We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction / Giovannuzzi, Simone; Chavarria, Daniel; Provensi, Gustavo; Leri, Manuela; Bucciantini, Monica; Carradori, Simone; Bonardi, Alessandro; Gratteri, Paola; Borges, Fernanda; Nocentini, Alessio; Supuran, Claudiu T.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 67:(2024), pp. 4170-4193. [10.1021/acs.jmedchem.4c00045]

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

Giovannuzzi, Simone;Provensi, Gustavo;Leri, Manuela;Bucciantini, Monica;Bonardi, Alessandro;Gratteri, Paola;Borges, Fernanda;Nocentini, Alessio
;
Supuran, Claudiu T.
2024

Abstract

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6 nM). Computational studies were conducted to elucidate the structure–activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.
2024
67
4170
4193
Goal 3: Good health and well-being
Giovannuzzi, Simone; Chavarria, Daniel; Provensi, Gustavo; Leri, Manuela; Bucciantini, Monica; Carradori, Simone; Bonardi, Alessandro; Gratteri, Paola; Borges, Fernanda; Nocentini, Alessio; Supuran, Claudiu T.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1355337
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