Selection of a trioxaquine as an antimalarial drug candidate

Abstract

Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC(50) value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.

Fig. 1.

Generation of C-centered alkylated radicals by heme-mediated reductive activation of trioxaquines.

Fig. 2.

Structural data. (A) Formula of the trioxaquine PA1103/SAR116242. (B) X-ray structures of both stereoisomers of PA1103/SAR116242 (identified as SSR136696 and SSR136697).

Fig. 3.

Synthesis of PA1103/SAR116242.

Fig. 4.

Comparison of compound effect on parasitemia in vivo after 24 h of 1 dose of 25 mg/kg per day for PA1103/SAR116242 per oral route in both CQS (P. vinckei petteri) and CQR (P. vinckei vinckei) rodent strains.