Design, synthesis and activity evaluation of dithiocarbamate-based L-homoserine lactone derivatives as Gram-negative bacteria quorum sensing inhibitors

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-05-11 DOI:10.1016/j.ejmech.2025.117756

Aichata Maiga , Li Hong Teng , Zhen Hao Jie , Zhang Xue Qing , Fan Zheng Min , Lin Zi Wei , Chunli Wu

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Abstract

Pseudomonas aeruginosa (P. aeruginosa) is an important Gram-negative opportunistic pathogen that uses quorum sensing to regulate its virulence and biofilm development, which contributes to its pathogenicity and drug resistance. As a result, focusing on the virulence and pathogenicity of P. aeruginosa through quorum sensing (QS) is considered a possible target for anti-infective therapy. In this work, we discovered new quorum-sensing inhibitors derived from the structural modification of the dithiocarbamate-based l-homoserine lactone derivatives library and the target compound (10p) demonstrated significant inhibitory activity against PAO1 biofilm (inhibition rate: 86.76 %), pyocyanin (68.05 %), rhamnolipid (34.56 %), LasA protease (61.01 %) and a low inhibitory on elastase production (6.59 %) at 60 μM. Moreover, compound 10p effectively attenuated P. aeruginosa motility, such as swimming (42.85 %) and swarming (72 %), and demonstrated no toxicity in vitro. The result indicates that compound 10p may serve as a promising new antibacterial synergist option for treating P. aeruginosa infections.

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基于二硫代氨基甲酸酯的l -高丝氨酸内酯衍生物作为革兰氏阴性菌群体感应抑制剂的设计、合成和活性评价。

铜绿假单胞菌（Pseudomonas aeruginosa， P. aeruginosa）是一种重要的革兰氏阴性条件致病菌，通过群体感应调节其毒力和生物膜的发育，这有助于其致病性和耐药性。因此，通过群体感应（quorum sensing， QS）研究P. aeruginosa的毒力和致病性被认为是抗感染治疗的可能靶点。在本研究中，我们通过对二硫代氨基甲酸酯基l -高丝氨酸内酯衍生物库进行结构修饰，发现了新的群体感应抑制剂，目标化合物（10p）对PAO1生物膜（抑制率86.76%）、pyocyanin（68.05%）、鼠李糖脂（34.56%）、LasA蛋白酶（61.01%）具有显著的抑制活性，对60μM弹性酶的产生具有较低的抑制作用（6.59%）。此外，化合物10p能有效地减弱P. aeruginosa的游动（42.85%）和蜂群（72%）的运动能力，且无体外毒性。结果表明，化合物10p可能是治疗铜绿假单胞菌感染的一种有前景的新型抗菌增效剂。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.