Organometallic N‐acylhydrazones of 5‐nitrofuran and 5‐nitrothiophene based: Synthesis, electrochemical, antiparasitic evaluation, and computational study

Abstract

In searching for new therapeutic agents for treating American trypanosomiasis and Human African trypanosomiasis, four nitroheterocyclic acylhydrazones of general formulae [R1‐CH=N‐NH‐C(O)‐(5‐C4H2X)] (where R1 = ferrocenyl or cyrhetrenyl, and X = O or S) have been synthesized and characterized by spectroscopic techniques. Comparative studies of their stability by 1H‐NMR and UV–Vis experiments were reported. Single‐crystal X‐ray diffraction confirmed the molecular structures of NF‐1 and NT‐2. Their X‐ray crystal structures reveal that both adopt an E‐configuration on the C=N moiety. Regarding the ‐NH‐C(O)‐ bond, the structure of NF‐1 confirmed a trans conformation, while NT‐2 exhibited a cis‐amide conformation. The cyclic voltammetry and electron spin resonance (ESR) experiments were conducted to study the electrochemical behavior of N‐acylhydrazones. The antiparasitic activities of compounds against Trypanosoma cruzi (epimastigotes) and Trypanosoma brucei (trypomastigotes) revealed that cyrhetrenyl complexes were more effective than their ferrocenyl analogs. The cyrhetrenyl derivative NT‐2 (EC50 = 2.25 μM) showed activity against T. brucei comparable to the standard drug nifurtimox (Nfx, EC50 = 3.56 μM). The ferrocenyl compound NT‐1 (>200 μM) was at least two times less cytotoxic than the Nfx (88.7 μM) against the L6 rat skeletal myoblast cell line and exhibited a selectivity like Nfx toward T. brucei. Density functional theory (DFT) calculations were utilized as an approximation to explain the impact of organometallic and heterocyclic rings on antiparasitic activities. This study supported the experimental results, confirming that the cyrhetrenyl fragment in N‐acylhydrazone derivatives plays a significant role in the antitrypanosomal activity, which can be attributed to an increase in positive charge on the metal.