Synthesis and in vitro evaluation of new 8-amino-1,4-benzoxazine derivatives as neuroprotective antioxidants.
A series of new 8-amino-1,4-benzoxazine derivatives 5a-o was synthesized and examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative stress-mediated neuronal degeneration in neuronal cell cultures. In particular, substituent effects at the 3- and 8-positions of the 1,4-benzoxazine ring were investigated by in vitro evaluation. In this aim, 3-alkyl substituents seemed to be essential for efficient neuroprotective activity. Furthermore, within the subseries of substituted 3-alkyl benzoxazines, the most active derivatives were those bearing an 8-benzylamino substituent. From the combined results of both toxicity and neuroprotection expressed in terms of the safety index, 8-benzylamino-substituted-3-alkyl-1,4-benzoxazines were identified as the most promising compounds, owing to their potent neuroprotective activity without the manifestation of intrinsic cytotoxicity.
Largeron
M
M
Laboratoire de Chimie Analytique et Electrochimie, UMR 8638 CNRS - Université René Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France,
Lockhart
B
B
Pfeiffer
B
B
Fleury
M B
MB
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology; D048588:Benzoxazines; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006624:Hippocampus; D051379:Mice; D015394:Molecular Structure; D009410:Nerve Degeneration / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D018384:Oxidative Stress; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
C402280:(8-benzylamino-3,3-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl)(phenyl)methanone; C402279:(8-benzylamino-3-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone; C402322:(8-benzylamino-3-spiro-1'-cyclopentyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl)(phenyl)methanone; D000975:Antioxidants; D001577:Benzophenones; D048588:Benzoxazines; D018696:Neuroprotective Agents; D010078:Oxazines; D011619:Psychotropic Drugs; D013141:Spiro Compounds; C052932:exifone