Synthesis and Neuroprotective Properties of N-Substituted C-Dialkoxyphosphorylated Nitrones

Herein, we report the synthesis and neuroprotective power of some N-substituted C-(dialkoxy)phosphorylated nitrones 4a-g, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified (Z)-N-tert-butyl-1-(diethoxyphosphoryl)methanimine oxide (4e) as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 μM concentrations. Thus, nitrone 4e could be a convenient promising compound for further investigation.The synthetic part of the project was supported by the National Science Centre (grant UMO-2015/17/B/ST5/ 00076). D.H.-L. gratefully acknowledges Dr A. Leo and Biobyte Corp., 201 West 4th Street, Suite 204, Claremont, CA 91711, for free access to the C-QSAR program. J.M.-C. and M.J.O.-G. thank MINECO (Government of Spain) (SAF2015- 65586-R) and Universidad Camilo José Cela (NitroStroke project, 2015-12) for support.Peer Reviewe