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Issue 52, 2016, Issue in Progress
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Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2H)-one derivatives as novel cholinesterase inhibitors

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Abstract

A new series of donepezil analogues based on the phthalazin-1(2H)-one scaffold was designed and synthesized with the aim of exploring its potential as human ChEIs. Biological results revealed that the structural modifications proposed significantly affected ChE inhibitory potency as well as selectivity for AChE/BuChE. Compound 1d showed promising in vitro inhibition of both enzymes in the μM range. However, most target compounds were significantly more active against AChE than BuChE, specifically 1f, 1h and 1j, with IC50 values in the low micromolar or submicromolar range, the most active compounds in the series. Docking simulations suggested that the most active compounds can recognize the donepezil binding site using a similar interactions network. These results allowed us to rationalize the observed structure–activity relationships. Moreover, the predicted physicochemical and ADME properties were also comparable to those of donepezil.

Graphical abstract: Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2H)-one derivatives as novel cholinesterase inhibitors

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Publication details

The article was received on 11 Feb 2016, accepted on 24 Apr 2016 and first published on 26 Apr 2016


Article type: Paper
DOI: 10.1039/C6RA03841G
Citation: RSC Adv., 2016,6, 46170-46185
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    Synthesis, biological evaluation and molecular modeling studies of phthalazin-1(2H)-one derivatives as novel cholinesterase inhibitors

    N. Vila, P. Besada, D. Viña, M. Sturlese, S. Moro and C. Terán, RSC Adv., 2016, 6, 46170
    DOI: 10.1039/C6RA03841G

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