Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules.

Abstract

We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a δ-lactone-that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding 'open-form' ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the 'open-form' analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H37Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64-128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.

• Authors: Wei Zhang, Ling-Ling Liu, Shichun Lun, Shuang-Shuang Wang, Shiqi Xiao, Hendra Gunosewoyo, Fan Yang, Jie Tang, William R Bishai, Li-Fang Yu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 213 Pg. 113202 (Mar 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33516983 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antitubercular Agents
• Bacterial Proteins
• Enzyme Inhibitors
• Quinolones
• polyketide synthase Pks13, Mycobacterium tuberculosis
• Polyketide Synthases

Topics

• Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Microbial Sensitivity Tests
• Models, Molecular
• Molecular Structure
• Mycobacterium tuberculosis (drug effects, enzymology, growth & development)
• Polyketide Synthases (antagonists & inhibitors, metabolism)
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship