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 compounds were significantly more potent inhibitors of lipid peroxidation in vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure 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 penetration of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2yl)ca rbonyl]-3'-(aminoethyl) indole (12), inhibited ex vivo lipid peroxidation in a head injury model and showed potent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed together with significant anti-anoxia activity. Compound 12 was a potent antagonist of methamphetamine-induced hypermotility resulting from dopamine release in the mouse brain. These results support the importance of cerebroprotective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radicals and dopamine in brain damage.
Vajragupta
O
O
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand. pyovj@mahidol.ac.th
Toasaksiri
S
S
Boonyarat
C
C
Wongkrajang
Y
Y
Peungvicha
P
P
Watanabe
H
H
Boonchoong
P
P
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy; D002839:Chromans / Q000138:chemical synthesis / Q000494:pharmacology*; D006259:Craniocerebral Trauma / Q000188:drug therapy; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000737:chemistry*; D017665:Hydroxyl Radical / Q000737:chemistry; D000860:Hypoxia / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology*
D002839:Chromans; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009536:Niacinamide; D017665:Hydroxyl Radical; D008694:Methamphetamine; D004298:Dopamine