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Mediation of metal chelation in cysteine-derived tetramate systems
Chemical Science ( IF 8.4 ) Pub Date : 2021-12-02 , DOI: 10.1039/d1sc05542a
Ruirui Zhang 1 , Miroslav Genov 2 , Alexander Pretsch 2 , Dagmar Pretsch 2 , Mark G Moloney 1, 3
Affiliation  

A study of bicyclic tetramates modified with a bulky ester, which leads to steric hindrance of distal chelating atoms as a route for the alteration of metal binding ability is reported. This approach required the development of a direct method for the synthesis of different esters of cysteine from cystine, which then provided access to bicyclic tetramates by Dieckmann cyclisation. Further derivation to ketones and carboxamides by Grignard addition and transamination reactions respectively provided rapid access to a chemical library of tetramates with diverse substitution. Of interest is that bicyclic tetramate ketones and carboxamides showed different tautomeric and metal binding behaviour in solution. Significantly, in both systems, the incorporation of bulky C-5 esters at the bridging position not only reduced metal binding, but also enhanced antibacterial potencies against Gram-positive MRSA bacteria. Those tetramates with antibacterial activity which was not metal dependent showed physiochemical properties of MSA of 559–737 Å2, MW of 427–577 Da, clogP of 1.8–6.1, clogD7.4 of −1.7 to 3.7, PSA of 83–109 Å2 and relative PSA of 12–15% and were generally Lipinski rule compliant. A subset of tetramates exhibited good selectivity towards prokaryotic bacterial cells. Given that the work reported herein is synthesis-led, without the underpinning detailed mechanistic understanding of biological/biochemical mechanism, that the most active compounds occupy a small region of chemical space as defined by MW, clogP, PSA and %PSA is of interest. Overall, the bicyclic tetramate template is a promising structural motif for the development of novel antibacterial drugs, with good anti-MRSA potencies and appropriate drug-like physiochemical properties, coupled with a potential for multi-targeting mechanisms and low eukaryotic cytotoxicity.

中文翻译:

半胱氨酸衍生的四酸盐系统中金属螯合的介导

报道了用大体积酯修饰双环四酸酯的研究,该研究导致远端螯合原子的空间位阻作为改变金属结合能力的途径。这种方法需要开发一种直接的方法,用于从胱氨酸合成不同的半胱氨酸酯,然后通过 Dieckmann 环化获得双环四酸酯。分别通过格氏加成和氨基转移反应进一步推导酮和甲酰胺提供了快速访问具有不同取代的 tetramates 的化学库。有趣的是,双环四酸酯酮和羧酰胺在溶液中表现出不同的互变异构和金属结合行为。值得注意的是,在这两个系统中,在桥接位置加入庞大的 C-5 酯不仅减少了金属结合,而且还增强了对革兰氏阳性 MRSA 细菌的抗菌效力。那些具有抗菌活性且不依赖金属的四联苯胺的 MSA 理化性质为 559-737 Å2,MW 427-577 Da,clogP 1.8-6.1,clogD 7.4 -1.7 至 3.7,PSA 83-109 Å 2和 12-15% 的相对 PSA,并且通常符合 Lipinski 规则。一个四甲酸盐子集对原核细菌细胞表现出良好的选择性。鉴于本文报道的工作是合成主导的,没有对生物/生化机制的详细机械理解的支持,最活跃的化合物占据由 MW、clogP、PSA 和 %PSA 定义的化学空间的小区域是令人感兴趣的。总体而言,双环四酸酯模板是开发新型抗菌药物的有前途的结构基序,具有良好的抗 MRSA 效力和适当的药物样理化特性,以及多靶向机制和低真核细胞毒性的潜力。
更新日期:2021-12-02
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