Novel S-adenosyl-L-methionine decarboxylase inhibitors as potent antiproliferative agents against intraerythrocytic Plasmodium falciparum parasites

•A highly specific inhibitor, Genz-644131, was identified for P. falciparum AdoMetDC.•Increased specificity for bifunctional over monofunctional PfAdoMetDC was shown.•Genz-644131 showed improved inhibition against in vitro P. falciparum parasites.•Immunoliposomes improved in vitro drug delivery of Genz-644131 by 32-fold.

S-adenosyl-l-methionine decarboxylase (AdoMetDC) in the polyamine biosynthesis pathway has been identified as a suitable drug target in Plasmodium falciparum parasites, which causes the most lethal form of malaria. Derivatives of an irreversible inhibitor of this enzyme, 5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine (MDL73811), have been developed with improved pharmacokinetic profiles and activity against related parasites, Trypanosoma brucei. Here, these derivatives were assayed for inhibition of AdoMetDC from P. falciparum parasites and the methylated derivative, 8-methyl-5′-{[(Z)-4-aminobut-2-enyl]methylamino}-5′-deoxyadenosine (Genz-644131) was shown to be the most active. The in vitro efficacy of Genz-644131 was markedly increased by nanoencapsulation in immunoliposomes, which specifically targeted intraerythrocytic P. falciparum parasites.

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