Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

J Med Chem. 2022 Jan 13;65(1):409-423. doi: 10.1021/acs.jmedchem.1c01586. Epub 2021 Dec 15.


With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Benzofurans / chemical synthesis
  • Benzofurans / pharmacology*
  • Cardiotoxicity
  • Drug Discovery
  • ERG1 Potassium Channel
  • Heart / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Mycobacterium tuberculosis / drug effects
  • Palmitoyl-CoA Hydrolase / antagonists & inhibitors*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacology*
  • Polyketide Synthases / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Antitubercular Agents
  • Bacterial Proteins
  • Benzofurans
  • ERG1 Potassium Channel
  • Piperidines
  • TAM16 compound
  • polyketide synthase Pks13, Mycobacterium tuberculosis
  • Polyketide Synthases
  • Palmitoyl-CoA Hydrolase