Abstract：
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 1H NMR, 13C 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.
摘要：
全球微生物耐药性严重威胁人类健康,和多靶向化合物被认为有希望对抗微生物抗性。在这项工作中,使用三乙氧基甲烷和取代的苯胺作为起始材料，通过多步反应开发了一系列具有多靶向抗菌潜力的新型噻唑基喹诺酮类药物。其结构经1HNMR确证,13CNMR和HRMS光谱。抗菌评价显示,一些目标化合物能有效抑制微生物生长。尤其是,硫代酰氨基肼基氨基噻唑基喹诺酮8a对耐药金黄色葡萄球菌具有很强的抑制活性，MIC值为0.0047mM，比诺氟沙星活性高5倍。高活性化合物8a表现出可忽略的溶血，在体外和体内没有明显的毒性，耐药性低,以及快速杀菌作用，这表明其良好的可药用性。此外，化合物8a能够有效地破坏细菌膜的完整性，插入DNA并抑制拓扑异构酶IV的活性，提示多靶向作用机制。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，作为化学治疗候选物的活性硫代氨基肼酰氨基噻唑基喹诺酮8a显示出解决耐药细菌感染的巨大潜力。
