Title : Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment - Zhang_2022_J.Med.Chem_65_13240 |
Author(s) : Zhang W , Lun S , Wang SS , Cai YP , Yang F , Tang J , Bishai WR , Yu LF |
Ref : Journal of Medicinal Chemistry , 65 :13240 , 2022 |
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 (IC(50) = 0.52 microM). 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 microg/mL) and exhibited limited hERG inhibition (IC(50) <= 25 microM). Moreover, 32 exhibited improved metabolic stability relative to parent compound 8 while showing favorable bioavailability in mouse models via serum inhibition titration assays. |
PubMedSearch : Zhang_2022_J.Med.Chem_65_13240 |
PubMedID: 36174223 |
Gene_locus related to this paper: myctu-PKS13 |
Inhibitor | Coumestan-cpd32 Coumestan-cpd8 |
Gene_locus | myctu-PKS13 |
Structure | 7VJT |
Zhang W, Lun S, Wang SS, Cai YP, Yang F, Tang J, Bishai WR, Yu LF (2022)
Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment
Journal of Medicinal Chemistry
65 :13240
Zhang W, Lun S, Wang SS, Cai YP, Yang F, Tang J, Bishai WR, Yu LF (2022)
Journal of Medicinal Chemistry
65 :13240