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

Abstract

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.

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum

“…9 These compounds, from the concentration of 25 μg/mL, did not differ statistically in the antileishmanial effect when compared to the reference drug. The presence of the pyridine ring, although not a significant influence in Bex activity has been shown to be an essential pharmacophoric moiety in other classes of compounds with leishmanicidal potential, such as chalcones, 24 pyrazoles, 25 and dyarylimidazoles. 26 In addition, the Bexs employed in this study had similar effects on the promastigotes of L. (V.) braziliensis and L. (L.) infantum, suggesting that they may be used in chemotherapy of both, CL and VL.…”

Fragment‐Based Phenotypic Lead Discovery: Cell‐Based Assay to Target Leishmaniasis

“…Figure shows some compounds that have been reported to be active against Leishmania parasite: A pentamidine‐aplysinopsin hybrid was effective against L. donovani promastigotes with an EC 50 of 2 μ m and a selectivity index of 53 . A combination of low doses of miltefosine and pyrazolopyridine derivatives were reported to decrease liver and spleen parasite burden by more than 89 % in rodent model, with EC 50 values of 7 μ m and 4 μ m against promastigotes and amastigotes, respectively . Further immunological and molecular studies showed that their lead compound exhibited a dual effect by acting as an immunostimulant and by directly killing the parasites .…”

“…[30] Further immunological and molecular studies showed that their lead compounde xhibited ad ual effectb ya cting as an immunostimulant and by directly killing the parasites. [30] Di-indolylmethane has been reported to be an inhibitor of L. donovani topoisomerase Iw ith an EC 50 of 1.2 mm, [31] while paullone derivatives have shown EC 50 values < 1 mm on axenic amastigotes, and high inhibition of L. donovani in infectedm acrophages at 5 mm. [11c] Pyrazolopyridine derivatives had EC 50 values < 1 mm on L. amazonensis promastigotes [32] and indazole N-oxide derivative induced high parasite lysis against L. amazonensis, L. infantum and L. braziliensis promastigotes at 100 mgmL À1 ,p ossibly by inducing damages into parasitec ells due to the nucleophilic properties of the compounds.…”

One-Pot Multicomponent Synthesis and Cytotoxic Evaluation of Novel 7-Substituted-5-(1H-Indol-3-yl)Tetrazolo[1,5-a] Pyrimidine-6-Carbonitrile

“…This method is advantageous relative to mainstream synthetic frameworks in easy set-up, cost-effectiveness and high yield. Recently, several MCRs have been used effectively to build nitrogen-heterocyclic compounds especially the indole substructure that possesses distinct pharmacological and biological activities [28][29][30][31][32][33][34][35][36][37][38][39].…”