Novel aryl(4-phenylpiperazin-1-yl)methanethione derivatives as new anti-Alzheimer agents: Design, synthesis, in vitro and in silico assays

•Successful synthesis of a new series of aryl(4-phenylpiperazin-1-yl)methanethione derivatives.•Screening of the title compounds against AChE, BChE, and α-glucosidase.•Most of the new compounds had a significant anti-AChE activity.•All the title compounds were more potent than positive control donepezil against BChE.•The most potent compounds interacted as well with AChE/BChE active sites. In this work, a new series of aryl(4-phenylpiperazin-1-yl)methanethione derivatives 4a-n was designed, synthesized, and evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. Most of the synthesized derivatives were more potent than standard inhibitor donepezil against AChE and all the synthesized compounds were more potent than donepezil against BChE. Moreover, some of these new compounds were more potent than acarbose (positive control) against α-glucosidase. The obtained results revealed that (3-chlorophenyl)(4-phenylpiperazin-1-yl)methanethione 4k and was the most potent compound against cholinesterase enzymes (AChE and BChE). Docking study of compound 4k in the active site of cholinesterase enzymes showed that this compound established important interactions with the main residues of the target enzymes. Druglikeness/ADME/Toxicity profile prediction of the most potent compounds also demonstrated that these compounds can be drug candidates and have the appropriate properties in terms of ADME and Toxicity. [Display omitted]