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 in vivo efficacy
| العنوان: | 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 in vivo efficacy |
|---|---|
| المؤلفون: | Edgardo Laborde, Steven VanderRoest, Mel C. Schroeder, John S. Kiely, Mark J. Suto, Themis E. Joannides, John M. Domagala, Martin A. Shapiro, Josephine A. Sesnie, Susan Elizabeth Hagen |
| المصدر: | Journal of Medicinal Chemistry. 36:871-882 |
| بيانات النشر: | American Chemical Society (ACS), 1993. |
| سنة النشر: | 1993 |
| مصطلحات موضوعية: | Pyrrolidines, Stereochemistry, Microbial Sensitivity Tests, Mice, Structure-Activity Relationship, Cricetulus, Anti-Infective Agents, In vivo, Cricetinae, Drug Discovery, Animals, Topoisomerase II Inhibitors, Moiety, Structure–activity relationship, Naphthyridines, Antibacterial agent, 4-Quinolones, Bicyclic molecule, Chemistry, Stereoisomerism, Biological activity, Molecular Medicine, Female, Phototoxicity, Antibacterial activity, Fluoroquinolones |
| الوصف: | A series of stereochemically pure 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1, 4-dihydro-4-oxoquinoline and 1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, were synthesized to study the effects of the 7-[3-(1-aminoethyl)-1- pyrrolidinyl] moiety on potency and in vivo efficacy relative to the known 7-[3-(aminomethyl)-1- pyrrolidinyl] derivatives. The antibacterial efficacies of the target compounds and their relevant reference agents were determined in vitro using an assortment of Gram-negative and Gram-positive organisms and in vivo using Escherichia coli and Streptococcus pyogenes mouse infection models. The effects of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] moiety were also examined at the level of the target enzyme by employing a DNA-gyrase supercoiling inhibition assay. Selected compounds were further evaluated for potential phototoxic and clastogenic liabilities using a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity assay. It was found that the differences in in vitro antibacterial activity between the stereoisomers were significantly greater than previously reported for other optically pure 3-substituted pyrrolidinyl side chains. Relative to their 7-[3-(aminomethyl)-1-pyrrolidinyl] analogs, the (3R,1S)-3-(1-aminoethyl)pyrrolidines generally conferred a 2-4-fold increase in Gram-positive in vitro activity and an average of 10-fold improvement in oral efficacy. The level of phototoxicity and cytotoxicity of the product quinolones was ultimately determined by the combined influence of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] side chains and the other quinolone substituents. From this study, several compounds were identified with outstanding antibacterial activity and low degrees of phototoxicity and mammalian cell cytotoxicity. One such agent, 34F-R,S (PD 140248), showed the best overall blend of safety and efficacy. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00059a012 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9465083060745813bc27d18171a3041b https://doi.org/10.1021/jm00059a012 |
| رقم الانضمام: | edsair.doi.dedup.....9465083060745813bc27d18171a3041b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
|---|---|
| DOI: | 10.1021/jm00059a012 |