Imamori K, Asaoka T, Matsumoto M, Maebashi K, Matsuda H, Tahara Y
United Graduate School of Agricultural Sciences, Gifu University, (Shizuoka University).
Jpn J Antibiot. 1995 Dec;48(12):1891-8.
A number of new quinolone antibacterial agents such as ofloxacin, norfloxacin, ciprofloxacin and sparfloxacin have been developed and introduced to the market. They possess a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Ciprofloxacin has the highest activity against Gram-positive is higher than other quinolones. The activity of these quinolones against Gram-negative bacteria is generally higher than against Gram-positive bacteria. The substitution group of quinolones at C-7 position is responsible to show similar antibacterial activity with broad spectrum and similar pharmacokinetic properties, and variety of the substituents have been synthesized in many laboratories. Most of the substituents are piperazinyl of six-membered ring or pyrrolidinyl of five-membered ring, being modified with an alkyl group or another group. The development of potent quinolones against bacteria involved in pneumonia was seemed to be useful, and we investigated structure-activity relationships of new quinolones with a stronger activity against Gram-positive bacteria. A quinolone derivative with a seven-membered ring, perhydrodiazepinone, at the C-7 position was found to be a candidate for further evaluation. No previous attempts have been made to synthesize this type of derivatives. The compound FA103, 5-amino-1-cyclopropyl-6,8-difluoro-7-(2,3,4,5,6,7-hexahydro-1 H-1,4-diazepin-5-on-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, was synthesized and evaluated. Chemical structure of FA103 is shown in Fig. 1. This is a new difluoroquinolone with a broad antibacterial spectrum and improved activity against Gram-positive bacteria. In this paper, we compare the in vitro activity of FA103 with that of ofloxacin, norfloxacin, sparfloxacin against Gram-positive and Gram-negative bacteria.
一些新型喹诺酮类抗菌剂，如氧氟沙星、诺氟沙星、环丙沙星和司帕沙星已被研发并投放市场。它们对革兰氏阳性菌和革兰氏阴性菌具有广谱活性。环丙沙星对革兰氏阳性菌的活性最高，高于其他喹诺酮类药物。这些喹诺酮类药物对革兰氏阴性菌的活性通常高于对革兰氏阳性菌的活性。喹诺酮类药物在C-7位的取代基负责表现出具有广谱抗菌活性和相似药代动力学性质，许多实验室已经合成了多种取代基。大多数取代基是六元环的哌嗪基或五元环的吡咯烷基，并被烷基或其他基团修饰。研发对引起肺炎的细菌有效的喹诺酮类药物似乎很有用，我们研究了对革兰氏阳性菌具有更强活性的新型喹诺酮类药物的构效关系。发现一种在C-7位带有七元环、全氢二氮杂卓酮的喹诺酮衍生物是进一步评估的候选物。此前尚未有人尝试合成这类衍生物。合成并评估了化合物FA103，即5-氨基-1-环丙基-6,8-二氟-7-(2,3,4,5,6,7-六氢-1H-1,4-二氮杂卓-5-酮-1-基)-1,4-二氢-4-氧代喹啉-3-羧酸。FA103的化学结构如图1所示。这是一种新型二氟喹诺酮，具有广谱抗菌活性且对革兰氏阳性菌的活性有所提高。在本文中，我们比较了FA103与氧氟沙星、诺氟沙星、司帕沙星对革兰氏阳性菌和革兰氏阴性菌的体外活性。
