PDF(Pubmed)
Abstract：
Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC50 values ranging from 17 to 40 µg/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections.
摘要：
生物膜相关感染由于其对常规抗微生物疗法的抗性而在医疗机构中提出了重大挑战。在过去的十年里，海洋环境一直是生物活性分子的宝贵来源，包括许多具有抗生物膜活性的衍生物。在这项研究中,我们报道了一组新的二十二种噻二唑并嘧啶酮衍生物的合成和生物学评估，这些衍生物是通过使用杂交方法结合两类重要的海洋化合物的相关化学特征获得的：nortopsentin类似物和Essramycin衍生物。体外测试合成的化合物在各种细菌菌株中抑制生物膜形成和破坏成熟生物膜的能力。在测试的化合物中，衍生物8j对相关革兰氏阳性和革兰氏阴性病原体的预先形成的生物膜表现出显着的分散活性，以及真菌白色念珠菌，显示BIC50值范围为17至40µg/mL。此外，在Galleriamellonella模型中体内测定化合物8j的毒性和抗感染作用。结果揭示了用于治疗严重的慢性生物膜介导的感染的抗感染特性和有利的毒性特征的有希望的组合。
