Discovery and Development of 8-Substituted Cycloberberine Derivatives as Novel Antibacterial Agents against MRSA,ACS Medicinal Chemistry Letters

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Discovery and Development of 8-Substituted Cycloberberine Derivatives as Novel Antibacterial Agents against MRSA
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-16 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00094
Tianyun Fan ₁ , Xinxin Hu ₁ , Sheng Tang ₁ , Xiaojia Liu ₁ , Yanxiang Wang ₁ , Hongbin Deng ₁ , Xuefu You ₁ , Jiandong Jiang ₁ , Yinghong Li ₁ , Danqing Song ₁

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8-Acetoxycycloberberine (2) with a unique skeleton was first identified to display a potent activity profile against Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values of 1–8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial effect. The structure–activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly enhance the potency against MRSA. Among them, compounds 5d and 9e demonstrated equally effective anti-MRSA potency as lead 2, with an advantage of having a more stable pharmacokinetics feature. A preliminary mechanism study indicated that compound 9e acted upon bacteria partly through catalyzing the cleavage of bacterial DNA. Therefore, we consider that 8-substituted CBBR derivatives constitute a promising class of antibacterial agents in the treatment of MRSA infections.

中文翻译：

发现和开发8-取代的小as碱衍生物作为新型抗MRSA抗菌剂

首先鉴定出具有独特骨架的8-乙酰氧基环小ber碱（2），以显示出对革兰氏阳性细菌，特别是耐甲氧西林金黄色葡萄球菌（MRSA）的有效活性谱，其最低抑菌浓度（MIC）值为1-8μg/ mL ，表明可能存在针对细菌的新型作用机制。以2为首，合成了23种新的8-取代的环小ber碱（CBBR）衍生物，包括醚，胺和酰胺，并对其抗菌效果进行了评估。结构-活性关系表明，在8位上引入合适的取代基可以大大增强抗MRSA的能力。其中，化合物5d和9e证明具有与铅2同样有效的抗MRSA效能，并具有更稳定的药代动力学特征。初步的机理研究表明，化合物9e部分通过催化细菌DNA的裂解而对细菌起作用。因此，我们认为8取代的CBBR衍生物构成了治疗MRSA感染的有希望的一类抗菌剂。

更新日期：2018-04-16

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