Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
State Key Laboratory Base of Eco-chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
Eur J Med Chem. 2024 Sep 5;275:116626. doi: 10.1016/j.ejmech.2024.116626. Epub 2024 Jun 27.
The global microbial resistance is a serious threat to human health, and multitargeting compounds are considered to be promising to combat microbial resistance. In this work, a series of new thiazolylquinolones with multitargeting antimicrobial potential were developed through multi-step reactions using triethoxymethane and substituted anilines as start materials. Their structures were confirmed by H NMR, C NMR and HRMS spectra. Antimicrobial evaluation revealed that some of the target compounds could effectively inhibit microbial growth. Especially, carbothioamido hydrazonyl aminothiazolyl quinolone 8a showed strong inhibitory activity toward drug-resistant Staphylococcus aureus with MIC value of 0.0047 mM, which was 5-fold more active than that of norfloxacin. The highly active compound 8a exhibited negligible hemolysis, no significant toxicity in vitro and in vivo, low drug resistance, as well as rapidly bactericidal effects, which suggested its favorable druggability. Furthermore, compound 8a was able to effectively disrupt the integrity of the bacterial membrane, intercalate into DNA and inhibit the activity of topoisomerase IV, suggesting multitargeting mechanism of action. Compound 8a could form hydrogen bonds and hydrophobic interactions with DNA-topoisomerase IV complex, indicating the insertion of aminothiazolyl moiety was beneficial to improve antibacterial efficiency. These findings indicated that the active carbothioamido hydrazonyl aminothiazolyl quinolone 8a as a chemical therapeutic candidate demonstrated immense potential to tackle drug-resistant bacterial infections.
全球微生物耐药性对人类健康构成严重威胁，多靶标化合物被认为是对抗微生物耐药性的有前途的药物。在这项工作中，以三乙氧基甲烷和取代苯胺为起始原料，通过多步反应，开发了一系列具有多靶标抗菌潜力的新型噻唑基喹诺酮类化合物。它们的结构通过 1 H NMR、 13 C NMR 和 HRMS 谱得到确认。抗菌评估表明，一些目标化合物可以有效抑制微生物的生长。特别是，碳硫酰胺基腙氨基噻唑基喹诺酮 8a 对耐药性金黄色葡萄球菌表现出很强的抑制活性，MIC 值为 0.0047 mM，比诺氟沙星活性高 5 倍。高活性化合物 8a 表现出轻微的溶血作用，体外和体内均无明显毒性，耐药性低，杀菌作用迅速，表明其具有良好的成药性。此外，化合物 8a 能够有效破坏细菌膜的完整性，插入 DNA 并抑制拓扑异构酶 IV 的活性，表明其具有多靶标作用机制。化合物 8a 可以与 DNA-拓扑异构酶 IV 复合物形成氢键和疏水相互作用，表明氨基噻唑基部分的插入有利于提高抗菌效率。这些发现表明，活性碳硫酰胺基腙氨基噻唑基喹诺酮 8a 作为一种化学治疗候选物，具有巨大的潜力来解决耐药性细菌感染的问题。
