title: Homodimeric bis-quaternary heterocyclic ammonium salts as potent acetyl- and butyrylcholinesterase inhibitors: a systematic investigation of the influence of linker and cationic heads over affinity and selectivity.
abstract: A molecular library of quaternary ammonium salts (QASs), mainly composed of symmetrical bis-quaternary heterocyclic bromides exhibiting choline kinase (ChoK) inhibitory activity, were evaluated for their ability to inhibit acetyl- and butyrylcholinesterase (AChE and BChE, respectively). The molecular framework of QASs consisted of two positively charged heteroaromatic (pyridinium or quinolinium) or sterically hindered aliphatic (quinuclidinium) nitrogen rings kept at an appropriate distance by lipophilic rigid or semirigid linkers. Many homodimeric QASs showed AChE and BChE inhibitory potency in the nanomolar range along with a low enzymatic selectivity. Computational studies on AChE, BChE, and ChoK allowed identification of the key molecular determinants for high affinity and selectivity over either one of the three enzymes and guided the design of a hybrid bis-QAS (56) exhibiting the highest AChE affinity (IC(50) = 15 nM) and selectivity over BChE and ChoK (SI = 50 and 562, respectively) and a promising pharmacological potential in myasthenia gravis and neuromuscular blockade.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Maria del Carmen
authors.initials: Mdel C
authors.lastname: Núñez
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000110:Acetylcholinesterase / Q000009:adverse effects*; D002091:Butyrylcholinesterase / Q000009:adverse effects*; D002412:Cations; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002412:Cations; D002800:Cholinesterase Inhibitors; D006571:Heterocyclic Compounds; D000644:Quaternary Ammonium Compounds; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase