Journal Article
Rational design of carbamate-based dual binding site and central AChE inhibitors by a "biooxidisable" prodrug approach: Synthesis, in vitro evaluation and docking studies
Ţînţaş, ML; Gembus, V; Alix, F; Barré, A; Coadou, G; Truong, L; Sebban, M; Papamicaël, C; Oulyadi, H; Levacher, V; ,
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
ISSY-LES-MOULINEAUX
Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.
Acetylcholine esterase inhibitors; Alzheimer; Dual-binding site inhibitor; 3 [[2 [2 [2 (1,3 dioxoisoindolin 2 yl)ethoxy]ethoxy]ethyl]carbamoyl] 1 methyl 1,4 dihydroquinolin 5 yl dimethylcarbamate; 5 [(dimethylcarbamoyl)oxy] 3 [[2 (2 hydroxyethyl)ethyl]carbamoyl] 1 methylquinolin 1 ium methylsulfate; acetylcholinesterase; amyloid beta protein[1-42]; carbamic acid derivative; cholinesterase inhibitor; donepezil; methyl 2 [[5 (dimethylcarbamoyloxy) 1 methylquinolin 1 ium 3 carbonyl]amino]acetate iodide; phthalic acid derivative; phthalimide; prodrug; quinoline derivative; serine derivative; serine hydroxyl; unclassified drug; [1 benzyl 3 (methylcarbamoyl)quinolin 1 ium 5 yl] n,n dimethylcarbamate bromide; [1 ethyl 3 (methylcarbamoyl)quinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [1 methyl 3 (methylcarbamoyl)quinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [1 methyl 3 (phenylcarbamoyl)quinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (2 methoxyethylcarbamoyl) 1 methylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (cyclohexylcarbamoyl) 1 methylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (dimethylcarbamoyl) 1 methylquinolin 1 ium 5 yl] n ethyl n methylcarbamate iodide; [3 (dimethylcarbamoyl) 1 methylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (dimethylcarbamoyl) 1,2 dimethylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (dimethylcarbamoyl) 1,2,4 trimethylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (dimethylcarbamoyl) 1,4 dimethylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (isopropylcarbamoyl) 1 methylquinolin 1 ium 5 yl] n,n dimethylcarbamate iodide; [3 (isopropylcarbamoyl) 1 methylquinolin 1 ium 5 yl]pyrrolidine 1 carboxylate iodide; acetylcholinesterase; amyloid beta protein; amyloid beta-protein (1-42); carbamic acid derivative; cholinesterase inhibitor; peptide fragment; prodrug; protein aggregate; quinoline derivative; Alzheimer disease; Article; binding site; Caco-2 cell line; carbamoylation; cell membrane permeability; controlled study; drug design; drug potency; drug protein binding; drug screening; drug structure; drug synthesis; enzyme active site; enzyme inhibition; human; IC50; in vitro study; molecular docking; oxidation reduction reaction; structure activity relation; substitution reaction; antagonists and inhibitors; binding site; chemical structure; chemistry; dose response; drug effect; metabolism; molecular docking; synthesis; Acetylcholinesterase; Amyloid beta-Peptides; Binding Sites; Caco-2 Cells; Carbamates; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Docking Simulation; Molecular Structure; Peptide Fragments; Prodrugs; Protein Aggregates; Quinolinium Compounds; Structure-Activity Relationship