氟喹諾酮衍生物之合成及抗菌活性評估

Synthesis and Antimicrobial Evaluation of Fluoroquinolone Derivatives

許嘉裕(Jia-Yuh Sheu)

指導教授 ： 曾誠齊

高雄醫學大學/藥學院/藥學研究所/博士(2005年)

摘要

氟喹諾酮類fluoroquinolones是人工合成的含氟的4-喹諾酮基本結構，其對革蘭氏陰性菌活性取決於DNA- gyrase的抑制作用，而對革蘭氏陽性菌的活性，則和DNA-topoisomerase IV酵素的抑制作用有關之具有選擇性抑制作用的抗菌藥物。
氟喹諾酮類藥物中如norfloxacin、ofloxacin、ciprofloxacin及temafloxacin也有許多具較強的抗結核分支桿菌活性，對非結核分支桿菌（鳥胞分支桿菌複合群除外）亦有作用，為臨床治療開拓了更為廣闊的前景。由於結核分支桿菌對氟喹諾酮產生自發突變率很低，為1/106∼107，與其他抗結核藥之間無交叉耐藥性，目前這類藥物已成為耐藥結核病的主要選用對象。所以氟喹諾酮類藥物目前發展迅速，臨床廣為使用。然致病菌耐藥性發展也較快，給臨床上造成了較嚴重的威脅。
其中temafloxacin曾為上市之藥物，然因毒性問題而下市。因此，本計畫初步構想即是以temafloxacin為修飾對象，期以增加其親脂性以利滲透細菌細胞內，而達降低其毒性之下，仍能維持其抗菌活性甚至提高活性之目的。
由合成的1-(Substituted aryl)-6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid 中，評估其抗菌活性及細胞毒性初步結果發現：
(1)N-1為不同取代基的benzyl化合物10、11、12系列，雖不具抗菌活性，但其中以F取代的benzyl (63g) 抗菌活性較高。
(2) N-1為不同取代基的phenyl化合物16a、18a以及C-7的piperazine上有p-fluoro和p-methoxy取代的acetophenone 化合物54c、54e、55e、57系列，其中化合物16a、18a、55e對S. aureus M-R、S. pneumoniae E&A-R均具抗菌活性化合物。54e對S. aureus M-R具低毒性高選擇性。57則明顯的具較norfloxacin低毒性高抗菌活性。
(3) N-1為不同取代基的phenyl以及C-7的piperazine上有p-fluoro和p-methoxy取代的oxime化合物58c、58e、59e、61系列中，p-methoxy、N-1位置 2’fluoro取代可提高抗菌活性，其中N-1位置 4’-nitro-2’fluoro取代(59e)活性最好，甚至較norfloxacin強達1.8-14倍之多。
(4)且將一系列的fluoroquinolone衍生物評估其抗肺結核活性及細胞毒性初步結果發現：化合物18a表現出低毒性高選擇性(18a,MIC (MtbH37Rv)=1.56μg/mL, SI＞40.06, EC90= 5.75)的抗結核能力。

關鍵字

氟喹諾酮 ； 抗菌

並列摘要

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 Temafloxacin was a clinically useful anti-TB drug but was withdrawn because of severe toxicity.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.

並列關鍵字

Fluoroquinolone ； Antimicrobial

參考文獻

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