Discovery of furo[2,3-b]isoquinoline derivatives as novel Pks13 inhibitors with reduced hERG inhibition.

Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as TAM16 have demonstrated significant efficacy in vitro and in vivo, their development was discontinued due to concerns about hERG inhibition. Herein, we designed and synthesized a series of novel furo[2,3-b]isoquinoline derivatives using ring fusion and basicity-reduction strategies. Through SAR studies, compound B23 was identified as a potent Pks13 inhibitor (IC50 = 1.12 μM) with significantly reduced hERG inhibition (IC50 > 10 μM). The markedly improved hERG selectivity not only validates our structural strategy for mitigating cardiotoxicity risks, but also provides a solid foundation for further development of Pks13-TE inhibitors that combine potent anti-TB activity with an improved safety profile.