A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro

Linna Zhou, Gavin Stewart, Emeline Rideau, Nicholas James Westwood, Terry K Smith

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)
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Abstract

Recently, the World Health Organization approved the nifurtimox–eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, 1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness.
Original languageEnglish
Pages (from-to)796–806
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
Early online date3 Jan 2013
DOIs
Publication statusPublished - 14 Feb 2013

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