Indole–Pyrazole Hybrids: Synthesis, Structure, and Assessment of Their Hemolytic and Cytoprotective Properties

In recent years, we have observed a growing interest in molecular hybridization, which involves combining chemically and pharmacologically diverse fragments into a single molecule. In this study, we designed and synthesized a series of indole-pyrazole hybrids, variously substituted at the pyrazole ring. The compounds were characterized by spectroscopic methods, and the structures of most of them were confirmed by X-ray analysis. Reactions of 3-(dimethylaminomethyl)indole with bromo-methyl-pyrazole derivatives proceeded in a tautomer-selective mode: the 4-bromo-3(5)-methyl-((1<i>H</i>-pyrazol-1-yl)methyl)-1<i>H</i>-indole tautomers, obtained from the 4-bromo-3-methyl-1<i>H</i>-pyrazole, could be isolated by column chromatography. In contrast, the 3-bromo-5-methyl-1<i>H</i>-pyrazole yielded the ((5-bromo-3-methyl-1H-pyrazol-1-yl)methyl)-1H-indole as the dominant reaction product. The 3-bromo-5-methyl tautomer could not be isolated nor could its presence be identified in solution. However, traces of it were recognized in the crystal of 5-bromo-3-methyl tautomer as a binary solid solution. In silico studies provided the physicochemical parameters of all compounds, enabling the estimation of some derivatives affinity to certain enzymes. In vitro evaluation of the hemolytic and cytoprotective properties of all derivatives showed that most of the compounds exhibited no hemolytic activity, while all demonstrated significant cytoprotective effects on human erythrocytes under oxidative stress.