Design, Molecular Docking, Synthesis and Evaluation of Xanthoxylin Hybrids as Dual Inhibitors of IL‐6 and Acetylcholinesterase for Alzheimer’s Disease

Abstract

AbstractBackgroundIL‐6 and AChE play a pivotal role in progression of AD, it is hypothesised that simultaneous inhibition of IL‐6 and AChE may prove as an effective strategy for treatment of AD. Therefore, the present study is undertaken to design novel molecules capable of acting as dual inhibitors of IL‐6 and AChE. Literature review reveals that xanthoxylin and a disubstituted amines or a carbamoyl amines are pharmacophores for IL‐6 and AChE inhibition, respectively.MethodXanthoxylin is coupled with various disubstituted amines or carbamoyl amines through alkyl linkers of different lengths (1‐4 carbon atoms) to design two series of 80 compounds. All designed compounds were docked into AChE to identify the best fit compounds for synthesis and evaluation of AChE inhibitory activity. The compounds showing >45% inhibition of EeAChE are selected for evaluation of IL‐6 and butyrylcholinesterase (BuChE) inhibitory activities. The compound found to be most potent against AChE, BuChE and IL‐6 inhibition was finally evaluated in vivo using STZ‐induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg).ResultCompound K13g is found to be the most potent inhibitor of EeAChE, BuChE and IL‐6. It is further evaluated in vivo, wherein it shows dose‐dependent effects. It is observed to be less active at lower doses, but completely reversed the STZ‐induced memory deficit at 0.8 mg/kg.ConclusionThe findings suggest that a compound having a xanthoxylin moiety connected to a piperazine ring through a three‐carbon atom chain may provide a useful template for the development of new chemical entities effective against AD.