Design, Synthesis and Evaluation of substituted Chromones as Acetylcholinesterase Inhibitors for the Treatment of Alzheimer’s Disease.

AbstractBackgroundAcetylcholinesterase (AChE) is one of the frontline targets involved in the progression of Alzheimer’s disease. AChE inhibitors are prescribed as the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease[1, 2]. AChE is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways[3]. The enzyme inactivation induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotine and muscarinic receptor and disrupted neurotransmission.MethodA series of chromone derivatives were virtually screened, synthesised and biologically evaluated as acetylcholinesterase inhibitors. All the compounds were characterised by 1H‐NMR, 13C‐NMR and mass spectrometry.ResultThe in‐vitro evaluation of the compounds against hAChE enzyme showed promising inhibition varying in lower micromolar range. In the synthesized series, NSS‐17 is found to be the most potent AChE inhibitors (IC50 = 1.59± 0.02 μM). In molecular docking studies, compound NSS‐17 showed similar interaction to AChE (1EVE) as shown by reference compound donepezil.ConclusionThus, NSS‐17 can be used as promising lead for the development of more potent AChE inhibitors by further biological assays and in‐vivo studies. References [1] B. Kumar, A.R. Dwivedi, B. Sarkar, S.K. Gupta, S. Krishnamurthy, A.K. Mantha, J. Parkash, V. Kumar, 4,6‐Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease, ACS Chemical Neuroscience 10(1) (2019) 252‐265.[2] B. Kumar, V. Kumar, V. Prashar, S. Saini, A.R. Dwivedi, B. Bajaj, D. Mehta, J. Parkash, V. Kumar, Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase, European Journal of Medicinal Chemistry 177 (2019) 221‐234.[3] B. Kumar, Sheetal, A.K. Mantha, V. Kumar, Recent developments on the structure–activity relationship studies of MAO inhibitors and their role in different neurological disorders, RSC Advances 6(48) (2016) 42660‐42683.