Evaluation of trypanocidal properties of ferrocenyl and cyrhetrenyl N-acylhydrazones with pendant 5-nitrofuryl group

Abstract

Four N-acylhydrazones of general formulae [R¹-C(O)-NH-N=C(R²)(5-nitrofuryl)] with (R¹ = ferrocenyl or cyrhetrenyl and R² = H or Me) are synthesized and characterized in solution and in the solid-state. Comparative studies of their stability in solution under different experimental conditions and their electrochemical properties are reported. NMR studies reveal that the four compounds are stable in DMSO‑d₆ and complementary UV-Vis studies confirm that they also exhibit high stability in mixtures DMSO:H₂O at 37 °C. Electrochemical studies show that the half-wave potential of the nitro group of the N-acylhydrazones is smaller than that of the standard drug nifurtimox and the reduction process follows a self-protonation mechanism. In vitro studies on the antiparasitic activities of the four complexes and the nifurtimox against Trypanosoma cruzi and Trypanosoma brucei reveal that: i) the N-acylhydrazones have a potent inhibitory growth activity against both parasites [EC₅₀ in the low micromolar (in T. cruzi) or even in the nanomolar (in T. brucei) range] and ii) cyrhetrenyl derivatives are more effective than their ferrocenyl analogs. Parallel studies on the L₆ rat skeletal myoblast cell line have also been conducted, and the selectivity indexes determined. Three of the four N-acylhydrazones showed higher selectivity towards T. brucei than the standard drug nifurtimox. Additional studies suggest that the organometallic compounds are bioactivated by type I nitroreductase enzymes.

Keywords: Cyclic voltammetry; Cyrhetrenyl N-acylhydrazones; Ferrocenyl N-acylhydrazones; Trypanocidal compounds; Type I nitroreductase.