Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential.
Synthesis and antibacterial activity of new quinolones containing a 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] moiety. Gram-positive agents with excellent oral activity and low side-effect potential.
复制标题
含有7-[3-(1-氨基-1-甲基乙基)-1-吡咯烷基]部分的新型喹诺酮类药物的合成和抗菌活性。
DOI：
10.1021/jm00032a005
复制
发表时间：
1994
影响因子：
7.3
通讯作者：
M. Suto
中科院分区：
文献类型：
--
作者：
S. Hagen;J. Domagala;S. Gracheck;J. Sesnie;M. Stier;M. Suto
制备了一系列7-[3-（1-氨基-1-甲基乙基）-1-吡咯烷基]-1,4-二氢-4-氧喹啉-和1,8-萘啶-3-羧酸的R和S异构体，以确定吡咯烷基部分远端氮相邻的两个甲基对效价的影响。这些二甲基化衍生物的抗菌效果与相关的7-[3-（氨基乙基）-1-吡咯烷基]母体化合物和7-[3-（氨基乙基）-1-吡咯烷基]类似物进行了比较。在体外用革兰氏阴性和革兰氏阳性生物进行活性测定，在体内用小鼠感染模型进行活性测定。然后在光毒性小鼠模型和体外哺乳动物细胞毒性方案中筛选选定的衍生物的潜在副作用。结果表明，与S异构体相比，R异构体的体外活性高2-20倍，体内活性高2-15倍。虽然在体外与7-[3-（氨基乙基）-1-吡罗烷基]母体化合物具有相同的效力，但7-[3-（1-氨基-1-甲基乙基）-1-吡罗烷基]类似物的R异构体在体内的效力显著增加，特别是通过口服给药途径。这些相同的R异构体似乎也具有较低的光毒性和细胞毒性风险。这种优异的体内性能与低程度的光毒性和哺乳动物细胞毒性的结合推荐这些药物进行进一步的研究。在这些药物中，萘啶16-R代表了效力和安全性的最佳组合。
A series of the R and S isomers of 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline- and 1,8-naphthyridine-3-carboxylic acids was prepared to determine the effect on potency of the two methyl groups adjacent to the distal nitrogen in the pyrrolidinyl moiety. The antibacterial efficacy of these dimethylated derivatives was compared to the relevant 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds and, to a lesser extent, the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] analogues. The activity of the title and reference compounds was assayed in vitro using an array of Gram-negative and Gram-positive organisms and in vivo using a mouse infection model. Selected derivatives were then screened for potential side effects in a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity protocol. The results showed that the R isomer displayed a 2-20-fold advantage in activity in vitro and a 2-15-fold advantage in vivo over the S isomer. Although equipotent to the 7-[3-(aminomethyl)-1-pyrrolidinyl] parent compounds in vitro, the R isomers of the 7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl] analogues showed a dramatic increase in in vivo potency, especially via the oral route of administration. These same R isomers also appeared to possess a reduced risk of phototoxicity and cytotoxicity. This combination of superior in vivo performance with a low degree of phototoxicity and mammalian cell cytotoxicity recommends these agents for further study. Of these agents, naphthyridine 16-R represents the optimal blend of potency and safety.