We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.

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Abstract. Chloroquine-resistant falciparum malaria is a serious problem in much of sub-Saharan Africa. However, it is desirable to continue to use chloroquine as first-line therapy for uncomplicated malaria where it remains clinically effective. To identify predictors of chloroquine treatment failure, a 14-day clinical study of chloroquine resistance in patients with uncomplicated falciparum malaria was performed in Kampala, Uganda. Among the 258 patients (88% follow-up), 47% were clinical failures (early or late treatment failure) and 70% had parasitological resistance (RI-RIII). Using multivariate analysis, an age less than five (odds ratio [OR] ϭ 3.4, 95% CI ϭ 1.8-6.3) and a presenting temperature over 38.0ЊC (OR ϭ 2.0, 95% CI ϭ 1.1-3.7) were independent predictors of treatment failure. In addition, patients who last took chloroquine 3 to 14 days prior to study entry were significantly more likely to be treatment failures compared to patients with very recent (less than 3 days) or no recent chloroquine use. In areas with significant chloroquine resistance, easily identifiable predictors of chloroquine treatment failure might be used to stratify patients into those for whom chloroquine use is acceptable and those for whom alternative treatment should be used.

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