A potent antimalarial activity of 5-fluoroorotate in combination with sulfamonomethoxine against Plasmodium falciparum in vitro and Plasmodium berghei in mice

Abstract The antimalarial activity of 5-fluoroorotate and sulfamonomethoxine, 4-amino- N -(6-methoxy-4-pyrimidinyl)benzenesulfonamide, was evaluated against Plasmodium falciparum in vitro and P. berghei in vivo. The concentrations of 5-fluoroorotate and sulfamonomethoxine required for 50% inhibition of growth (IC 50 ) of P. falciparum were 4.8 nM and 1.2 μM, respectively. In vitro, a combination of 5-fluoroorotate with sulfamonomethoxine showed potent synergy: the required concentrations in combination for 5-fluoroorotate and sulfamonomethoxine were as low as 1/12 and 1/15 of the respective IC 50 values. In vivo, although either 5-fluoroorotate or sulfamonomethoxine given orally reduced parasitemia, neither completely eliminated parasites from mice. In contrast, a combination of 5-fluoroorotate and sulfamonomethoxine produced a rapid decrease in parasitemia within 24 h and achieved complete cure of mice, with no parasite recrudescence or toxicity. These results suggest that a combination of 5-fluoroorotate and sulfamonomethoxine could form the basis of a new antimalarial combination for the treatment of human malaria.