Novel multipotent tacrine-dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer's disease.
In this work we describe the synthesis and biological evaluation of the tacrine-1,4-dihydropyridine (DHP) hybrids (3-11). These multipotent molecules are the result of the juxtaposition of an acetylcholinesterase inhibitor (AChEI) such as tacrine (1) and a 1,4-DHP such as nimodipine (2). Compounds 3-11 are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca2+ channel blockade effect. Consequently, these molecules are new potential drugs for the treatment of Alzheimer's disease.
Marco-Contelles
José
J
Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain. iqoc21@iqog.csic.es
León
Rafael
R
de Los Ríos
Cristóbal
C
Guglietta
Antonio
A
Terencio
José
J
López
Manuela G
MG
García
Antonio G
AG
Villarroya
Mercedes
M
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000737:chemistry*; D004524:Eels / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry*
D000975:Antioxidants; D015220:Calcium Channels; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D013619:Tacrine; C038806:1,4-dihydropyridine; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D000110:Acetylcholinesterase; D002118:Calcium