title: Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease.
abstract: This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Bautista-Aguilera
authors.forename: Matilde
authors.initials: M
authors.lastname: Yañez
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Ramón
authors.initials: R
authors.lastname: Cacabelos
authors.forename: Raimon Puig
authors.initials: RP
authors.lastname: de la Bellacasa
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
authors.affiliation: Laboratorio de Quimica Medica (IQOG, CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain. iqoc21@iqog.csic.es.
authors.forename: Jose
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002802:Cholinesterases / Q000378:metabolism; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D012717:Sesquiterpenes; C050426:huperzine A; D013619:Tacrine; D000110:Acetylcholinesterase; D002802:Cholinesterases