Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors

Abstract

Alzheimer’s disease (AD) is a complex multifactorial disorder, mainly characterized by the progressive loss of memory and cognitive, motor, and functional capacity. The absence of effective therapies available for AD alongside the consecutive failures in the central nervous system (CNS) drug development has been motivating the search for new disease-modifying therapeutic strategies for this disease. To address this issue, the multitarget directed ligands (MTDLs) are emerging as a therapeutic alternative to target the multiple AD-related factors. Following this concept, herein we describe the design, synthesis, and biological evaluation of a family of chromeno[3,4-b]xanthones as well as their (E)-2-[2-(propargyloxy)styryl]chromone precursors, as first-in-class acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation dual-inhibitors. Compounds 4b and 10 emerged as well-balanced dual-target inhibitors, with IC50 values of 3.9 and 2.9 μM for AChE and inhibitory percentages of 70 and 66% for Aβ aggregation, respectively. The molecular docking showed that most of the compounds bound to AChE through hydrogen bonds with residues of the catalytic triad and π-stacking interactions between the main scaffold and the aromatic residues present in the binding pocket. The interesting well-balanced activities of these compounds makes them interesting templates for the development of new multitarget compounds for AD.

Inhibition of Human Cholinesterases and in vitro β‐Amyloid Aggregation by Rationally Designed Peptides

“…[15] Many reported anti-aggregation compounds showed interactions with this residue. [35][36][37] Despite this, we must consider that a direct W3-Aβ interaction may be contributing to the inhibition, as reported for other peptides or mini-proteins. Murray et al designed a mini-protein that inhibited Aβ aggregation through protein-protein interactions.…”

Cromeno[3,4-b]xantonas: Novos Inibidores da Acetilcolinesterase e Agregação Beta-amiloide

“…Nos últimos anos, diversos compostos derivados de xantonas e cromenos naturais e sintéticos têm sido descritos na literatura devido ao seu perfil farmacológico, como potenciais compostos multifuncionais, particularmente para o tratamento da DA [23,24]. Tendo como inspiração o perfil farmacológico interessante deste tipo de compostos e considerando o conceito de compostos multialvo, neste artigo descreve-se o design, a síntese e a avaliação biológica de uma nova família de cromeno [3,4-b]xantonas e dos seus respetivos precursores (E)-2-[2-(propargiloxi)estiril] cromonas, como uma nova classe de inibidores duplos da AChE e agregação Aβ [25].…”

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

“…Malafaia et al 104 reported the design, synthesis, and biological evaluation of a family of 2-styrylchromones as AChE and amyloid-β aggregation dual inhibitors. The authors reported that compound 41 (Scheme 21) was observed to be a well-balanced dual-target inhibitor with an IC 50 value of 3 μM for eeAChE and inhibitory percentage of 66% for amyloid-β aggregation.…”