High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors

Abstract

The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the “double-drug” approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC50) as low as 0.1 μM was obtained, an excellent improvement in comparison with inhibitors previously reported (IC50 = 2−20 μM). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K i = 1−700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 μM and were highly selective for PLMs vs human cathepsin D.

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

“…PQ is usually employed in combination with blood schizonticides, in particular chloroquine (12) or ART derivatives (9,32,33), to prevent relapses in P. vivax infections and to reduce malaria transmission following treatment (31,33). Two studies on chimeric PQ-containing molecules, in which PQ was linked to statin-based inhibitors of plasmepsins, have been reported (10,30). Although these dou- (Fig.…”

Discovery of oxybisbenzoylamides as a new class of antimalarial agents

“…Compound 6 being the most active was also tested for cytotoxicity against normal human fibroblast (FDH) 6 and against a macrophage cell line (HMEC-1), showing an effect only in the micromolar range (FDH, IC 50 : 17.99 ± 8.7 µM; HMEC-1, IC 50 : 17.58 ± 7.8 µM) with a good therapeutic index (approx. 450).…”

“…Although the haemoglobin digestion process appears to be a good pharmacological target, molecules with a useful in vivo efficacy have not been obtained, yet. During our studies interesting results were generated by applying the "double-drug" approach: [5][6][7][8][9] we synthesized molecules characterized by the presence of statin, a β-hydroxyl amino acid able to inhibit aspartic proteases, such as PLMs, joined with the 8-aminoquinolinic ring system (1) derived from primaquine (PQ) or a hepatic schizonticidal atovaquone (2) or the 4-aminoquinolinic ring system (3) derived from chloroquine (CQ). (Figure 1) These compounds were potent PLMs inhibitors and showed an antimalarial activity at concentrations significantly lower than any PLMs inhibitor previously reported.…”

Antiplasmodial activity of Punica granatum L. fruit rind

“…Recombinant Pro-PLM 2 and 4 were purified from BL21-(DE3) pLysS Escherichia coli (Invitrogen) according to Hill et al (1994), with slight modifications (Dell'Agli et al, 2006). The protein concentration was determined according to Bradford (1976).…”