Selective Inhibition of the Periodontal Pathogen Porphyromonas gingivalis by Third-Generation Zafirlukast Derivatives

Kaitlind C. Howard, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Periodontal diseases are inflammatory diseases triggered by pathogenic oral bacterial species, such as Porphyromonas gingivalis. Zafirlukast (ZAF) has displayed antibacterial activity against P. gingivalis. Herein, we report the design, synthesis, and selective antibacterial activity of 14 novel third-generation ZAF derivatives. Two second-generation ZAF derivatives were tested as they were not previously tested against P. gingivalis ATCC 33277. Most third-generation derivatives displayed superior/selective antibacterial activity against P. gingivalis compared to ZAF and its second-generation derivatives. The compounds displayed bactericidal activity against P. gingivalis, inhibited biofilm growth, displayed no hemolytic activity, and displayed less cytotoxicity against mammalian cells than ZAF. The superior/selective antibacterial activity of ZAF derivatives against P. gingivalis, increased safety profile, and inhibition of biofilm growth compared to ZAF indicate that the compounds, especially 21a, 21b, and 24g, show promise as antibacterial agents for future studies to test their potential for preventing and treating P. gingivalis-induced periodontal diseases.

Original languageEnglish
Pages (from-to)14938-14956
Number of pages19
JournalJournal of Medicinal Chemistry
Volume65
Issue number21
DOIs
StatePublished - Nov 10 2022

Bibliographical note

Funding Information:
This work was supported by a National Institutes of Health (NIH) F31 fellowship DEO29661 (to K.C.H.). The authors thank the UK PharmNMR Center (in the College of Pharmacy) for NMR support, Dr. Octavio A. Gonzalez (University of Kentucky) for discussions as well as help with the reagents and use of instruments, Dr. Nishad Thamban Chandrika for his help with HPLC and HRMS, and Dr. J. G. Rheinwald (Harvard Medical School) for sharing the oral keratinocyte cell line OKF6/hTERT (OKF6).

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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