ABSTRACT
Cholinesterase inhibitors remain the mainstay of Alzheimer's disease treatment, and the search for new inhibitors with better efficacy and side effect profiles is ongoing. Virtual screening (VS) is a powerful technique for searching large compound databases for potential hits. This study used a sequential VS workflow combining ligand-based VS, molecular docking and physicochemical filtering to screen for central nervous system (CNS) drug-like acetylcholinesterase inhibitors (AChEIs) amongst the 6.9 million compounds of the CoCoCo database. Eleven in silico hits were initially selected, resulting in the discovery of an AChEI with a Ki of 3.2 µM. In vitro kinetics and in silico molecular dynamics experiments informed the selection of an additional seven analogues. This led to the discovery of two further AChEIs, with Ki values of 2.9 µM and 0.65 µM. All three compounds exhibited reversible, mixed inhibition of acetylcholinesterase. Importantly, the in silico physicochemical filter facilitated the discovery of CNS drug-like compounds, such that all three inhibitors displayed high in vitro blood-brain barrier model permeability.
Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Animals , Binding Sites , Butyrylcholinesterase/metabolism , Catalytic Domain , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Databases, Chemical , Donepezil/chemistry , Donepezil/metabolism , Donepezil/therapeutic use , Electrophorus/metabolism , Horses/metabolism , Kinetics , Molecular Dynamics Simulation , Permeability/drug effectsABSTRACT
A strategy based on Pd-mediated ring closure of 1,2-disubstituted indoles containing an unactivated olefin leading to indole-1,2-fused 8- and 9-membered rings has been developed for the identification of new and potential scaffolds for apoptosis. A large number of fused indole derivatives containing an endocyclic double bond were synthesized using this robust methodology. A representative compound showed promising apoptotic properties in zebrafish embryos.
Subject(s)
Apoptosis/drug effects , Indoles/chemistry , Indoles/pharmacology , Palladium/chemistry , Zebrafish/metabolism , Animals , Drug Design , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/drug effects , Indoles/chemical synthesis , Iodine/chemistry , Magnetic Resonance Spectroscopy , Methotrexate/pharmacology , Stereoisomerism , Time Factors , Zebrafish/embryologyABSTRACT
Unprecedented synthesis of functionalized indoles of potential pharmacological interest has been developed via a Pd-mediated cascade reaction involving an intramolecular Heck coupling followed by the construction of a fused cyclopentane ring in a single pot.
Subject(s)
Cyclopentanes/chemical synthesis , Indoles/chemical synthesis , Palladium/chemistry , Cyclization , Models, MolecularABSTRACT
A new, versatile and direct Pd-mediated method involving intramolecular cyclization of N-(2-iodoaryl)-N-(1-alkyl-1H-indol-2-yl)alkane/arene/heteroarene sulfonamide has been developed leading to a diverse and unique class of indolo[2,3-b]indoles for the potential inhibition of sirtuins.
