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 EC(50)=254+/-65nM. Concerning the 5-subtituted chroman analogues, isoxazole derivative 29 exhibited the strongest activity (EC(50)=245+/-38nM). However, 29 was cytotoxic at concentrations higher than 1microM, while the triazole analogue 24 (EC(50)=801+/-229nM), was non-toxic at all concentrations tested.
Koufaki
Maria
M
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece. mkoufa@eie.gr
Theodorou
Elissavet
E
Alexi
Xanthippi
X
Alexis
Michael N
MN
D000818:Animals; D001393:Azoles / Q000737:chemistry; D002396:Catechols / Q000138:chemical synthesis* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002839:Chromans / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001393:Azoles; D002396:Catechols; D002839:Chromans