Isoxazole substituted chromans against oxidative stress-induced neuronal damage

Isoxazole substituted chromans against oxidative stress-induced neuronal damage

URI: https://www.openarchives.gr/aggregator-openarchives/edm/helios/000024-10442_12298
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Title

Isoxazole substituted chromans against oxidative stress-induced neuronal damage

Creator

Tsatsaroni, Alexandra

Alexi, Xanthippi

Guerrand, Helene

Alexis, Michael N.

Zerva, Sofia

Description

We have previously reported that catechol-bearing regioisomers of 5-isoxazolyl-6-hydroxy-chroman display higher in vitro neuroprotective activity, compared to hybrids with other nitrogen heterocycles, but their activity is hampered by cytotoxicity at higher concentrations. In an effort to discover non-cytotoxic isoxazole substituted chromans of high neuroprotective activity, 20 new 3- and 5-substituted (chroman-5-yl)-isoxazoles and (chroman-2-yl)-isoxazoles were synthesized using the copper(I)-catalysed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes. An additional aim was to further explore the effect of the isoxazole ring substituents on the neuroprotective activity. The activity of these compounds against oxidative stress-induced death (oxytosis) of neuronal HT22 cells was evaluated and interesting SARs for this group of analogues were derived. The vast majority of new chroman analogues displayed high in vitro neuroprotective activity displaying EC(50) values below 1 mu M and lacked cytotoxicity. The position of substituents on the isoxazole ring influences the activity of the regioisomers, with the 3-aryl-5-(chroman-5-yl)-isoxazoles, 17 and 18 and bis-chroman 20 displaying higher neuroprotective activity (EC(50) similar to 0.3 mu M) compared to other (chroman-5-yl) and (chroman-2-yl)-isoxazoles.

Type

Article