States.
  • 3. Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
PMID: 36174223 DOI: 10.1021/acs.jmedchem.2c01064
Abstract

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.

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