Triazolopyridopyrimidine: A New Scaffold for Dual-Target Small Molecules for Alzheimer's Disease Therapy.

Lazhar Zribi,Òscar M Bautista-Aguilera,José Marco-Contelles,Daniel Diez-Iriepa,Irene Pachòn-Angona,Isabel Iriepa,Fakher Chabchoub,Lhassane Ismaili

doi:10.3390/molecules25143190

Abstract

Alzheimer’s disease (AD) is multifactorial disease characterized by the accumulation of abnormal extracellular deposits of amyloid-beta (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), along with dramatic neuronal death and decreased levels of choline acetyltransferase. Given the limited therapeutic success of available drugs, it is urgent to explore all the opportunities available to combat this illness. Among them, the discovery of new heterocyclic scaffolds binding different receptors involved in AD should offer structural diversity and new therapeutic solutions. In this context, this work describes new triazolopyridopyrimidine easily prepared in good yields showing anticholinesterase inhibition and strong antioxidant power, particularly the most balanced: 6-amino-5-(4-methoxyphenyl)-2-phenyl-[1,2,4]triazolo[1′,5′:1,6] pyrido[2,3-d]pyrimidine-4-carbonitrile(3c) with IC50 equal to 1.32 μM against AChE and oxygen radical absorbance capacity (ORAC) value equal to 4.01 Trolox equivalents (TE); thus representing a new and very promising hit-triazolopyridopyrimidine for AD therapy.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of senile dementia, and constitutes one of the major public health problems, mainly due to the increasing old population in developed countries [1,2]
The ability of triazolopyridopyrimidines 3a–k to reduce the amount of peroxyl radicals was determined by the oxygen radical absorbance capacity by fluorescence (ORAC-FL) method [26,27] using fluorescein (FL) as the fluorescent probe, and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (Trolox) as standard compound
Results were expressed as μmol Trolox equivalents (TE)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of senile dementia, and constitutes one of the major public health problems, mainly due to the increasing old population in developed countries [1,2]. Memantine, a N-methyl-d-aspartate antagonist [8,10], being the only clinically administered drugs, albeit with limited therapeutic success. In view of this situation, new strategies have been promoted based on the multitarget small molecules (MSM) approach [11] for the development of new drugs able to bind simultaneously diverse enzymatic systems or receptors involved in AD pathology [11,12,13,14,15]

Methods

Results

Conclusion