title: 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.
authors.forename: Devireddy
authors.initials: D
authors.lastname: Anand
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Yadav
authors.forename: Om P S
authors.initials: OP
authors.lastname: Patel
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Parmar
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Maurya
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Vishwakarma
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Kanumuri S R
authors.initials: KS
authors.lastname: Raju
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Isha
authors.initials: I
authors.lastname: Taneja
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: M
authors.initials: M
authors.lastname: Wahajuddin
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Kar
authors.affiliation: Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110025, India.
authors.forename: Prem P
authors.identifier: 0000-0002-5387-7477
authors.initials: PP
authors.lastname: Yadav
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007891:Leishmania / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000981:Antiprotozoal Agents; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D010767:Phosphorylcholine; C039128:miltefosine