中文摘要 7-

7- 羥基香豆素與 3- 羧酸基香豆素衍生物之合成及抗菌活性評估之研究

Synthesis and antibacterial activities evaluation of 7-hydroxycoumarin and coumarin-3-carboxamide derivatives

中文摘要

7-羥基香豆素與 3-羧酸基香豆素衍生物之合成及 抗菌活性評估之研究

香豆素 (coumarin) 廣泛存在於植物，目前已有許多合成之香豆素衍生物應用於染料、食品添 加劑及多種醫療用途，近年來香豆素在醫藥之研究上具重要角色，例如抗凝血之雙香豆素、抗 病毒、抗細菌、抗真菌、抗腫瘤、抗致癌、抗發炎、抗氧化、降血脂，也可做為軟骨移植之前驅藥物。

在體內香豆素之代謝物以7-羥基香豆素 (7-hydroxy coumarin) 為主，而抗生素

novobiocin、chlorobiocin 與 coumerymycin A1 在第 7 位碳上有取代，第 3 位碳上為醯胺，

醯胺旁邊接有取代之苯環或為雙體，也有文獻報導coumarin dimer 有抗病毒之作用，因此本 研究合成三系列之香豆素衍生物，一方面以7-羥基香豆素為起始物，與活化之氮丙啶 (N- activated aziridin) 合成衍生物，另外一方面以 3-羧酸基香豆素 (coumarin-3-carboxylic acid) 與烷基雙胺類 (alkyldiamine) 反應形成雙 3-羧酸基香豆素醯胺，[bis-(3-coumaric acid)-alkylene diamide]，或將 3-羧酸基香豆素與胺基苯胺 (aminobenzylamine) 形成 3- 羧酸基香豆素苯醯胺 (coumarin 3-carboxylic acid amino-benzylamide)，以上所有合成 之化合物之物性與化性均以核磁共振儀測定其結構，質譜儀、高解析質譜儀測定其分子量，紅 外線光譜儀測定部分官能基團並測定熔點。

本實驗之抗菌試驗是採用本實驗室自行建立之改良式微量藥物感受性試驗法(modified microplate antibiotic susceptibility test method, MMAST)，比傳統之方法方便、快速與 準確，而且所需之樣品只要微量，在24 小時內就可獲得結果，故本試驗可以提供小量之合成 或天然之化合物檢品，同時進行多種細菌之藥物感受性試驗之新方法；雖然本研究合成之化合 物1-20 均無明顯之抗菌作用，但可以作為將來合成其他抗菌性香豆素衍生物之參考，也可將 化合物1-20 嘗試抗凝血、抗腫瘤、抗病毒等其他生物活性之評估。

英文摘要

Synthesis and antibacterial activities evaluation

of 7-hydroxycoumarin and coumarin-3-carboxamide derivatives

Coumarin is widely distributed in plants and the coumarin derivatives are used as fluorescence dye, laser dye, food additives and medicines at present. Nowadays coumarins are an important group of organic compounds that are used as anticoagulant (dicoumarol), antiviruses, antibacterial, antifungi, antitumor,

antimutagenic, anti-inflammatory and antioxidant agents. It also use as prodrug in cartilage explants.

The major metabolite of coumarin is 7-hydroxy coumarin and the antiviruses effect of

coumarin dimer present in previous studies. The structure of antibiotic novobiocin, chlorobiocin, and coumerymycin A1 which possess amide group on C-3 and substituted on C-7. Three serious of coumarin derivatives were synthesized from 7- hydroxy coumarin and coumarin 3-carboxylic acid in this study. First, we used 7- hydroxycoumarin and N-activated aziridines, a class of compounds important in both chemical synthesis and in chemotherapy of cancer, as starting materials to synthesize 7-hydroxycoumarin derivatives. Second, we used coumarin-3-carboxylic acid and alkyl diamine to synthesize coumarin-3-carboxamide dimer, Bis-(3-coumaric acid)- alkylene diamide. Coumarin 3-carboxylic acid amino-benzylamide was also

synthesized by coumarin-3-carboxylic acid and aminobenzylamine. The physical and chemical characteristics of the synthesized compound 1-20 were measured by 1H- NMR, 13C-NMR, IR, EI Mass, HRMS spectrometry, and melting point dector.

In this study, we used a new modified microplate antibiotic susceptibility test method

(MMAST), which is more convenient, rapid and accurate than before. Only minute

sample required for this test and the results obtained within 24 hours. Though there is

no obvious antibacterial effect of the all tested compounds. The other biological

evaluation will be tried again such as antiplatelet, antitumor, or antiviruses activities

in the further study.