Abstract
Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of
in vivo
antimalarial activities of new pyrazolylpyrazoline derivatives against
Plasmodium berghei
infected mice. Further evaluation of
5b
and
6a
against chloroquine-resistant strain (RKL9) of
P. falciparum
showed higher potency than chloroquine.
In vitro
antileishmanial activity testing against
Leishmania aethiopica
promastigote and amastigote forms indicated that
5b
,
6a
and
7b
possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds
via
folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism
via
targeting leishmanial DHFR and PTR1. The compounds were non-toxic at 125, 250 and 500 mg/kg. In addition, docking of the most active compound against putative malarial target
Pf
-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of
7a
against leishmanial PTR1.