Antimalarial Activities of ( Z )-2-(Nitroheteroarylmethylene)-3(2 H )-Benzofuranone Derivatives: In Vitro and In Vivo Assessment and β-Hematin Formation Inhibition Activity

Abstract

A series of ( Z )-2-(nitroheteroarylmethylene)-3(2 H )-benzofuranones possessing nitroheteroaryl groups of nitroimidazole, nitrofuran, and nitrothiophene moieties was screened for antiplasmodium activity against a drug-sensitive strain (3D7 strain) and a multidrug-resistant (chloroquine [CQ] and pyrimethamine) strain (K1 strain) of Plasmodium falciparum . 5-Nitroimidazole and 4-nitroimidazole analogs were highly selective and active against resistant parasites, while 5-nitrofuran and 5-nitrothiophene derivatives were more potent against the 3D7 strain than against the K1 strain. Among the synthetic analogues, ( Z )-6-chloro-2-(1-methyl-5-nitroimidazol-2-ylmethylene)-3(2 H )-benzofuranone (compound 5h ) exhibited the highest activity (50% inhibitory concentration [IC 50 ], 0.654 nM) against the K1 strain and ( Z )-7-methoxy-2-(5-nitrothiophen-2-ylmethylene)-3(2 H )-benzofuranone ( 10g ) showed the highest activity (IC 50 , 0.28 μM) against the 3D7 strain in comparison with the activities of CQ (IC 50 s of 3.13 and 206.3 nM against 3D7 and K1 strains, respectively).