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Planta Med 2004; 70(8): 711-717
DOI: 10.1055/s-2004-827200
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

Inhibiting Activities of the Secondary Metabolites of Phlomis brunneogaleata against Parasitic Protozoa and Plasmodial Enoyl-ACP Reductase, a Crucial Enzyme in Fatty Acid Biosynthesis

Hasan Kırmızıbekmez1 , Ihsan Çalıs1 , Remo Perozzo2 , Reto Brun3 , Ali A. Dönmez4 , Anthony Linden5 , Peter Rüedi5 , Deniz Tasdemir5
  • 1Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
  • 2Department of Chemistry and Applied Biosciences, ETH Zurich, Zürich, Switzerland
  • 3Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland
  • 4Department of Biology, Faculty of Science, Hacettepe University, Ankara, Turkey
  • 5Institute of Organic Chemistry, University of Zurich, Zürich, Switzerland
Further Information

Publication History

Received: December 29, 2003

Accepted: April 12, 2004

Publication Date:
24 August 2004 (online)

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Abstract

Anti-plasmodial activity-guided fractionation of Phlomis brunneogaleata (Lamiaceae) led to the isolation of two new metabolites, the iridoid glycoside, brunneogaleatoside and a new pyrrolidinium derivative (2S,4R)-2-carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt [(2S,4R)-1,1-dimethyl-4-(E)-p-coumaroyloxyproline inner salt]. Moreover, a known iridoid glycoside, ipolamiide, six known phenylethanoid glycosides, verbascoside, isoverbascoside, forsythoside B, echinacoside, glucopyranosyl-(1→Gi-6)-martynoside and integrifolioside B, two flavone glycosides, luteolin 7-O-β-D-glucopyranoside (10) and chrysoeriol 7-O-β-D-glucopyranoside (11), a lignan glycoside liriodendrin, an acetophenone glycoside 4-hydroxyacetophenone 4-O-(6′-O-β-D-apiofuranosyl)-β-D-glucopyranoside and three caffeic acid esters, chlorogenic acid, 3-O-caffeoylquinic acid methyl ester and 5-O-caffeoylshikimic acid were isolated. The structures of the pure compounds were elucidated by means of spectroscopic methods (UV, IR, MS, 1D and 2D NMR, [α]D) and X-ray crystallography. Compounds 10 and 11 were determined to be the major anti-malarial principles of the crude extract (IC50 values of 2.4 and 5.9 μg/mL, respectively). They also exhibited significant leishmanicidal activity (IC50 = 1.1 and 4.1 μg/mL, respectively). The inhibitory potential of the pure metabolites against plasmodial enoyl-ACP reductase (FabI), which is the key regulator of type II fatty acid synthases (FAS-II) in P. falciparum, was also assessed. Compound 10 showed promising FabI inhibiting effect (IC50 = 10 μg/mL) and appears to be the first anti-malarial natural product targeting FabI of P. falciparum.

Abbreviations

ACP:Acyl Carrier Protein

CC:Column Chromatography

FabI:Enoyl-Acyl Carrier Protein Reductase

FAS-I:Type I Fatty Acid Synthase System

FAS-II:Type II Fatty Acid Synthase System

MPLC:Medium Pressure Liquid Chromatography

Key words

Phlomis brunneogaleata - Lamiaceae - iridoid - pyrrolidinium derivative - betonicine - luteolin 7-O-β-D-glucopyranoside - Plasmodium falciparum enoyl-acyl carrier protein reductase (FabI) - type II fatty acid synthase (FAS-II)

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Dr. Deniz Tasdemir

Institute of Organic Chemistry

University of Zurich

Winterthurerstrasse 190

8057 Zürich

Switzerland.

Phone: +41-1-635-4213

Fax: +41-1-635-6812

Email: deniz@oci.unizh.ch

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