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.

FIG. 1

Chemical structure of DBB. DBB is a 2,3-benzindene and is closely related to benflumetol (lumefantrine).

FIG. 2

Mean concentration response (SMI%) lines of DBB for the years 1997 and 1998 for P. falciparum from Mae Hong Son (MHS) and Mae Sot (MS), with data points. Higher EC values from Mae Sot are indicated by the flatter regression line. The mean EC₅₀ from Mae Sot in 1998 (MS 98) was found to be significantly higher than the corresponding value from Mae Hong Son (MHS 98).

FIG. 3

Mean concentration response (SMI%) lines for DBB and benflumetol (BEN) for P. falciparum, with 95% confidence intervals and data points. Parallel pooled data (n = 154) of 1997 and 1998 in Thailand are shown. The position of the regression line and the smaller number of data points reflect the higher activity of DBB.

FIG. 4

Scatter diagram of individual EC₅₀ values for DBB and benflumetol (BEN) for P. falciparum from Thailand, 1997 and 1998 (n = 154), showing distinct correlation and reflecting the close relationship between benflumetol and DBB. Concentrations are in nanomoles per liter.