Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 DOI:10.1021/acsmedchemlett.4c0045810.1021/acsmedchemlett.4c00458

Zhengmin Fan, Ziwei Lin, Hongjin Zhai, Yaquan Cao*, Huanhuan Wang, Aichata Maiga, Firas Obald Arhema Frejat, Changzhong Ren and Chun-Li Wu*,

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Abstract

The widespread use of tylosin family drugs in clinical practice has led to bacterial resistance and reduced therapeutic efficacy. We designed and synthesized a series of new semisynthetic derivatives of tylosin with 5-O-mycaminosyltylonolide as the mother nucleus, mainly by introducing a variety of amino groups at its C-23 position. Some of the compounds showed high antibacterial activity against Gram-negative and Gram-positive bacteria. These findings indicate that the best compound, c9, possessed significant antibacterial activity (MIC = 0.5 ug/mL), excellent bactericidal efficacy, and a low induction rate of drug resistance against Staphylococcus aureus and Escherichia coli; it also showed good antibacterial activity against drug-resistant bacteria. In addition, compound c9 has a low toxicity in vitro and in vivo. In conclusion, compound c9 could be a potential antimicrobial lead compound that could also contribute to the development of macrolide antibiotics.

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C-23 改性 5-O-Mycaminosyltylonolide 衍生物的设计、合成和活性评估

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.