RESUMO
Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted ß-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfomicina/análogos & derivados , Aldose-Cetose Isomerases/antagonistas & inibidores , Aldose-Cetose Isomerases/química , Antiprotozoários/síntese química , Antiprotozoários/metabolismo , Técnicas de Química Sintética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Fosfomicina/síntese química , Fosfomicina/química , Fosfomicina/metabolismo , Fosfomicina/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/química , Oxirredutases/antagonistas & inibidores , Oxirredutases/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Pró-Fármacos/síntese química , Pró-Fármacos/metabolismo , Conformação ProteicaRESUMO
Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.
