Encecalol angelate, an unstable chromene from Ageratum conyzoides L. : total synthesis and investigation of its antiprotozoal activity

In 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 etiological 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. Its mass spectrum and NMR data of the degraded product indicated its chemical identity as encecalol angelate (1) which was eventually confirmed by its total synthesis via a linear six steps synthesis with an overall yield of 15%. This new practical approach also provides access to the related chromenes encecalin (7) and encecalol (8) with improved yields compared with reported methods. The synthesized encecalol angelate was chromatographically and spectroscopically identical with the natural product. The compound degraded in methanol with a half-life of approximately 6h 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 so that it is most likely not responsible for the high antitrypanosomal activity of the freshly prepared plant extract