Chroman amide and nicotinyl amide derivatives: Inhibition of lipid peroxidation and protection against head trauma

A series of chroman amide and nicotinyl amide derivatives was designed and synthesized for the treatment of traumatic and ischemic CNS injury. Five co mpounds were significantly more potent inhibitors of lipid peroxidation ill vitro than the reference antioxidant, trolox (p < 0.01). Quantitative stru cture activity studies demonstrated that the inhibitory action was related to the ability to donate electrons, charge on hydroxy group and E-LUMO, to scavenging radicals and to the lipophilicity log P, which determines penetr ation of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydrox y2,5,7,8-tetramethyl-2H-1-benzopyran-2yl) carbonyl](aminoethyl) indole (12) , inhibited ex vivo lipid peroxidation in a head injury model and showed po tent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed tog ether with significant anti-anoxia activity. Compound 12 was a potent antag onist of methamphetamine-induced hypermotility resulting from dopamine rele ase in the mouse brain. These results support the importance of cerebroprot ective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radica ls and dopamine in brain damage.