Structure-Based Development of 3,4-Fused Tricyclic Benzofuran Derivatives as Polyketide Synthase 13 Inhibitors with Negligible hERG Inhibition

Polyketide synthase 13 (Pks13) is vital for synthesizing mycolic acid, which are essential for the survival of Mycobacterium tuberculosis (Mtb). Compounds that target Pks13 hold significant promise for developing new chemical entities for multidrug-resistant TB. The early lead benzofuran-3-carboxamide TAM16, demonstrated robust in vivo efficacy in murine models of tuberculosis infection; however, its further advancement was halted due to the cardiotoxicity associated with hERG inhibition. We implemented a conformational restriction strategy to explore the chemical space of 3,4-fused tricyclic benzofurans and indoles employing a structure-based design approach. Representative compounds were identified as Pks13-TE inhibitors, showing resistance against mutant strains from coumestan-resistant Mtb colonies. Notably, 29 and 30 exhibited potent antitubercular activity against Mtb H37Rv strain (MIC = 0.0156-0.0313 μg/mL), with negligible hERG inhibition (IC₅₀ > 100 μM) suggesting that the 3,4-fused tricyclic benzofurans may present promising scaffold for developing Pks13-TE inhibitors without hERG liability.