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

Kaitlind C. Howard; Octavio A. Gonzalez; Sylvie Garneau-Tsodikova

doi:10.1021/acsmedchemlett.9b00614

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

Kaitlind C. Howard, Octavio A. Gonzalez, Sylvie Garneau-Tsodikova

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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 language	English
Pages (from-to)	1905-1912
Number of pages	8
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00614
State	Published - Oct 8 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Funding

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.

Funders	Funder number
University of Kentucky

Keywords

Oral microbiome species
dental plaque
oral dysbiosis
periodontal disease

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00614

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title = "Second Generation of Zafirlukast Derivatives with Improved Activity against the Oral Pathogen Porphyromonas gingivalis",

abstract = "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.",

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doi = "10.1021/acsmedchemlett.9b00614",

language = "English",

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AU - Gonzalez, Octavio A.

AU - Garneau-Tsodikova, Sylvie

PY - 2020/10/8

Y1 - 2020/10/8

N2 - 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.

AB - 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.

KW - Oral microbiome species

KW - dental plaque

KW - oral dysbiosis

KW - periodontal disease

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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