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Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles

Ellis, G. L., Amewu, R., Sabbani, S., Stocks, Paul A., Shone, Alison, Stanford, D., Gibbons, P., Davies, Jill, Vivas, L., Charnaud, S., Bongard, E., Hall, Charlotte, Rimmer, Karen, Lozanom, S., Jesus, M., Gargallo, D., Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and O'Neill, P. M. (2008) 'Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles'. Journal of Medicinal Chemistry, Vol 51, Issue 7, pp. 2170-2177.

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Abstract

A rapid, two-step synthesis of a range of dispiro-1,2.4,5-tetraoxanes with potent antimalarial activity both in vitro and in vivo has been achieved. These 1,2,4,5-tetraoxanes have been proven to be superior to 1,2,4-trioxolanes in terms of stability and to be superior to trioxane analogues in terms of both stability and activity. Selected analogues have in vitro nanomolar antimalarial activity and good oral activity and are nontoxic in screens for both cytotoxicity and genotoxicity. The synthesis of a fluorescent 7-nitrobenza-2-oxa-1,3-diazole (NBD) tagged tetraoxane probe and use of laser scanning confocal microscopy techniques have shown that tagged molecules accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine (DFO).

Item Type: Article
Uncontrolled Keywords: crystal-structure artemisinin malaria peroxides derivatives spiro-1,2,4,5-tetraoxacycloalkanes 1,2,4,5-tetraoxacycloalkanes dispiro-1,2,4-trioxolanes mechanism iron(ii)
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm701435h
Depositing User: Mary Creegan
Date Deposited: 23 Aug 2010 10:52
Last Modified: 17 Jul 2020 10:58
URI: https://archive.lstmed.ac.uk/id/eprint/773

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