New pyrazolylpyrazoline derivatives as dual acting antimalarial-antileishamanial agents: synthesis, biological evaluation and molecular modelling simulations

Abstract

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