Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads.

ABSTRACT

Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure-activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 µg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 µM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.