Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine

A series of pyrazolo­(dihydro)­pyridines
was synthesized and evaluated
for antileishmanial efficacy against experimental visceral leishmaniasis
(VL). Among all compounds, 6d and 6j exhibited
better activity than miltefosine against intracellular amastigotes.
Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal
route for 5 days and displayed >91 and >93% clearance of splenic
and
liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c
mice almost completely ameliorated the disease (>97% inhibition)
by
augmenting nitric oxide generation and shifting the immune response
toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced
molecular events, such as a loss in mitochondrial membrane potential,
externalization of phosphatidylserine, and DNA fragmentation, that
ultimately resulted in the programmed cell death of the parasite.
These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct
therapy with miltefosine.