Chu D T, Fernandes P B, Claiborne A K, Shen L, Pernet A G
Anti-infective Research Division, Abbott Laboratories, Abbott Park, IL 60064.
Drugs Exp Clin Res. 1988;14(6):379-83.
Over the past years it was found that modification of the 3-carboxylic acid group of quinolones generally produced compounds with a substantial decrease in antibacterial activity. The 3-carboxylic acid moiety together with the 4-carbonyl function are believed to be the most structurally critical sites for this class of compounds to DNA gyrase. The authors have designed and synthesized a series of quinolone analogues in which the 3-carboxylic acid group has been modified. These compounds, 2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-diones, possess biological activities far superior to their parent counterparts. For example, the MICs (microgram/ml) for A-62824 (ciprofloxacin 3-carboxylic acid modified analogue) and ciprofloxacin against some organisms are as follows: S. aureus ATCC 6538P (0.02, 0.2); S. epidermidis 3519 (0.05, 0.2); E. coli Juhl (0.005, 0.01); P. aeruginosa A5007 (0.05, 0.1) and Acinetobacter sp. CMX 699 (0.05, 0.78). This investigation has produced the first successful modification of the 3-carboxylic acid group of quinolones resulting in a series of extremely potent antibacterials. The design and synthesis as well as the biological activities of these new derivatives are described.
在过去几年中发现，喹诺酮类药物3 - 羧酸基团的修饰通常会产生抗菌活性大幅降低的化合物。3 - 羧酸部分与4 - 羰基官能团被认为是这类化合物作用于DNA促旋酶的最关键结构位点。作者设计并合成了一系列3 - 羧酸基团已被修饰的喹诺酮类似物。这些化合物，即2,3,4,9 - 四氢异噻唑并[5,4 - b]喹啉 - 3,4 - 二酮，具有远优于其母体化合物的生物活性。例如，A - 62824（环丙沙星3 - 羧酸修饰类似物）和环丙沙星对某些微生物的最低抑菌浓度（微克/毫升）如下：金黄色葡萄球菌ATCC 6538P（0.02，0.2）；表皮葡萄球菌3519（0.05，0.2）；大肠杆菌Juhl（0.005，0.01）；铜绿假单胞菌A5007（0.05，0.1）和不动杆菌属CMX 699（0.05，0.78）。这项研究首次成功地对喹诺酮类药物的3 - 羧酸基团进行了修饰，从而得到了一系列极具强效的抗菌药物。本文描述了这些新衍生物的设计与合成以及生物活性。
