Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen Porphyromonas gingivalis

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5 Scopus citations


Porphyromonas gingivalis is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast (ZAF) was recently shown to display antibacterial activity against P. gingivalis. Here, 15 novel ZAF derivatives were synthesized and evaluated for their antibacterial activity against P. gingivalis and for their cytotoxic effects. Most derivatives displayed superior antibacterial activity against P. gingivalis compared to ZAF and its first generation derivatives along with little to no growth inhibition of other oral bacterial species. The most active compounds displayed bactericidal activity against P. gingivalis and less cytotoxicity than ZAF. The superior and selective antibacterial activity of ZAF derivatives against P. gingivalis along with an increased safety profile compared to ZAF suggest these new compounds, especially 14b and 14e, show promise as antibacterials for future studies aimed to test their potential for preventing/treating P. gingivalis-induced periodontal disease.

Original languageEnglish
Pages (from-to)1905-1912
Number of pages8
JournalACS Medicinal Chemistry Letters
Issue number10
StatePublished - Oct 8 2020

Bibliographical note

Funding Information:
This work was supported by startup funds from the University of Kentucky (UK) (to S.G.-T. and O.A.G.) and a grant from the UK Igniting Research Collaborations Pilot Program (to S.G.-T. and O.A.G.). We thank the UK PharmNMR Center for NMR support. We thank Nishad Thamban Chandrika for his help with HPLC and MS. We thank J. G. Rheinwald (Harvard Medical School) for sharing the oral keratinocyte cell line OKF6/hTERT.

Publisher Copyright:
Copyright © 2020 American Chemical Society.


  • Oral microbiome species
  • dental plaque
  • oral dysbiosis
  • periodontal disease

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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