Mitscher L A, Sharma P N, Chu D T, Shen L L, Pernet A G
J Med Chem. 1986 Oct;29(10):2044-7. doi: 10.1021/jm00160a042.
New quinolone antimicrobial agents (racemic, (1'S,2'R)- and (1'R,2'S)-6-fluoro-7-(1-piperazinyl)-1-(2'-trans-phenyl-1'-cyclopropyl)- 1, 4-dihydro-4-oxoquinoline-3-carboxylic acids) were synthesized, and their in vitro antimicrobial potencies and spectra were determined. As compared to their conceptual parents, these agents retained a considerable amount of the antimicrobial potency and spectra of ciprofloxacin and of 6-fluoro-1-phenyl-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxy lic acid against Gram-positives. Gram-negatives were considerably less sensitive. The (-)-(1'S,2'R) analogue was the more potent of the enantiomers, but the degree of chiral discrimination by most bacteria was only 4-fold. The 4-fold chiral discrimination was observed also using purified DNA gyrase obtained from Micrococcus luteus, whereas the two enantiomers were essentially equiactive against the enzyme derived from Escherichia coli. These results confirm that there is a substantial degree of bulk tolerance available at N-1 of quinolone antimicrobial agents and suggest that electronic factors controlled by substitution at that site are of considerable importance. On the other hand, chiral recognition brought about by attachment of optically active groups to the N-1 position in these derivatives is relatively small.
合成了新型喹诺酮类抗菌剂（外消旋体、(1'S,2'R)-和(1'R,2'S)-6-氟-7-(1-哌嗪基)-1-(2'-反式苯基-1'-环丙基)-1,4-二氢-4-氧代喹啉-3-羧酸），并测定了它们的体外抗菌效力和谱。与它们的概念母体相比，这些药剂对革兰氏阳性菌保留了相当数量的环丙沙星和6-氟-1-苯基-7-(1-哌嗪基)-1,4-二氢-4-氧代喹啉-3-羧酸的抗菌效力和谱。革兰氏阴性菌的敏感性则低得多。(-)-(1'S,2'R)类似物是对映体中效力更强的，但大多数细菌的手性识别程度仅为4倍。使用从藤黄微球菌获得的纯化DNA促旋酶也观察到了4倍的手性识别，而这两种对映体对源自大肠杆菌的酶基本上具有同等活性。这些结果证实，喹诺酮类抗菌剂的N-1位存在相当程度的体积耐受性，并表明该位点取代所控制的电子因素相当重要。另一方面，这些衍生物中光学活性基团连接到N-1位所带来的手性识别相对较小。
