Rational design of novel organometallic N-acylhydrazones with potent antiparasitic activity on Trypanosoma cruzi and brucei

Abstract

This work describes the synthesis and characterization of organometallic N-acylhydrazones (NAHs) of general formula R¹-C(O)-NH-NC(R²)(4- or 5-nitrothienyl) (4a,b–7a,b), where R¹ = ferrocenyl (a) or cyrhetrenyl (b) and R² = H or Me. The X-ray crystal structures of 4b, 5a, 5b, and 6b are described. UV–Vis studies confirmed that the compounds remained stable in DMSO/buffer mixtures for 24 h. In vitro studies of the biological activities of 4a,b–7a,b against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) showed that the organometallic derivatives were more active against T. brucei (EC₅₀ = 0.18–12.9 μM) than against T. cruzi (EC₅₀ = 4.24–78.8 μM). Except for 5b, cyrhetrenyl derivatives were more potent than their ferrocenyl analogs, showing up to a 7-fold increase in antiparasitic activity. In all cases, the 5-nitrothiophene derivatives (6a,b–7a,b) also outperformed their 4-nitro analogs (4a,b–5a,b), underscoring the strong impact of nitro-group positioning on biological activity. Compound 6b proved to be the most promising anti-T. brucei agent due to its potency (EC₅₀ = 0.47 μM) and selectivity (SI = 110). Comparison of data for 6a and 6b and their isomers 8a and 8b [R¹-C(H)N-NH-C(O)(5-nitrothienyl)] revealed that antiparasitic activity and cytotoxicity are strongly influenced by the position of the acylhydrazone group linking the organometallic fragment and the nitroheterocycle. Evaluation of T. brucei susceptibility showed that the 5-nitro derivatives undergo Type I nitroreductase–dependent activation (–tet/+tet ratios: 4.2–5.6), while the 4-nitro counterparts exhibited only minor shifts (1.5–2.0). These results indicate that small structural modifications in NAHs can significantly affect their antiparasitic properties.