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Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity.

Gibbons, Peter, Verissimo, Edite, Araujo, Nuna C, Barton, Victoria, Nixon, Gemma L, Amewu, Richard K, Chadwick, James, Stocks, Paul A., Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Srivastava, Abhishek, Rosenthal, Philip J, Gut, Jiri, Guedes, Rita C, Moreira, Rui, Sharma, Raman, Berry, Neil, Cristiano, M Lurdes S, Shone, Alison, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and O'Neill, Paul M (2010) 'Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity.'. Journal of medicinal chemistry, Vol 53, Issue 22, pp. 8202-6.

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Abstract

We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.

Item Type: Article
Uncontrolled Keywords: Plasmodium falciparum resistance;
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 34 Experimental pharmacology (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm1009567
Related URLs:
Depositing User: Mary Creegan
Date Deposited: 11 Feb 2011 16:07
Last Modified: 06 Feb 2018 13:02
URI: https://archive.lstmed.ac.uk/id/eprint/1728

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