English Abstract
Abstract:
Malaria and leishmaniasis are two highly detrimental parasitic diseases with a global impact.
Attempts to eradicate malaria and control leishmaniasis are generally unsuccessful due to the rapidly
developing resistance to currently used drug therapy. The pyrazole ring is a key moiety reported to have
a variety of biological activities. The current study aimed to design, synthesize and evaluate an array of
pyrazole derivatives for potential antimalarial antileishmanial activity. The scheme for the synthesis of
the pyrazole derivatives is presented. The antimalarial activity was assessed in-vivo on P. berghei
ANKA infected mice to determine % parasitemia and mean survival time. The antileishmanial activity
was assessed in-vitro, and IC50 for each compound was calculated. In-vivo acute toxicity and molecular
docking on putative antimalarial and antileishmanial drug targets were performed using the most active
compounds. All the derivatives exhibited significant antimalarial activity, the highest being 95%
suppression of parasitemia with compounds 9a and 9b. The mean survival time of mice treated with
these two compounds was also the highest (16-17 days) but was lower than chloroquine, the standard
agent. Compounds 9a and 9b exhibited superior antileishmanial activity as compared to miltefosine.
However, they were less potent than amphotericin. The compounds were safe and well-tolerated at
toxic, oral and intraperitoneal, doses of 150mg/kg and 75mg/kg, respectively. Molecular docking of
compound 9a revealed a good fitting pose with plasmodial Pf-DHFR enzyme and Lm-PTR1 enzyme,
which explains the biological activity noted with this compound. Pyrazole derivatives 9a and 9b
exhibited substantial dual antimalarial antileishmanial activity and may be a valuable scaffold for the
design of further derivatives with antiprotozoal potential.
