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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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 \u03bcM). Of these, PP-9 and PP-10 were the most effective<jats:italic>in vitro<\/jats:italic>and demonstrated strong efficacies<jats:italic>in vivo<\/jats:italic>through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania donovani<\/jats:named-content>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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania<\/jats:named-content>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.<\/jats:p>","DOI":"10.1128\/aac.00700-11","type":"journal-article","created":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T05:44:10Z","timestamp":1319521450000},"page":"432-445","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis"],"prefix":"10.1128","volume":"56","author":[{"given":"Partha","family":"Palit","sequence":"first","affiliation":[{"name":"Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhijit","family":"Hazra","sequence":"additional","affiliation":[{"name":"Steroid and Terpenoid Division, Indian Institute of Chemical Biology, Kolkata, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arindam","family":"Maity","sequence":"additional","affiliation":[{"name":"Steroid and Terpenoid Division, Indian Institute of Chemical Biology, Kolkata, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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