title: Isoxazole substituted chromans against oxidative stress-induced neuronal damage.
abstract: 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 μM 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)∼0.3 μM) compared to other (chroman-5-yl) and (chroman-2-yl)-isoxazoles.
authors.affiliation: National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, 48 Vas. Constantinou Ave., 11635 Athens, Greece. mkoufa@eie.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Koufaki
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tsatsaroni
authors.forename: Xanthippi
authors.initials: X
authors.lastname: Alexi
authors.forename: Helène
authors.initials: H
authors.lastname: Guerrand
authors.forename: Sofia
authors.initials: S
authors.lastname: Zerva
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alexis
mesh_terms: D000818:Animals; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D002396:Catechols; D002839:Chromans; D007555:Isoxazoles; D018696:Neuroprotective Agents