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
  • 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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