ABSTRACT
Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aß self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aß self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
Subject(s)
Cholinesterase Inhibitors/chemistry , Free Radical Scavengers/chemistry , Sulfonamides/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Binding Sites , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Catalytic Domain , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/therapeutic use , Donepezil , Free Radical Scavengers/metabolism , Free Radical Scavengers/therapeutic use , Humans , Indans/chemistry , Indans/metabolism , Molecular Dynamics Simulation , Piperidines/chemistry , Piperidines/metabolism , Protein Binding , Sulfonamides/metabolism , Sulfonamides/therapeutic useABSTRACT
A selective reduction of a broad variety of ketones is described. The method is based on the combination of a Ni-Al alloy and high hydrostatic pressure (HHP, 2.8 kbar) in an aqueous medium. The reaction of the Ni-Al alloy with water provides in situ hydrogen generation and the high pressure ensures that the H(2) formed remains in the solution, thus the C=O reduction readily occurs. The application of the HHP resulted in selective formation of the desired products and the common problem of non-selective overhydrogenation could be avoided. In most cases the reductions resulted in high yields and excellent selectivities without the use of any base.
