A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives

Chamseddine Derabli; Imen Boualia; Ahmed B Abdelwahab; Raouf Boulcina; Chawki Bensouici; Gilbert Kirsch; Abdelmadjid Debache

doi:10.1016/j.bmcl.2018.05.063

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2481-2484. doi: 10.1016/j.bmcl.2018.05.063. Epub 2018 Jun 1.

Authors

Chamseddine Derabli¹, Imen Boualia¹, Ahmed B Abdelwahab², Raouf Boulcina³, Chawki Bensouici⁴, Gilbert Kirsch⁵, Abdelmadjid Debache¹

Affiliations

¹ Laboratory of Synthesis of Molecules with Biological Interest, Frères Mentouri-Constantine University, 25000 Constantine, Algeria.
² SRSMC, Lorraine University, 1 Boulevard Arago, 57070, France; Chemistry of Natural Compounds Department, National Research Centrer, El-Behoos St. 33, Dokki, Cairo 12622, Egypt.
³ Laboratory of Synthesis of Molecules with Biological Interest, Frères Mentouri-Constantine University, 25000 Constantine, Algeria; Faculty of Technology, Batna 2 University, 05000 Batna, Algeria. Electronic address: r.boulcina@univ-batna2.dz.
⁴ Biotechnology Research Center, Constantine, Algeria.
⁵ SRSMC, Lorraine University, 1 Boulevard Arago, 57070, France.

PMID: 29887354
DOI: 10.1016/j.bmcl.2018.05.063

Abstract

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC₅₀ values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC₅₀ values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC₅₀ values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.

Keywords: Alzheimer’s disease; Cholinesterase inhibition; Docking study; Multicomponent reaction; Tacrine-pyranopyrazole derivatives.

MeSH terms

Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Cholinesterases / metabolism*
Dose-Response Relationship, Drug
Humans
Molecular Docking Simulation*
Molecular Structure
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Tacrine / chemistry
Tacrine / pharmacology*

Substances

Cholinesterase Inhibitors
Pyrazoles
Tacrine
Cholinesterases