69433-07-4Relevant academic research and scientific papers
Design, molecular Docking, synthesis and evaluation of xanthoxylin hybrids as dual inhibitors of IL-6 and acetylcholinesterase for Alzheimer's disease
Bansal, Yogita,Kaur, Sukhvir
, (2022/02/22)
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.
Dual inhibitors of Interleukin-6 and acetylcholinesterase for treatment of Alzheimer's disease: Design, docking, synthesis and biological evaluation
Bansal, Yogita,Kaur, Sukhvir
, (2021/11/13)
Multitarget compounds intercept two or more functionally complementary pathways simultaneously, and are therefore considered to have potential in effectively treating complex multifactorial diseases like Alzheimer's disease (AD). In the present study, novel molecules are designed by coupling a chromone and a N,N-disubstituted carbamoyl amine as pharmacophore for interleukin-6 (IL-6) and acetylcholinesterase (AChE) inhibition, respectively. Four series (Y1–Y4) of 40 compounds are designed by using alkyl linkers of different lengths (1–4 carbon atoms) for the coupling of the two selected pharmacophore. Docking of all designed compounds in AChE leads to the identification of twelve best fit compounds (Docking score >8.3). The data suggests that a 1- or 2-carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti-AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL-6 inhibitory activity. Compound Y1f is found to be the most potent inhibitor of both AChE and IL-6 (IC50 0.7 and 0.8 ?μM, respectively). It suggests that a chromone moiety connected to a piperidine ring through a 1-carbon atom linker may provide a useful template to medical chemists for the development of new chemical entities effective against AD.
