Design, Synthesis and Biological Evaluation of N -phenylindole Derivatives as Pks13 Inhibitors against Mycobacterium tuberculosis .

Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis ( Mtb ), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb . The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N -phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure-activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds.