2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling

Giovanna L Delogu; Maria J Matos; Maura Fanti; Benedetta Era; Rosaria Medda; Enrico Pieroni; Antonella Fais; Amit Kumar; Francesca Pintus

doi:10.1016/j.bmcl.2016.03.039

2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling

Bioorg Med Chem Lett. 2016 May 1;26(9):2308-13. doi: 10.1016/j.bmcl.2016.03.039. Epub 2016 Mar 11.

Authors

Giovanna L Delogu¹, Maria J Matos², Maura Fanti³, Benedetta Era¹, Rosaria Medda¹, Enrico Pieroni⁴, Antonella Fais⁵, Amit Kumar⁶, Francesca Pintus¹

Affiliations

¹ Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
² Department of Organic Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain.
³ Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
⁴ Biomedicine Department, Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy.
⁵ Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy. Electronic address: fais@unica.it.
⁶ Biomedicine Department, Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy; Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Cagliari, Italy. Electronic address: amit369@gmail.com.

PMID: 26995529
DOI: 10.1016/j.bmcl.2016.03.039

Abstract

A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Benzofurans; Butyrylcholinesterase; Cholinesterase inhibitors; Docking; Molecular dynamics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzofurans / chemical synthesis*
Benzofurans / chemistry
Benzofurans / pharmacology*
Butyrylcholinesterase / drug effects*
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Models, Molecular

Substances

Benzofurans
Cholinesterase Inhibitors
Butyrylcholinesterase
benzofuran