A Class of 5-Nitro-2-furancarboxylamides with Potent Trypanocidal Activity against Trypanosoma brucei in Vitro

作者：Zhou Linna; Stewart Gavin; Rideau Emeline; Westwood Nicholas J^*; Smith Terry K

来源：Journal of Medicinal Chemistry, 2013, 56(3): 796-806.

DOI：10.1021/jm301215e

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, similar to 1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human He La 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.

• 出版日期2013-2-14