Toosendanin relatives, trypanocidal principles from Meliae Cortex
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ORIGINAL PAPER
Toosendanin relatives, trypanocidal principles from Meliae Cortex Michel N. Mifundu1,2 · Nobutoshi Murakami1 · Tomikazu Kawano3 · Satoru Tamura1,3 Received: 3 April 2020 / Accepted: 7 June 2020 © The Japanese Society of Pharmacognosy 2020
Abstract Africa Trypanosomiasis remains a serious health problem, but the approved drugs for this disease are so few that novel trypanocidal compounds are demanded. In search for trypanocidal principles from medicinal plants, we found MeOH extracts of Meliae Cortex with potent activity through the screening from about 300 kinds of methanolic extract. By bioassay-guided fractionation from this extract through the liquid–liquid partition and subsequent chromatographic technique using silica gel and ODS, finally we disclosed toosendanin (1) and its relatives as active principles. These active congeners showed not only potent trypanocidal activity but also little cytotoxicity to display the excellent selective index. Taking the isolated amount as well as trypanocidal activity into consideration, 1 was disclosed to be the responsible active principle in Meliae Cortex. Additionally, the derivatives of 1 were chemically prepared from 1 and bioactivity of them were also evaluated. Through the comparison with their trypanocidal activity among the isolated relatives and the synthesized derivatives of 1, the epoxide moiety was revealed to be essential for their potent trypanocidal activity. Furthermore, 3-O-acetyl group and 7-hydroxyl group were presumed to be important functional groups and introduction of methylpropionyl group into hemiacetal hydroxy moiety was clarified to enhance their typanocidal activity. Keywords Toosendanin · Trypanocidal activity · Meliae Cortex · SAR analysis
Introduction Human Africa Trypanosomiasis, also known as sleeping sickness, has been resurgent in Sub-Saharan Africa since the late 1900s [1]. The African trypanosomiasis is pathogenic to humans and domestic animals by infection of Trypanosoma brucei, a parasite transmitted by tsetse flies (Glossina spp.). The number of reported new infections was declined year by year, but that in 2018 was still estimated to be about 1000 cases by World Health Organization (WHO). Furthermore, there have been several epidemics in Africa over the last Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11418-020-01422-9) contains supplementary material, which is available to authorized users. * Satoru Tamura satamura@iwate‑med.ac.jp 1
Graduate School of Pharmaceutical Sciences, Osaka University, 1‑6 Yamada‑oka Suita, Osaka 565‑0871, Japan
2
Department of Chemistry, Faculty of Sciences, University of Kinshasa, Kinshasa, Democratic Republic of the Congo
3
School of Pharmacy, Iwate Medical University, 1‑1‑1 Idai‑dori Yahaba‑cho Siwa‑gun, Iwate 019‑3694, Japan
century, thus anyone cannot deny next one. WHO estimated that sleeping sickness threatens the population in 36 countries in sub-Saharan Africa and some 65 million people lived in infectious-risk
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