Ferrocenyl and cyrhetrenyl azines containing a 5-nitroheterocyclic moiety: Synthesis, structural characterization, electrochemistry and evaluation as anti-Trypanosoma cruzi agents

Abstract

The synthesis of unsymmetrical ferrocenyl and cyrhetrenyl azines [(η5-C5H4)-CR=N-N=CH-2-C4H2X-5-NO2]M (M=Re(CO)3, Fe(η5-C5H5); R = H, CH3, X = O, S) has led to the development of new derivatives of 5-nitroheterocycles as potential anti-trypanosomal agents. The structures of compounds have been confirmed using conventional spectroscopic techniques (FT-IR, 1H and 13C NMR), mass spectrometry, including single-crystal X-ray diffraction analysis of compounds 2NT and 4NT. Based on the chemical shifts of the iminic carbons (C6, C7) and the reduction potential of the nitro group (E1/2 NO2), an extensive π-conjugation of the azine bridge (-C(R)=N-N=CH-) was observed along with a correlation between the opposing electronic effects of the cyrhetrenyl and ferrocenyl fragments. It was established that the existence of an electron-withdrawing group (cyrhetrene) could facilitate the generation of radical species (RNO2 to RNO2−) through the azine bridge. The organometallic azines were evaluated for anti-trypanosomal activity in vitro against the epimastigote form of the Dm28c strain of T. cruzi, yielding IC50 values in the low micromolar range.