A series of (
Z
)-2-(nitroheteroarylmethylene)-3(2
H
)-benzofuranones possessing nitroheteroaryls groups of nitroimidazole, nitrofuran and nitrothiophene moieties was screened for antiplasmodium activity against drug-sensitive (3D7) as well as a chloroquine (CQ) and multi-drug resistant (K1) strains of
P. 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 the K1 strain. Among the synthetic analogues, (
Z
)-6-chloro-2-(1-methyl-5-nitroimidazol-2-ylmethylene)-3(2
H
)-benzofuranone (
5h
) exhibited the highest activity (IC
50
: 0.654 nM) against 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 CQ (IC
50
s of 3.13 and 206.3 nM against 3D7 and K1 strains, respectively). The more active compounds with IC
50
s lower than 5 μg/mL (∼20 μM) were further studied for their cytotoxicity responses using KB cells. From these studies, 5-nitroimidazole, 4-nitroimidazole and 5-nitrofuran analogues were shown to be cytotoxic against KB cells, while 5-nitrothiophene analogues were shown to have the least cytotoxic effects. To gain some insight into their potential contributing mechanism of action, three derivatives
10e
,
10g
and
10h
(from nitrothiophene subgroup possessing 6-methoxy, 7-methoxy and 6,7-dimethoxy substituents on their benzofuranone moieties, respectively) showing the least toxicity and highest selectivity indices were assessed for their β-hematin formation inhibition activity.
10g
demonstrated the highest inhibition activity (IC
50
: 10.78 μM) in comparison with CQ (IC
50
: 2.63 μM) as the reference drug. Finally, these three analogues (
10e
,
10g
and
10h
) were further evaluated for their
in vivo
activity against
P. berghei
/albino mice model (Peter’s test). Tested analogues were shown to be active, reducing the percentage of erythrocytes that contained parasites by 53.4, 48.8 and 32.4%, respectively.
The antileishmanial activity of a series of (
Z
)-2-(heteroarylmethylene)-3(2
H
)-benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against
Leishmania major
promastigotes and some analogues exhibited prominent activities. Compounds with IC
50
values lower than 20 μM were further examined against
L. donovani
axenic amastigotes.
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