Inhibition of Pseudomonas aeruginosa Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-10-25 DOI:10.1021/acs.jmedchem.4c01555

Beatrice Marinacci, Ilaria D’Agostino, Andrea Angeli, Simone Carradori, Francesco Melfi, Rossella Grande, Micol Corsiani, Marta Ferraroni, Mariangela Agamennone, Anna Rita Tondo, Susi Zara, Valentina Puca, Benedetta Pellegrini, Chiara Vagaggini, Elena Dreassi, Marianna A. Patrauchan, Clemente Capasso, Orazio Nicolotti, Fabrizio Carta, Claudiu T. Supuran

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引用次数: 0

Abstract

Ciprofloxacin (CPX) is one of the most employed antibiotics in clinics to date. However, the rise of drug-resistant bacteria is dramatically impairing its efficacy, especially against life-threatening pathogens, such as Pseudomonas aeruginosa. This Gram-negative bacterium is an opportunistic pathogen, often infecting immuno-compromised patients with severe or fatal outcomes. The evidence of the possibility of exploiting Carbonic Anhydrase (CA, EC: 4.2.1.1) enzymes as pharmacological targets along with their role in P. aeruginosa virulence inspired the derivatization of CPX with peculiar CA-inhibiting chemotypes. Thus, a large library of CPX derivatives was synthesized and tested on a panel of bacterial CAs and human isoenzymes I and II. Selected derivatives were evaluated for antibacterial activity, revealing bactericidal and antibiofilm properties for some compounds. Importantly, promising preliminary absorption, distribution, metabolism, and excretion (ADME) properties in vitro were found and no cytotoxicity was detected for some representative compounds when tested in Galleria mellonella larvae.

Abstract Image

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抑制铜绿假单胞菌碳酸酐酶，探索环丙沙星功能化以开发新型抗菌剂：一项深入的多学科研究

环丙沙星（CPX）是迄今为止临床上使用最多的抗生素之一。然而，耐药性细菌的增加正在极大地削弱它的疗效，尤其是对铜绿假单胞菌等危及生命的病原体的疗效。这种革兰氏阴性细菌是一种机会性病原体，经常感染免疫力低下的病人，造成严重或致命的后果。有证据表明，可以利用碳酸酐酶（CA，EC：4.2.1.1）作为药理靶点，同时它们在铜绿假单胞菌毒力中的作用也激发了人们用特殊的 CA 抑制化学型对 CPX 进行衍生。因此，我们合成了一个庞大的 CPX 衍生物库，并在一组细菌 CA 和人类同工酶 I 和 II 上进行了测试。对所选衍生物的抗菌活性进行了评估，发现一些化合物具有杀菌和抗生物膜特性。重要的是，发现了一些具有代表性的化合物在体外吸收、分布、代谢和排泄（ADME）方面具有良好的初步特性，而且在对小白鼠幼虫进行测试时，没有发现这些化合物具有细胞毒性。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.