The piperazine derivatives have been shown to inhibit human acetylcholinesterase. Virtual screening by molecular docking of piperazine derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K), 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S1), and 4-(4-chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S3) has been shown to bind at peripheral anionic site and catalytic sites, whereas 4-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S4) and 4-(2,5-dichloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S7) do not bind either to peripheral anionic site or catalytic site with hydrogen bond. All the derivatives have differed in number of H-bonds and hydrophobic interactions. The peripheral anionic site interacting molecules have proven to be potential therapeutics in inhibiting amyloid peptides aggregation in Alzheimer’s disease. All the piperazine derivatives follow Lipinski’s rule of five. Among all the derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K) was found to have the lowest TPSA value. 1. Introduction Acetylcholinesterase (AChE) hydrolyses acetylcholine is associated with nerves and muscles mainly found in synapses. AChE plays an important role in regulation of cholinergic function. It has been shown to be involved in dysfunction of the central cholinergic system in Alzheimer’s disease (AD). It is a progressive neurodegenerative disorder, characterized by an impairment of cognitive function leading to dementia. The main characteristic features of the disease include β-amyloid (Aβ) plaques, neurofibrillary tangles, and their by synaptic loss. AD is estimated to account for about 50–60% dementia cases, in persons over 65 years of age [1]. Symptoms of Alzheimer’s disease include memory loss, language deficit, depression, agitation, and mood disturbances [2–4]. But the exact cause for AD is still not known. Several hypotheses tried to explain the cause of the disease [5]. Among those, the oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine [1]. Even though the hypothesis failed to get widespread support, but it can be stated that cholinergic scarcity is responsible for the symptoms of AD [5]. This led to the designing and synthesis of AChE inhibitors. The inhibition causes an increase in the concentration of acetylcholine in cholinergic synapse. This might ameliorate the disease symptoms of AD [6, 7]. Tacrine, Donepezil, Rivastigmine,
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