Inhibiting activities of the secondary metabolites of Phlomis brunneogaleata against parasitic protozoa and plasmodial enoyl-ACP Reductase, a crucial enzyme in fatty acid biosynthesis.
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 (2 S,4 R)-2-carboxy-4-( E)- p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt [(2 S,4 R)-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-->G (i)-6)-martynoside and integrifolioside B, two flavone glycosides, luteolin 7- O-beta- D-glucopyranoside ( 10) and chrysoeriol 7- O-beta- D-glucopyranoside ( 11), a lignan glycoside liriodendrin, an acetophenone glycoside 4-hydroxyacetophenone 4- O-(6'- O-beta- D-apiofuranosyl)-beta- 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, [alpha] (D)) and X-ray crystallography. Compounds 10 and 11 were determined to be the major anti-malarial principles of the crude extract (IC (50) values of 2.4 and 5.9 micrograms/mL, respectively). They also exhibited significant leishmanicidal activity (IC (50) = 1.1 and 4.1 micrograms/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 (IC (50) = 10 micrograms/mL) and appears to be the first anti-malarial natural product targeting FabI of P. falciparum.
Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Hasan
H
Kirmizibekmez
Ihsan
I
Calis
Remo
R
Perozzo
Reto
R
Brun
Ali A
AA
Dönmez
Anthony
A
Linden
Peter
P
Rüedi
Deniz
D
Tasdemir
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line / Q000187:drug effects; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D032446:Myoblasts / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D031345:Phlomis; D008517:Phytotherapy; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D014345:Trypanosoma / Q000187:drug effects
D000962:Antimalarials; D010936:Plant Extracts; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)