Synthesis and antibacterial medicinal evaluation of carbothioamido hydrazonyl thiazolylquinolone with multitargeting antimicrobial potential to combat increasingly global resistance.

Autor: Zang ZL; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China., Wang YX; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China., Battini N; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China., Gao WW; State Key Laboratory Base of Eco-chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China. Electronic address: gww501@qust.edu.cn., Zhou CH; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China. Electronic address: zhouch@swu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116626. Date of Electronic Publication: 2024 Jun 27.
DOI: 10.1016/j.ejmech.2024.116626
Abstrakt: 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 1 H NMR, 13 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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