Time-dependent diaryl ether inhibitors of InhA: Structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy

Pan Pan, Susan E. Knudson, Gopal R. Bommineni, Huei Jiun Li, Cheng Tsung Lai, Nina Liu, Miguel Garcia-Diaz, Carlos Simmerling, Sachindra S. Patil, Richard A. Slayden, Peter J. Tonge

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity. No turning back: A series of diaryl ethers was designed with modifications to the B-ring. Structure-activity relationship studies shed light on the mechanism of time-dependent inhibition of InhA: during inhibitor binding, a slow step that leads to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the substrate binding loop. In a mouse model of tuberculosis infection, two of the time-dependent InhA inhibitors synthesized decreased the antibacterial load by 0.5-0.7 log units.

Original languageEnglish (US)
Pages (from-to)776-791
Number of pages16
JournalChemMedChem
Volume9
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • InhA
  • diaryl ethers
  • enoyl-ACP reductases
  • fatty acid biosynthesis
  • inhibitors
  • structure-activity relationships
  • time-dependent inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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    Pan, P., Knudson, S. E., Bommineni, G. R., Li, H. J., Lai, C. T., Liu, N., Garcia-Diaz, M., Simmerling, C., Patil, S. S., Slayden, R. A., & Tonge, P. J. (2014). Time-dependent diaryl ether inhibitors of InhA: Structure-activity relationship studies of enzyme inhibition, antibacterial activity, and in vivo efficacy. ChemMedChem, 9(4), 776-791. https://doi.org/10.1002/cmdc.201300429