Estudo experimental e teórico das propriedades estruturais e espectroscópicas de ferrocenos quirais e avaliação do potencial ansiolítico

Abstract

Ferrocene compounds are an important class of organometallic complexes that display countless applications in the most varied fields. Among them, chiral ferrocenes stand out as valuable catalysts in asymmetric synthesis. This work describes the experimental and theoretical study of structural and spectroscopic properties of four planar chiral 1,2-disubstituted ferrocenes, including one ferrocenyl-alcohol (1) and three ferrocenyl-amines (2, 3, and 4). Additionally, in vivo biological assays were performed using zebrafish models to evaluate their anxiolytic potential. Vibrational and electronic characteristics were investigated through FT-IR, FT-Raman, and UV-Vis techniques. Electrochemical profiles were obtained through cyclic voltammetry analyses. Determination of absolute configurations was carried out by single crystal X-ray diffraction (XRD) analysis, and chiroptical properties of enantiopure compounds were investigated through electronic circular dichroism (ECD). Theoretical calculations involving Time-Dependent Density Functional Theory (TD-DFT) were performed to further investigate the spectroscopic and electronic characteristics of the compounds. The vibrational modes assignment was made in accordance with theoretical data, which presented similar profiles comparing to the experimental results. UV-Vis absorption spectra also corroborates with theoretical results, with maximum absorption bands around 207, 257 and 435 nm for all compounds. Electronic transitions were assigned and HOMO-LUMO energy gaps were estimated by TD-DFT calculations. Cyclic voltammograms exhibited a quasi-reversible redox process for all compounds and a second redox process for compounds 2 and 4. XRD analyses of the single crystals revealed the obtention of pure enantiomers (Rp)-1, (Rp)-2, (Sp)-3 and (Sp)-4. The results also showed that alcohol (Rp)-1 crystallizes in a tetragonal structure, while amines (Rp)-2, (Sp)-3 and (Sp)-4 crystallize in an orthorhombic structure. The ECD spectra exhibited similar behaviors with intense and opposite absorption profiles between derivatives with inverse configuration. Zebrafish assays revealed that all samples were non-toxic, did not induce anatomical changes in tested animals, and exhibited a likely sedative effect. Compounds 2, 4, and (Sp)-4 showed anxiolytic effect similar to Diazepam (reference benzodiazepine anxiolytic) at all tested doses, while (Rp)-2 exhibited similar effects only with a 4 mg/Kg dose. The tests also suggested that compounds 2, 4, and (Rp)-2 present neuromodulated anxiolytic effects via GABAA.