4-Substituted D-glutamic acid analogues:: The first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity
4-Substituted D-glutamic acid analogues:: The first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity
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DOI：
10.1021/jm020901d
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发表时间：
2002-09-26
影响因子：
7.3
通讯作者：
Smith, MC
中科院分区：
文献类型：
--
作者：
de Dios, A;Prieto, L;Smith, MC
描述了第一个显示全细胞抗菌活性的谷氨酸消旋酶（MurI）的有效抑制剂。具有（2 R，4S）立体化学并带有芳基-、杂芳基-、肉桂基-或联芳基-甲基取代基的光学纯的4-取代的D-谷氨酸类似物代表一类新的谷氨酸消旋酶抑制剂。对D-Glu核心的探索导致了先导化合物（-）-8和10的鉴定。2-发现萘甲基衍生物10是谷氨酸消旋酶活性的有效竞争性抑制剂（Ki = 16 nM，圆二色性测定; IC 50 = 0.1 μ g/mL高效液相色谱（HPLC）测定）。彻底的结构-活性关系（SAR）研究导致苯并噻吩衍生物如69和74具有增加的效力（IC 50分别= 0.036和0.01 μ g/mL，HPLC测定）。这些化合物对沙门氏菌具有较强的全细胞抗菌活性。pneumoniae PN-R6，与酶活性测定结果具有良好的相关性。化合物69、74和联芳基衍生物52在体内鼠大腿感染模型中显示出抗肺炎链球菌的功效。本文描述的数据表明谷氨酸消旋酶可能是开发新抗菌剂的可行靶标。
The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (K-i = 16 nM, circular dichroism assay; IC50 = 0.1 mug/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC50 = 0.036 and 0.01 mug/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.