Design, molecular Docking, synthesis and evaluation of xanthoxylin hybrids as dual inhibitors of IL-6 and acetylcholinesterase for Alzheimer's disease

Interleukin-6 (IL-6) and acetylcholinesterase (AChE) are two important targets implicated in progression of Alzheimer's Disease (AD). Simultaneous inhibition of both IL-6 and AChE by a molecule presents an effective strategy for the treatment of AD. In this study, the pharmacophores for inhibition of IL-6 and AChE are identified, and coupled to design novel molecules capable of acting as dual inhibitors of IL-6 and AChE. Literature review reveals that xanthoxylin and a disubstituted or a carbamoyl amine are pharmacophore for IL-6 and AChE inhibition, respectively. Therefore, xanthoxylin 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 are docked in AChE. Based on their docking score, 15 compounds are selected 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. Compound Y13g is found to be the most potent inhibitor of EeAChE, BuChE and IL-6. It is further evaluated in vivo using STZ-induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg), wherein it shows dose-dependent effects. At 0.8 mg/kg, it reverses the STZ-induced memory deficit, and shows histopathology similarly as in normal animals. The findings suggest that compounds derived from coupling of xanthoxylin with piperazine through a 3-carbon chain provides a useful template for the development of new chemical entities effective against AD.