Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis.
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 μM). 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.
Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.
Partha
P
Palit
Abhijit
A
Hazra
Arindam
A
Maity
R S K
RS
Vijayan
Prabu
P
Manoharan
Sukdeb
S
Banerjee
Nirup B
NB
Mondal
Nanda
N
Ghoshal
Nahid
N
Ali
D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000138:chemical synthesis; D000818:Animals; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D017209:Apoptosis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004351:Drug Resistance; D005978:Glutathione / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000382:microbiology; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011798:Quinaldines / Q000008:administration & dosage* / Q000138:chemical synthesis; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D011798:Quinaldines; D017382:Reactive Oxygen Species; C507002:4-amino-2-methylquinoline; D013762:Tetrahydrofolate Dehydrogenase; D005978:Glutathione; D000967:Antimony Sodium Gluconate