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Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease

dc.contributor.authorRodríguez-Lavado J.
dc.contributor.authorGallardo-Garrido C.
dc.contributor.authorMallea M.
dc.contributor.authorBustos V.
dc.contributor.authorOsorio R.
dc.contributor.authorHödar-Salazar M.
dc.contributor.authorChung H.
dc.contributor.authorAraya-Maturana R.
dc.contributor.authorLorca M.
dc.contributor.authorPessoa-Mahana C.D.
dc.contributor.authorMella-Raipán J.
dc.contributor.authorSaitz C.
dc.contributor.authorJaque P.
dc.contributor.authorReyes-Parada M.
dc.contributor.authorIturriaga-Vásquez P.
dc.contributor.authorPessoa-Mahana H.
dc.date.accessioned2020-09-02T22:27:07Z
dc.date.available2020-09-02T22:27:07Z
dc.date.issued2020
dc.identifier10.1016/j.ejmech.2020.112368
dc.identifier.citation198, , -
dc.identifier.issn02235234
dc.identifier.urihttps://hdl.handle.net/20.500.12728/6061
dc.descriptionDuring the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease β-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 μM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 μM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant β-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 μM) and 25 (35% inhibition, 10 μM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease. © 2020 Elsevier Masson SAS
dc.language.isoen
dc.publisherElsevier Masson SAS
dc.subjectAChE
dc.subjectAlzheimer's disease
dc.subjectDual-active compounds
dc.subjectIndole derivatives
dc.subjectMultitarget
dc.subjectSERT
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 (4 benzoylpiperazin 1 yl)ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (2 bromobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (3 bromobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (3 chlorobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (3 fluorobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (3methoxybenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4 chlorobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4 fluorobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4 methoxybenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4bromobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4methylbenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl) 2 [4 (4 methylbenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4 fluorobenzoyl)piperazin 1 yl]ethan 1 one
dc.subject1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl] 2 [4 (4 methoxybenzoyl)piperazin 1 yl]ethan 1 one
dc.subject2 (4 benzoylpiperazin 1 yl) 1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl]ethan 1 one
dc.subject2 [4 (4 bromobenzoyl)piperazin 1 yl] 1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl]ethan 1 one
dc.subject2 [4 (4 chlorobenzoyl)piperazin 1 yl] 1 [4 [3 (5 fluoro 1h indol 3 yl)propyl]piperazin 1 yl]ethan 1 one
dc.subjectcholinesterase inhibitor
dc.subjectpiperazine derivative
dc.subjecttert butyl 4 [2 (4 benzoylpiperazin 1 yl)acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (2 bromobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (3 bromobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (3 chlorobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (3 fluorobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (4 bromobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (4 chlorobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (4 fluorobenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (4 methoxybenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjecttert butyl 4 [2 [4 (4 methylbenzoyl)piperazin 1 yl]acetyl]piperazine 1 carboxylate
dc.subjectunclassified drug
dc.subjectunindexed drug
dc.subjectAlzheimer disease
dc.subjectanimal cell
dc.subjectArticle
dc.subjectcarbon nuclear magnetic resonance
dc.subjectcell viability
dc.subjectcholinesterase inhibition
dc.subjectcontrolled study
dc.subjectdrug synthesis
dc.subjectHEK293 cell line
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthydrogen bond
dc.subjectIC50
dc.subjectin vitro study
dc.subjectmolecular docking
dc.subjectmouse
dc.subjectNeuro-2a cell line
dc.subjectnonhuman
dc.subjectproton nuclear magnetic resonance
dc.subjectSH-SY5Y cell line
dc.titleSynthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease
dc.typeArticle


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