Identification of unique indolylcyanoethylenyl sulfonylanilines as novel structural scaffolds of potential antibacterial agents.

Autor: Zhou XM; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China., Li QY; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China., Lu X; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China., Bheemanaboina RRY; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China., Fang B; College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, PR China. Electronic address: fangbo2100@163.com., Cai GX; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China. Electronic address: gxcai@swu.edu.cn., Zhou CH; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Aplied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China. Electronic address: zhouch@swu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Nov 15; Vol. 260, pp. 115773. Date of Electronic Publication: 2023 Aug 30.
DOI: 10.1016/j.ejmech.2023.115773
Abstrakt: The increasing incidence of antibiotic resistance has forced the development of unique antimicrobials with novel multitargeting mechanisms to combat infectious diseases caused by multidrug-resistant pathogens. Structurally unique indolylcyanoethylenyl sulfonylanilines (ISs) were exploited as novel promising antibacterial agents to confront stubborn drug resistance. Some prepared ISs possessed favorable bacteriostatic action towards the tested bacteria. Especially, hydroxyethyl IS 14a exerted 8-fold more potent inhibitory efficacy against multidrug-resistant A. baumannii and E. coli 25922 with the low MIC of 0.5 μg/mL than norfloxacin, and showed low cell toxicity and rapid bactericidal property. Moreover, this compound also possessed obvious effect of eradicating bacterial biofilm, which could effectually relieve the development of drug resistance. A preliminary assessment of the antibacterial mechanism indicated that compound 14a could disintegrate membrane integrity leading to the leakage of intracellular protein, inactivation of lactate dehydrogenase and metabolism inhibition. Hydroxyethyl IS 14a mediated the accumulation of excess reactive oxygen species, which further contributed to reducing glutathione, resulting in oxidative damage to bacteria. Furthermore, IS 14a could intercalate into DNA to hinder the biological function of DNA. Quantum chemical study disclosed that IS 14a with the lowest energy gap was conducive to displaying high bioactivity. These findings demonstrated that hydroxyethyl IS 14a as a prospective antimicrobial candidate for combating A. baumannii and E. coli 25922 would be a promising starting point.
Competing Interests: Declaration of competing interest The authors declare no competing financial interest.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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