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J Enzyme Inhib Med Chem. 2020 Dec;35(1):211-226. doi: 10.1080/14756366.2019.1689237.

Novel tacrine-benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer's Disease.

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Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
Department of Earth Sciences, University of Pisa, Pisa, Italy.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
CNC-Center for Neuroscience and Cell Biology, Universidade de Coimbra, Coimbra, Portugal.
Institute of Molecular and Cell Biology, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.


Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.


AChE inhibitors; Alzheimer’s disease; metal chelators; multi-target drugs; tacrine-benzofuran hybrids

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