Encecalol angelate, an unstable chromene from Ageratum conyzoides L.: total synthesis and investigation of its antiprotozoal activity |
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Authors: | Harel Dipak Khalid Sami A Kaiser Marcel Brun Reto Wünsch Bernhard Schmidt Thomas J |
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Affiliation: | a Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Münster, Germany b University of Science and Technology, Department of Pharmacognosy, Faculty of Pharmacy, P.O. Box 1996, Khartoum, Sudan c Swiss Tropical and Public Health Institute, Socinstraße 57, CH-4002 Basel, Switzerland d University of Basel, CH-4003 Basel, Switzerland e Institut für Pharmazeutische Biologie und Phytochemie (IPBP), Westfälische Wilhelms-Universität Münster, Münster, Germany |
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Abstract: | Ethnopharmacological relevanceIn agreement with ethnomedicinal reports, the dichloromethane extract of Ageratum conyzoides L. (Asteraceae) was recently shown to be of considerable activity against Trypanosoma brucei rhodesiense, the etiologic agent of East African Human Trypanosomiasis (East African Sleeping Sickness). Isolated compounds, namely, methoxylated flavonoids as well as the chromene derivative encecalol methyl ether, were less active than the crude extract. The activity of the extract was found to decrease considerably while stored in solution. An unstable compound was detected in the fresh extract by HPLC, which was converted rapidly into the encecalol methyl ether while stored in methanolic solution. This compound, deemed to represent a constituent with antitrypanosomal activity, could not be isolated from the extract in intact form.Aim of the studyTo elucidate the structure of this unstable compound and to investigate its potential role in the antitrypanosomal activity of the total extract.Materials and MethodsUHPLC/ESI-qQTOF MSMS and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was therefore prepared by total synthesis via a linear six steps synthesis, starting from resorcinol and 2-methylbut-3-en-2-ol.ResultsTotal synthesis, in an overall yield of 15%, led to pure 1, which was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6 h to yield encecalol methyl ether (2). The antiprotozoal activity of synthetic encecalol angelate against T. brucei rhodesiense as well as T. cruzi, Leishmania donovani and Plasmodium falciparum was investigated and found to be quite low.ConclusionsThe synthetic approach applied here for the first time also provides access to the related bioactive chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. Encecalol angelate, however, is most likely not responsible for the high antitrypanosomal activity of the freshly prepared dichloromethane extract of A. conyzoides. |
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Keywords: | Ageratum conyzoides L Asteraceae Chromenes Encecalol angelate Total synthesis Antiprotozoal activity |
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