Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity |
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Authors: | Kinuko Iwasa Yumi Nishiyama Momoyo Ichimaru Masataka Moriyasu Hye-Sook Kim Yusuke Wataya Takao Yamori Turuo Takashi Dong-Ung Lee |
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Institution: | a Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada-ku, Kobe 658-8558, Japan;b Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan;c Division of Experimental Chemotherapy, Cancer Chemotherapy Center, 1-37-1 kamiikebukuro, Toyoshima-ku, Tokyo 170-8455, Japan;d Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 yayoi, bunkyo-ku, Tokyo 113-0000, Japan;e Department of Biochemistry, College of Natural Science, Dongguk University, Kyongju Kyongbuk 780-714, South Korea |
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Abstract: | Seventeen quaternary protoberberine alkaloids related to berberine 1 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the oxygen substituents on rings A, C and D and the position of the oxygen functions on ring D. The position of the oxygen functions on ring D and the type of the oxygen substituents at the C-13 position (ring C) strongly influenced the activity. Shifting the oxygen functions at C-9 and C-10 to C-10 and C-11 on ring D resulted in a significant increase in the activity. Compounds bearing a methylenedioxy function at C-2 and C-3 (ring A) or C-9 and C-10 (ring D) showed higher activity than those which have methoxy groups at the same positions. Introduction of a methoxy group into the C-1 position (ring A) decreased the activity. Replacement of a hydroxy group at C-2 or C-3 (ring A) by a methoxy group led to a reduction in the activity. Displacement of a hydroxy function at C-13 (ring C) by the oxygen substituents such as OMe, OEt, OCOOEt, and OCON(Me)2 reduced the activity. In the same replacement at C-9 (ring D), the activity depended upon the type of the oxygen function. Six protoberberines displayed more potent activity than berberine 1. The activity decreased in the order: 10, 11, 17 and 18 > 7 and 8 > 1. |
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Keywords: | in vitro antimalarial activity structure-activity relationships protoberberinium salts |
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