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

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

  • J Med Chem. 2024 Mar 14;67(5):4170-4193. doi: 10.1021/acs.jmedchem.4c00045.
Simone Giovannuzzi 1,  Daniel Chavarria 2,  Gustavo Provensi 3,  Manuela Leri 4,  Monica Bucciantini 4,  Simone Carradori 5,  Alessandro Bonardi 6,  Paola Gratteri 6,  Fernanda Borges 2,  Alessio Nocentini 1,  Claudiu T Supuran 1
Affiliations

Affiliations

  • 1 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
  • 2 CIQUP-IMS, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
  • 3 NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, via G. Pieraccini 6, 50139 Florence, Italy.
  • 4 Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy.
  • 5 Department of Pharmacy, "G. D'Annunzio" University of Chieti and Pescara, via dei Vestini 31, 66100 Chieti, Italy.
  • 6 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
PMID: 38436571 DOI: 10.1021/acs.jmedchem.4c00045
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.

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