Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell death

A new generation of chroman/catechol hybrids bearing heterocyclic five-membered rings, such as 1,2,4-oxadiazole 1,3,4-oxadiazole, 1,2,3-triazole, tetrazole and isoxazole, were designed and synthesized. The activity of the new derivatives against oxidative stress induced neuronal damage, was evaluated using glutamate-challenged hippocampal HT22 cells.Compound 3 in which a 3,4-dimethoxyphenyl moiety, is directly attached to the 1,2,4-oxadiazole ring was the most active among the 2-substituted chroman analogues, with EC₅₀ = 254 ± 65 nM. Concerning the 5-subtituted chroman analogues, isoxazole derivative 29 exhibited the strongest activity (EC₅₀ = 245 ± 38 nM). However, 29 was cytotoxic at concentrations higher than 1 μM, while the triazole analogue 24 (EC₅₀ = 801 ± 229 nM), was non-toxic at all concentrations tested.