Desbutyl-Benflumetol, a Novel Antimalarial Compound: In Vitro Activity in Fresh Isolates of Plasmodium falciparum from Thailand

Abstract

Desbutyl-benflumetol (DBB) is a novel antimalarial compound closely related to benflumetol (lumefantrine), of which it is a putative metabolite. The in vitro response of Plasmodium falciparum to DBB was studied in Mae Hong Son and Mae Sot, in northwest Thailand, in 1997 and 1998. In total, 155 fresh isolates were successfully tested using the World Health Organization standard in vitro microtest system (Mark II). The mean 50% effective concentration (EC 50 ) and 90% effective concentration of DBB were 6.36 and 31.09 nmol/liter, respectively. The comparison of the activity of DBB and benflumetol yielded a highly significant potency ratio of 4.52, corresponding to a more than four times higher efficacy of DBB. A considerable potency difference was found between isolates from Mae Hong Son and those from Mae Sot, reflecting lesser sensitivity in the area with marked resistance to mefloquine and quinine. This observation is also supported by a highly significant activity correlation with benflumetol (P < 0.001) and to a similar degree with mefloquine (P < 0.001), reflecting a close relationship of DBB with the class II aryl amino alcohol blood schizontocides. A less distinct association was also found with artemisinin, which was significant only at the EC 50 level, and there was no correlation at all with chloroquine. DBB is a promising antimalarial compound that merits further investigation in order to define its practical therapeutic potential.

Desbutyl-Lumefantrine Is a Metabolite of Lumefantrine with Potent In Vitro Antimalarial Activity That May Influence Artemether-Lumefantrine Treatment Outcome

“…The two laboratory-adapted strains of P. falciparum were more sensitive in vitro to DBL than to lumefantrine, consistent with data from previous studies using field isolates (17,23,24). This effect was independent of CQ sensitivity.…”

“…DBL is more potent in vitro against chloroquine (CQ)-resistant Plasmodium falciparum and Plasmodium vivax field isolates than lumefantrine (13,17,23). There is evidence of in vitro synergy between lumefantrine and DBL against P. falciparum but at ratios (999:1 and 995:5) that were presumably selected at a time when plasma concentrations of DBL were assumed to be very much lower than those of the parent compound (23,24).…”

Are Transporter Genes Other than the Chloroquine Resistance Locus ( pfcrt ) and Multidrug Resistance Gene ( pfmdr ) Associated with Antimalarial Drug Resistance?

“…2). Similar strong correlations have been observed in previous southeast Asian studies (5,17,30), suggesting that the data are reliable. (iii) We also see expected strong associations between pfmdr-1042 and in vitro resistance to MFQ and LUM (21).…”

“…There is also good evidence that levels of in vitro resistance vary both within and between countries within southeast Asia. These data come from measurement of in vitro resistance (17,30), from drug efficacy rates (27), and from genotyping of known drug resistance markers (16).…”

Pharmacologically Active Metabolites of Currently Marketed Drugs: Potential Resources for New Drug Discovery and Development

“…N-Desmethylivabradine Bradycardia Lumefantrine 129) Desbutyllumefantrine Anti-malarial Mianserin 90) N-Desmethylmiaserin Anti-depressant Verapamil 130) Norverapamil Anti-arrhythmic Oxybutynin 95) N-Desethyloxybutynin Smooth muscle relaxant Rosuvastatin 131) N-Desmethylrosuvastatin Anti-hypercholesterolemia Sertraline 102) N-Desmethylsertraline Anti-depressant Sibutramine 24) N-Desmethylsibutramine N,N-Didesmethylsibutramine…”