期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 219, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2021.111428
关键词
N-acylhydrazones; Cyclic voltammetry; Trypanocidal compounds; Type I nitroreductase
资金
- Ministerio de Economia y Competitividad of Spain [CTQ-2015-65040P]
- [3200273]
Four N-acylhydrazones were synthesized and characterized, showing high stability in solution and strong inhibitory activity against parasites, with cyrhetrenyl derivatives being more effective. The electrochemical studies revealed a self-protonation mechanism and bioactivation by nitroreductase enzymes.
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.
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