流行性感冒在近百年來是常見且對人類健康有著重大威脅的疾病,目前瑞樂沙、克流感以及帕拉米弗為抑制神經胺酸酶主要藥物,然而,帕拉米弗進入人體後能被生物吸收利用的效率太差(2~3%),導致它只能透過靜脈注射方式投藥,本論文針對帕拉米弗生物等配體進行合成及活性測試。 在本研究內容中,將羧酸官能基用具有拉電子效果的磺胺類生物等配體以及三唑類生物等配體作取代,期望可以增加此部份與神經胺酸酶Arg118、Arg292以及Arg371活性區域的離子作用力。 利用文獻報導之合成帕拉米弗的方法為基礎,成功合成出磺胺類化合物18、22以及26與三唑化合物31。生物活性測試的結果顯示,不管是針對神經胺酸酶抑制性(IC50)或是抗流感活性(EC50)都沒有好的效果,本論文的研究能夠提供合成peramivir相關衍生物的有效方法,並提供設計生物等配物官能基的參考。
Influenza is a major threat to human health. Currently, zanamivir (Relenza), oseltamivir (Tamiflu) and peramivir (Rapiacta) are the main anti-influenza drugs to inhibit the viral neuraminidases. However, the bioavailability of peramivir is pretty low (2–3%), so that it can only be administered by intravenous injection. This thesis is aimed to the synthesis and bioassay of peramivir bioisosteres. In this study, the electron-withdrawing groups, such as sulfonamide and triazole are used as the bioisosteres of carboxylic acid. These functional groups are expected to increase the ionic interactions with the Arg118, Arg292 and Arg371 residues in the neuraminidase active region. According to the previously reported synthesis of peramivir and our modified procedure, the sulfonamide compounds 18, 22 and 26 as well as triazole compound 31 were synthesized and submitted for bioassay. Unfortunately, these compounds showed no neuraminidase inhibition (IC50) or anti-influenza activity (EC50). This study provides an effective method for synthesis of peramivir bioisosteres. This study can also serve as a reference for designing drug bioisosteres.
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