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Evaluating 5-nitrofurans as trypanocidal agents
Christopher Bot1, Belinda S Hall, Guzmán Alvarez
1Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
Antimicrobial Agents and Chemotherapy
|January 22, 2013
Summary
New 5-nitrofuran compounds show potent activity against Trypanosoma brucei, the parasite causing African sleeping sickness. These nitroheterocycles, activated by a specific nitroreductase enzyme, could become next-generation partners in eflornithine combination therapies.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Human African trypanosomiasis (HAT) treatment options are limited, with nifurtimox-eflornithine combination therapy being a key strategy.
- Nifurtimox, a nitroheterocycle prodrug, requires activation by a type I nitroreductase (NTR) to generate cytotoxic metabolites.
- Identifying new nitroaromatic compounds is crucial for developing improved HAT therapies.
Purpose of the Study:
- To evaluate the trypanocidal activities of various 5-nitrofuran derivatives against Trypanosoma brucei.
- To identify novel nitroaromatic compounds that can serve as potential partners with eflornithine in HAT treatment.
- To understand the role of Trypanosoma brucei nitroreductase (TbNTR) in the activation and efficacy of these compounds.
Main Methods:
- Biochemical screening of 5-nitrofurans using purified TbNTR to determine substrate efficacy (kcat/Km).
- Mass spectrometry to characterize the in vitro reduction products of selected nitrofurans by TbNTR.
- In vitro testing of 5-nitrofuran derivatives against bloodstream-form T. brucei to assess growth-inhibitory properties (IC50).
- Genetic manipulation of T. brucei to alter TbNTR levels (knockdown and overexpression) and assess drug resistance/hypersensitivity.
Main Results:
- All tested 5-nitrofurans were substrates for TbNTR, with some exhibiting significantly higher catalytic efficiency (kcat/Km) than nifurtimox.
- In vitro reduction yielded unsaturated and saturated open-chain nitriles, consistent with the proposed activation mechanism.
- Many 5-nitrofuran derivatives demonstrated potent trypanocidal activity, with IC50 values as low as approximately 200 nM.
- Antiparasitic activity was confirmed to be TbNTR-dependent, with reduced enzyme levels conferring resistance and overexpression leading to hypersensitivity.
Conclusions:
- Other 5-nitrofuran derivatives possess significant potential as trypanocidal agents.
- These compounds can be activated by TbNTR, similar to nifurtimox.
- The 5-nitrofuran class represents a promising source for next-generation nitroaromatic prodrugs to partner with eflornithine in HAT combination therapy.
