title: Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptors.
abstract: The synthesis and the biological activity of compounds 5-40 as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as modulators of voltage-dependent Ca(2+) channels and nicotinic receptors, are described. These molecules are tacrine analogues, which have been prepared from polyfunctionalized 6-amino-5-cyano-4H-pyrans, 6-amino-5-cyano-pyridines and 5-amino-2-aryl-3-cyano-1,3-oxazoles via Friedländer reaction with selected cycloalkanones. These compounds are moderate acetylcholinesterase and butyrylcholinesterase inhibitors, the BuChE/AChE selectivity of the most active molecules ranges from 10.0 (compound 29) to 76.9 (compound 16). Interestingly, the 'oxazolo-tacrine' derivatives are devoid of any activity. All compounds showed an important inhibitory effect on the nicotinic acetylcholine receptor. Most of them also blocked L-type Ca(2+) channels, and three of them, 64, 19 and 67, the non-L type of Ca(2+) channels. Molecular modelling studies suggest that these compounds might bind at the peripheral binding site of AChE, which opens the possibility to design inhibitors able to bind at both, the catalytic and peripheral binding sites of the enzyme.
authors.affiliation: Laboratorio de Radicales Libres, IQOG, CSIC, C/ Juan de la Cierva 3, 28006 Madrid, Spain. iqoc@iqog.csic.es
authors.forename: José L
authors.initials: JL
authors.lastname: Marco
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: M Carmo
authors.initials: MC
authors.lastname: Carreiras
authors.forename: Carla
authors.initials: C
authors.lastname: Martins
authors.forename: Ana
authors.initials: A
authors.lastname: Eleutério
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.forename: M
authors.initials: M
authors.lastname: Orozco
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D002091:Butyrylcholinesterase / Q000187:drug effects*; D015220:Calcium Channels / Q000187:drug effects*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011978:Receptors, Nicotinic / Q000187:drug effects*
chemical_list: D015220:Calcium Channels; D002800:Cholinesterase Inhibitors; D006571:Heterocyclic Compounds; D011978:Receptors, Nicotinic; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase