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 an d examined for their intrinsic cytotoxicity and their capacity to inhibit o xidative stress-mediated neuronal degeneration in neuronal cell cultures. I n particular, substituent effects at the 3- and 8-positions of the 1,4-benz oxazine ring were investigated by in vitro evaluation.. In this aim, 3-alky l substituents seemed to be essential for efficient neuroprotective activit y. Furthermore, within the subseries of substituted S-alkyl benzoxazines, t he most active derivatives were those bearing an 8-benzylamino substituent. From the combined results of both toxicity and neuroprotection expressed i n terms of the safety index, 8-benzylamino-substituted-3-alkyl-1,4-benzoxaz ines were identified as the most promising compounds, owing to their potent neuroprotective activity without the manifestation of intrinsic cytotoxici ty.