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.牙周疾病是由致病性口腔细菌（如牙龈卟啉单胞菌（Porphyromonas gingivalis））诱发的炎症性疾病。扎鲁司特（Zafirlukast，ZAF）已被证实对牙龈卟啉单胞菌具有抗菌活性。本研究报道了14种新型第三代ZAF衍生物的设计、合成及其选择性抗菌活性。由于此前未针对牙龈卟啉单胞菌ATCC 33277对这2种第二代ZAF衍生物开展过相关测试，因此本研究对其进行了抗菌活性检测。与ZAF及其第二代衍生物相比，多数第三代衍生物对牙龈卟啉单胞菌展现出更优异且具选择性的抗菌活性。此类化合物对牙龈卟啉单胞菌具有杀菌活性，可抑制生物膜生长；与ZAF相比，其无溶血活性，且对哺乳动物细胞的细胞毒性更低。相较于ZAF，ZAF衍生物对牙龈卟啉单胞菌展现出的优异选择性抗菌活性、更优的安全性以及对生物膜生长的抑制作用，表明此类化合物（尤其是21a、21b与24g）具备成为抗菌制剂的潜力，可用于后续研究以验证其预防和治疗牙龈卟啉单胞菌引发的牙周疾病的潜能。