Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine
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- 作者：Devireddy Anand ; Pawan Kumar Yadav ; Om P. S. Patel ; Naveen Parmar ; Rahul K. Maurya ; Preeti Vishwakarma ; Kanumuri S. R. Raju ; Isha Taneja ; M. Wahajuddin ; Susanta Kar ; Prem P. Yadav
- 刊名：Journal of Medicinal Chemistry
- 出版年：2017
- 出版时间：February 9, 2017
- 年：2017
- 卷：60
- 期：3
- 页码：1041-1059
- 全文大小：999K
- ISSN：1520-4804
文摘
A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, <b>6db> and <b>6jb> exhibited better activity than miltefosine against intracellular amastigotes. Compound <b>6jb> (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 <b>6jb> 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 <b>6jb> 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 <b>6jb> could be a promising lead for treating VL as an adjunct therapy with miltefosine.