New C8-substituted caffeine derivatives as promising antioxidants and cytoprotective agents in human erythrocytes

Abstract

New structurally diverse groups of C8-substituted caffeine derivatives were synthesized and evaluated for their chemical and biological properties. Mass spectrometry, FT-IR, and NMR characterizations of these derivatives were performed. The cytotoxic activity of the derivatives was estimated in vitro using human red blood cells (RBC) and in silico pharmacokinetic studies. The antioxidant capacity of the compounds was analyzed using a ferrous ion chelating activity assay. The ability of the derivatives to protect RBC from oxidative damage, including the oxidation of hemoglobin to methemoglobin, was assessed using a water-soluble 2,2′-azobis(2-methyl-propionamidine) dihydrochloride (AAPH) as a standard inducer of peroxyl radicals. The level of intracellular oxidative stress was assessed using the fluorescent redox probe 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA). The results indicate that all derivatives are biocompatible compounds with significant antioxidant and cytoprotective potential dependent on their chemical structure. In order to explain the antioxidant and cytoprotective activity of the derivatives, a mechanism of hydrogen atom transfer (HAT), radical adduct formation (RAF), or single electron transfer (SET), as well as the specific interactions of the derivatives with the lipid bilayer of RBC membrane, have been proposed. The results show that selected modifications of the caffeine molecule enhance its antioxidant properties, which expands our knowledge of the structure–activity relationship of caffeine-based cytoprotective compounds.

Novel C3-Methylene-Bridged Indole Derivatives with and without Substituents at N1: The Influence of Substituents on Their Hemolytic, Cytoprotective, and Antimicrobial Activity

“…Compounds 2 and 5 were found to be hydrophilic, with logP values of 1.80 and 1.94, respectively. They contained polar substituents in Position C3 of the indole ring, resulting in a "polar head-non-polar tail" structure, which enhanced the stability of the RBC membrane by interacting in the lipid bilayer of the cell membrane [14,60]. The high cytoprotective activity also characterized Derivative 10 (84.9% ± 1.3), especially in comparison to its benzothiazole analog [16].…”