Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
School of Chemistry and Chemical Engineering, Qiannan Normal University for Nationalities, Duyun, 558000, China.
Eur J Med Chem. 2023 Dec 15;262:115878. doi: 10.1016/j.ejmech.2023.115878. Epub 2023 Oct 14.
A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5-2 μg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.
一种新型苯并吡喃介导的喹诺酮类（BMQs）被合理设计并高效合成，作为新型潜在抗菌分子，以克服全球日益严重的耐药性问题。一些合成的 BMQs 有效抑制了受试菌株的生长，优于临床药物。值得注意的是，亚乙基衍生的 BMQ 17a 表现出优异的抗菌潜力，对临床药物诺氟沙星的 MIC 值低至 0.5-2μg/mL，不仅显示出快速的杀菌性能和抑制细菌生物膜形成的能力，而且对人红细胞和正常 MDA-kb2 细胞的毒性较低。机制研究表明，BMQ 17a 可以有效地诱导细菌代谢紊乱，并促进活性氧的增强，从而破坏细菌的抗氧化防御系统。研究发现，活性分子 BMQ 17a 不仅可以与乳酸脱氢酶形成超分子复合物，从而干扰其生物学功能，还可以有效地嵌入小牛胸腺 DNA，从而影响 DNA 的正常功能并导致细胞死亡。这项工作为开发新的分子以降低耐药性和扩大抗菌谱提供了新的思路。
