Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives.

Abstract

Sixteen compounds were synthesized and evaluated on Plasmodium berghei in CD1 mouse. The nature of the salt associated to the active principle can give some advantages in the field of activity, bioavailability and toxicity. beta-Resorcylic acid was chosen in this study because of its previously described antimalarial activity and its expected enhancement of quinine antimalarial activity. While treatment with subcutaneous quinine sulphate at 1 mmol/kg cured 6/10 mice, quinine beta-resorcylate cured all the mice under identical conditions. Although such a result appeared promising, in vitro investigation should be performed to draw clear conclusions regarding a synergy between quinine and beta-resorcylate. Cinchonidine beta-resorcylate was also active; all mice were cured at 1 mmol/kg and the mean survival time was 13.8 +/- 2.4 days after a subcutaneous treatment at 0.5 mmol/kg in a single dose. In the series of acridines, (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine cured all mice at 50 mumol/kg under the same conditions. The maximum tolerated doses in mice ranged from 100 to 150 mumol/kg for these acridine derivatives. The chemotherapeutic index of (N-alpha, sigma-dioxopentyl)-5-amino-1,2,3,4-tetrahydroacridine was estimated at 2-3. Other salts expected to reduce the toxicity, such as alpha-ketoglutarate and p-chlorophenoxyacetate, did not enhance the activity of the active principles. These results prompt us to further investigations including plasma kinetic evaluation in rats and in vitro on Plasmodium falciparum.