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Structural optimization of quinolon-4(1H)-imines as dual-stage antimalarials: toward increased potency and metabolic stability.

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Ressurreição, Ana S, Gonçalves, Daniel, Sitoe, Ana R, Albuquerque, Inês S, Gut, Jiri, Góis, Ana, Gonçalves, Lídia M, Bronze, Maria R, Hanscheid, Thomas, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Rosenthal, Philip J, Prudêncio, Miguel, O'Neill, Paul, Mota, Maria M, Lopes, Francisca and Moreira, Rui (2013) 'Structural optimization of quinolon-4(1H)-imines as dual-stage antimalarials: toward increased potency and metabolic stability.'. Journal of Medicinal Chemistry, Vol 56, Issue 19, pp. 7679-7690.

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Official URL: http://pubs.acs.org/doi/abs/10.1021/jm4011466

Abstract

Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including the obligatory developmental phase in the liver, which precedes the erythrocytic stage. We have previously reported that N-Mannich-based quinolon-4(1H)-imines are potent antiplasmodial agents but present several stability liabilities. We now report our efforts to optimize quinolon-4(1H)-imines as dual-stage antiplasmodial agents endowed with chemical and metabolic stability. We report compounds active against both the erythrocytic and exoerythrocytic forms of malaria parasites, such as the quinolon-4(1H)-imine 5p (IC50 values of 54 and 710 nM against the erythrocytic and exoerythrocytic forms), which constitute excellent starting points for further lead optimization as dual-stage antimalarials.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 250 Anti-infective agents (General) QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1021/jm4011466
Depositing User:	Mary Creegan
Date Deposited:	07 Nov 2014 11:10
Last Modified:	06 Feb 2018 13:07
URI:	https://archive.lstmed.ac.uk/id/eprint/4532

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