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

• Published in: Antimicrobial Agents and Chemotherapy 2012, Vol.56 (1), p.432-445
• Main Authors: Palit, Partha, Hazra, Abhijit, Maity, Arindam, Vijayan, R. S. K, Manoharan, Prabu, Banerjee, Sukdeb, Mondal, Nirup B, Ghoshal, Nanda, Ali, Nahid
• Format: Article
• Language: English
• Subjects: Administration, Oral; amastigotes; Aminoquinolines; Aminoquinolines - administration & dosage; Aminoquinolines - chemical synthesis; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; antimony; Antimony Sodium Gluconate - administration & dosage; Antiprotozoal Agents; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - chemical synthesis; apoptosis; Apoptosis - drug effects; Biological and medical sciences; cytotoxicity; death; dihydrofolate reductase; DNA fragmentation; DNA Fragmentation - drug effects; Drug Resistance; enzyme inhibition; Experimental Therapeutics; glutathione; Glutathione - antagonists & inhibitors; Human protozoal diseases; Infectious diseases; Inhibitory Concentration 50; Injections, Intraperitoneal; Leishmania donovani; Leishmania donovani - drug effects; Leishmania donovani - growth & development; Leishmaniasis, Visceral; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - microbiology; Leshmaniasis; lipid peroxidation; Lipid Peroxidation - drug effects; mechanism of action; Medical sciences; membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred BALB C; mitochondrial membrane; oral administration; parasites; Parasitic diseases; Pharmacology. Drug treatments; promastigotes; proteinases; Protozoal diseases; Protozoan Proteins; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Quinaldines; Quinaldines - administration & dosage; Quinaldines - chemical synthesis; reactive oxygen species; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; sodium; strains; Tetrahydrofolate Dehydrogenase - metabolism; visceral leishmaniasis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00700-11

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.