title: Encecalol angelate, an unstable chromene from Ageratum conyzoides L.: total synthesis and investigation of its antiprotozoal activity.
abstract: BACKGROUND
  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 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.
  
  
  OBJECTIVE
  To elucidate the structure of this unstable compound and to investigate its potential role in the antitrypanosomal activity of the total extract.
  
  
  METHODS
  UHPLC/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.
  
  
  RESULTS
  Total 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 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Dipak
authors.initials: D
authors.lastname: Harel
authors.forename: Sami A
authors.initials: SA
authors.lastname: Khalid
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
mesh_terms: D031163:Ageratum / Q000737:chemistry; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006207:Half-Life; D007893:Leishmania donovani / Q000187:drug effects / Q000254:growth & development; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D032448:Myoblasts, Skeletal / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D028321:Plant Preparations / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000254:growth & development; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development
chemical_list: C568837:(1-(7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethyl)-2-methylbutenoate; D000981:Antiprotozoal Agents; D001578:Benzopyrans; D008689:Methacrylates; D028321:Plant Preparations