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

被引:12
作者
HAGEN, SE
DOMAGALA, JM
GRACHECK, SJ
SESNIE, JA
STIER, MA
SUTO, MJ
机构
[1] Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
关键词
D O I
10.1021/jm00032a005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:733 / 738
页数:6
相关论文
共 26 条
  • [1] Chu D. T. W., 1991, ADV DRUG RES, V21, P39
  • [2] SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW ARYLFLUORONAPHTHYRIDINE ANTIBACTERIAL AGENTS
    CHU, DTW
    FERNANDES, PB
    CLAIBORNE, AK
    GRACEY, EH
    PERNET, AG
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (11) : 2363 - 2369
  • [3] INVITRO ACTIVITY OF CI-934, A QUINOLONE CARBOXYLIC-ACID ACTIVE AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
    COHEN, MA
    GRIFFIN, TJ
    BIEN, PA
    HEIFETZ, CL
    DOMAGALA, JM
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1985, 28 (06) : 766 - 772
  • [4] ENANTIOMERS OF 1-ETHYL-7-[3-[(ETHYLAMINO)METHYL]-1-PYRROLIDINYL]-6,8-DIFLUORO-1,4-DIHYDRO-4-OXO-3-QUINOLINE-CARBOXYLIC ACID - PREPARATION AND BIOLOGICAL-ACTIVITY
    CULBERTSON, TP
    DOMAGALA, JM
    NICHOLS, JB
    PRIEBE, S
    SKEEAN, RW
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (10) : 1711 - 1715
  • [5] CULBERTSON TP, 1989, QUINOLONES, P47
  • [6] QUINOLONE ANTIBACTERIALS CONTAINING THE NEW 7-[3-(1-AMINOETHYL)-1-PYRROLIDINYL] SIDE-CHAIN - THE EFFECTS OF THE 1-AMINOETHYL MOIETY AND ITS STEREOCHEMICAL CONFIGURATIONS ON POTENCY AND INVIVO EFFICACY
    DOMAGALA, JM
    HAGEN, SE
    JOANNIDES, T
    KIELY, JS
    LABORDE, E
    SCHROEDER, MC
    SESNIE, JA
    SHAPIRO, MA
    SUTO, MJ
    VANDERROEST, S
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (07) : 871 - 882
  • [7] GRACHECK SJ, 1991, 31ST INT C ANT AG CH
  • [8] HAGEN S, 1991, 31ST INT C ANT AG CH
  • [9] NEW QUINOLONE ANTIBACTERIAL AGENTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF 7-(3,3 OR 3,4-DISUBSTITUTED-1-PYRROLIDINYL)QUINOLINE-3-CARBOXYLIC ACIDS
    HAGEN, SE
    DOMAGALA, JM
    HEIFETZ, CL
    SANCHEZ, JP
    SOLOMON, M
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (02) : 849 - 854
  • [10] HAGEN SE, 1992, 204TH M AM CHEM SOC