Synthesis and Antimicrobial Evaluation of Fluoroquinolone Derivatives
| Autor: | Jia-Yuh Sheu, 許嘉裕 |
|---|---|
| Rok vydání: | 2004 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 92 Certain fluoroquinolone derivatives were synthesized and evaluated for antibacterial, antimycobacterial, and cytotoxic activities. The antibacterial activities of fluoroquinolones are related to inhibition of DNA gyrase and topoisomerase IV (topo IV). In general, DNA gyrase is more sensitive in G(-)-bacteria while topo IV is more sensitive in G(+)-bacteria, and the more sensitive enzyme represents the primary drug target. Fluoroquinolones such as norfloxacin, ofloxacin, ciprofloxacin, and temafloxacin are active against not only bacteria but also Mycobacterium tuberculosis infection which provides a wide clinical application. Temafloxacin was a clinically useful anti-TB drug but was withdrawn because of severe toxicity. The purpose of this dissertation is to modify the structure of temafloxacin to improve its anti-TB potency and to decrease its toxicity. Preliminary results indicated (1) for 1-substituted benzyl derivatives, the fluoro group substituted at 4''-position possesses the most potent antibacterial activity; (2) 1-aryl 6-fluoroquinolons, both 7-piperazinyl and 7-(4-methyl)piperazinyl derivatives, are able to completely inhibit the growth of M. tuberculosis at a concentration of 6.25 μg/ml, while the 7-[4-(2-oxo-2-phenylethyl)-piperazin-1-yl]- counterpart, exhibits only marginal growth inhibition at the same concentration; (3) for 1-ethyl 6-fluoroquinolones, both 7-[4-(2-oxopropyl)piperazin-l-yl]- and 7-[4-(2- oxo-2-phenylethyl)piperazin-l-yl]-derivatives, show complete inhibition while their 2-iminoethyl and substituted phenyl counterparts are less active. In addition, the 6,8-difluoro derivative was a more favorable inhibitor than its 6-fluoro counterpart; (4) compound 18a proved to be a potent anti-TB agent with the selective index (SI) > 40 and an EC90 value of 5.75 μg/ml. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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