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Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

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Title Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues
as Apoptotic Inducers with Activity against Experimental
Visceral Leishmaniasis
 
Creator Palit, Partha
Hazra, Abhijit
Maity, Arindam
Vijayan, R S K
Manoharan, Prabu
Banerjee, Sukdeb
Mondal, Nirup B
Ghoshal, Nanda
Ali, Nahid
 
Subject Chemistry
Infectious Diseases and Immunology
Structural Biology & Bioinformatics
 
Description Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral
delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials.
4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50%
inhibitory concentration range, 0.94 to 127�M). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated
strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony
gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95%
protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate
reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation,
evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote
mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA
fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential
for treating visceral leishmaniasis (VL) through the oral route.
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1561/1/ANTIMICROBIAL_AGENTS_AND_CHEMOTHERAPY___56_(1)_432%2D445;2012[90].pdf
Palit, Partha and Hazra, Abhijit and Maity, Arindam and Vijayan, R S K and Manoharan, Prabu and Banerjee, Sukdeb and Mondal, Nirup B and Ghoshal, Nanda and Ali, Nahid (2012) Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis. Antimicrobial Agents and Chemotherapy, 56 (1). pp. 432-445.
 
Relation http://dx.doi.org/10.1128/AAC.00700-11
http://www.eprints.iicb.res.in/1561/