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

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.