Design synthesis and biological evaluation of compounds for the treatment of alzheimers disease

Abstract

Alzheimer s dementia is a major cause of disability and mortality. The typical newlineneuropathological hallmarks are deposition of protein aggregates or plaques, newlineformation of neurofibrillary tangles and neuronal cell death. Alzheimer s disease newline(AD) is a complex neurological condition where several genes act independently/in newlinecoordination with each other and/or with environmental agents. The role of newlinesulphonamide functional moiety in design of anti-AD agents is well supported by newlinevarious research groups. Some of the successfully evaluated includes Nacylsulfonamides, N-benzylisatin sulfonamide analogues, and N-aryl sulfonamide newlinesubstituted 3-morpholino arecoline derivatives with selectivity for reducing Aand#946; newlineaggregation. A recent example is Verubecestat prepared by Cu-catalyzed C-N newlinecoupling as well as diastereoselective Mannich type reaction. newlineThe present work aims to provide a possible solution for AD. In view of this, newlinea series of substituted aryl sulfonamide derivatives was developed using computeraided drug design methods such as quantitative structure-activity relationship newline(QSAR) and molecular docking. Series of N-(5-chloro-2-hydroxymethyl)-N-alkylarylsulfonamides was used to develop QSAR models. The molecular level newlineinteractions of substituted arylsulfonamides towards and#947;-secretase and human AChE newlinewere studied using AutoDock4.0 using reported docking protocol. Selected newlinecompounds were synthesized and characterized. During biological evaluation, newlineinitially acute toxicity studies were performed. The synthesized compounds were newlineevaluated for their effect on acquisition in scopolamine induced anterograde amnesia newlineand neuroprotective activity. Behavioural assessment was carried out using Morris newlineWater Maze (MWM) test and effect on spatial and temporal memory was recorded. newlineAfter the MWM treatment period, group showing significant results were sacrificed newlineby decapitation under mild anaesthesia and brains were immediately isolated, newlineprocessed for performing biochemical assays like lipid peroxidation (LPO), reduced newlineglutathione (GSH), and AChE