Chalcones and flavonoids: New perspectives in the modulation of Trypanosoma brucei metacaspase-2.

African Human Trypanosomiasis (AHT), caused by Trypanosoma protozoa, faces therapeutic challenges due to limited efficacy and adverse effects. Natural compounds, such as chalcones and flavonoids, represent promising alternatives. This study evaluated nine compounds (six chalcone derivatives and three flavonoids) as modulators of Trypanosoma brucei metacaspase-2. Screening at 1 and 6 μM revealed inhibitory activity, with compounds EM-1A, EM-1B, EM-1C, and EM-F12C showing notable IC50 values. Mechanistic studies identified competitive inhibition for EM-1A, EM-1C, and EM-F12C, while EM-1B exhibited non-competitive inhibition. These findings demonstrate chalcone and flavonoid derivatives as potential anti-AHT agents, effectively inhibiting T. brucei metacaspase-2 at micromolar concentrations. Further research is essential to validate their efficacy and safety for therapeutic use.