Enhancement of the antiplasmodial activity of quassin by transformation into a gamma-lactone.
The naturally occurring bitter principle quassin (1) was converted chemically into the gamma-lactone quassilactone (13) in an attempt to enhance its antiplasmodial activity. The in vitro antiplasmodial activity of 13 against Plasmodium falciparum (K1) (IC(50) = 23 microM) was 40-fold greater than that of 1. However, one of the intermediates, compound 8, the 15beta-hydroxy,16-O-m-chlorobenzoyl analogue of 1, was 506-fold more active than 1 against P. falciparum (IC(50) = 1.8 microM) and only 3-fold less potent than chloroquine. In addition, 8 displayed the best cytotoxic/antiplasmodial ratio (112) of all of the compounds tested. In the course of this work a dimer, neoquassin ether (6), linked at C-16 was also prepared; 6 was found to have weak antiplasmodial activity (IC(50) = 9.7 microM).
Lang'at-Thoruwa
Caroline
C
Centre for Pharmacognosy and Phytotherapy, and Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, U.K.
Kirby
Geoffrey C
GC
Phillipson
J David
JD
Warhurst
David C
DC
Watt
Robert A
RA
Wright
Colin W
CW
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D036702:Quassins / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D007783:Lactones; D036702:Quassins; C482483:quassilactone; C010317:quassin