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.
Following our ongoing interest on modified steroidal compounds for biological purposes, herein we endeavor the two-step regioselective synthesis of three-substituted pyran-cholestane fused compounds (6 examples, yields up to 83%) at C-2:C-3 A-ring side of the steroid scaffold. In the presence of higher amounts of malononitrile, the intermediate α,β-unsaturated carbonyl substrates give rise to competing reactions leading to the formation of the corresponding 2-aminoisophthalonitrile fused compounds (2 examples, up to 37% yield).
Chromeno[3,4-b]xanthones: new AChE andAβ Aggregation Dual-Inhibitors. 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 for AD and consecutive failures in the central nervous system (CNS) drug development motivated the search for new disease-modifying therapeutic strategies for this disease. To address this issue, multitarget-directed ligands (MTDLs) are emerging as a therapeutic alternative to target 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.
2-Styrylchromones (2-SCs) are interesting compounds for their biological properties as well as versatility as starting materials for further transformations. Herein, we disclose a new 2-SC derivative—2,2’-[(1E,1’E)-{[hexa-2,4-diyne-1,6-diylbis(oxy)]bis(2,1-phenylene)}bis(ethene-2,1-diyl)]bis(4H-chromen-4-one)—which is a dimeric compound formed by two units of 2-SC linked through a 1,3-diyne moiety. It was obtained in excellent yield (96%) through the copper-catalyzed homocoupling of two molecules of O-propargyl-2-SC. Its structure was unveiled by 1D (1H and 13C) and 2D (HSQC and HMBC) NMR techniques together with HRMS.
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