Hong C Y, Kim Y K, Chang J H, Kim S H, Choi H, Nam D H, Kim Y Z, Kwak J H
Biotech Research Institute, Yu-Sung, Tae-Jon, Korea.
J Med Chem. 1997 Oct 24;40(22):3584-93. doi: 10.1021/jm970202e.
New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
已合成了在吡咯烷环的4-位带有烷氧基肟取代基且在3-位带有氨甲基取代基的新型吡咯烷衍生物，并将其与各种喹啉羧酸偶联以制备一系列新型氟喹诺酮抗菌剂。发现这些氟喹诺酮对革兰氏阴性和革兰氏阳性菌均具有强效抗菌活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）。喹啉核C-8位的取代基变化包括氟、氯、氮、甲氧基和氢原子取代。对于革兰氏阳性菌，C-8取代基赋予取代喹啉核的活性顺序为F（C5-NH2）＞F（C5-H）＞萘啶＞Cl = OMe = H。对于革兰氏阴性菌株，活性顺序为F（C5-NH2）＞萘啶 = F（C5-H）＞H＞Cl＞OMe。通过将喹诺酮新引入的肟基与去氧肟基化合物30进行比较，清楚地证明了其优势。此外，肟部分极大地改善了新型喹诺酮的药代动力学参数。在这些化合物中，化合物20（LB20304）在动物体内显示出最佳的体内疗效和药代动力学特征，以及良好的物理性质。LB20304、化合物30和环丙沙星对几种测试菌的最低抑菌浓度（微克/毫升）如下：金黄色葡萄球菌6538p（0.008、0.031和0.13）、耐甲氧西林金黄色葡萄球菌241（4、16和128）、表皮葡萄球菌887E（0.008、0.016和0.13）、耐甲氧西林表皮葡萄球菌178（4、32和128）、粪肠球菌29212（0.063、0.13和1）、铜绿假单胞菌1912E（0.25、0.5和0.13）、大肠杆菌3190Y（0.008、0.016和0.008）、阴沟肠杆菌P99（0.008、0.031和0.008）、醋酸钙不动杆菌15473（0.063、0.13和0.25）。基于这些有前景的结果，LB20304被选为进一步评估的候选物。
