The synthesis and antibacterial activity of totarol derivatives. Part 1: Modifications of ring-c and pro-drugs
The synthesis and antibacterial activity of totarol derivatives. Part 1: Modifications of ring-c and pro-drugs
复制标题
DOI：
10.1016/s0968-0896(99)00162-5
复制
发表时间：
1999-09-01
影响因子：
3.5
通讯作者：
Scott, GK
中科院分区：
文献类型：
--
作者：
Evans, GB;Furneaux, RH;Scott, GK
为了阐明抗菌活性的最低结构要求和寻找具有良好体内生物利用度的化合物，合成了一系列有效抗菌二萜托他洛尔（1）的类似物和潜在的前药。这些类似物的芳环结构特征不同，前药为O-糖基化衍生物。在体外对三种革兰氏阳性菌进行了检测：β-内酰胺酶阳性和高水平庆大霉素耐药粪肠球菌、青霉素耐药肺炎链球菌和甲氧西林耐药金黄色葡萄球菌（MRSA）;以及革兰氏阴性多重耐药肺炎克雷伯菌。这些类似物中没有一种比totarol本身更有效，totarol在MIC值为7 μ M时对这些革兰氏阳性菌有效。结果进行了评价的构效关系，这表明，酚部分是必不可少的有效的抗菌活性。在前药中，证明了对甲苯基α-D-吡喃甘露糖苷（22）在体外最具活性（MIC 18 μ M）。在小鼠感染模型中评估化合物1、22和Totarol β-乳糖苷（23）的体内抗菌活性，但发现它们无效。化合物1和22显示对增殖的人细胞培养物CH 2983、HeLa和MG 63具有细胞毒性，但仅在> 30 μ M的浓度下。(C)1999 Elsevier Science Ltd.保留所有权利。
A series of analogues of, and potential pro-drugs derived from, the potent antibacterial diterpene totarol (1) were synthesized in order to elucidate the minimum structural requirements for antibacterial activity and to seek compounds with good bioavailability in vivo. These analogues varied in the structural features of their aromatic rings and the prodrugs were O-glycosylated derivatives. They were tested in vitro against three Gram-positive bacteria: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus (MRSA); and against the Cram-negative multi-drug-resistant Klebsiella pneumoniae. None of the analogues was more potent than totarol itself, which is effective against these Gram-positive bacteria at MIC values of 7 mu M. The results were evaluated in terms of a structure-activity relationship and this showed that a phenolic moiety was essential for potent antibacterial activity. Amongst the pro-drugs, totaryl alpha-D-mannopyranoside (22) proved the most active in vitro (MIC 18 mu M). The in vivo antibacterial activities of compounds 1, 22 and totarol beta-lactoside (23) were assessed in a mouse model of infection, but they were found to be ineffective. Compounds 1 and 22 were shown to be cytotoxic towards proliferating human cell cultures, CH 2983, HeLa, and MG 63, but only at concentrations of > 30 mu M. (C) 1999 Elsevier Science Ltd. All rights reserved.