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


ABSTRACT: 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.

SUBMITTER: Cai Y 

PROVIDER: S-EPMC9106008 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Cai Yanpeng Y   Zhang Wei W   Lun Shichun S   Zhu Tongtong T   Xu Weijun W   Yang Fan F   Tang Jie J   Bishai William R WR   Yu Lifang L  

Molecules (Basel, Switzerland) 20220429 9


Polyketide synthase 13 (Pks13), an essential enzyme for the survival of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against <i>Mtb</i>. 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 <i>N</i> moieties. Thirty-si  ...[more]

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