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

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.