2. Academic Validation
  3. Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

  • J Med Chem. 2024 Feb 1. doi: 10.1021/acs.jmedchem.3c02190.
Cristina M Al-Matarneh 1 2,  Mariana Pinteala 1,  Alina Nicolescu 3,  Mihaela Silion 4,  Francesca Mocci 5,  Razvan Puf 1,  Andrea Angeli 6,  Marta Ferraroni 7,  Claudiu T Supuran 6,  Susi Zara 8,  Simone Carradori 8,  Niccolò Paoletti 5 6,  Alessandro Bonardi 6 9,  Paola Gratteri 9
Affiliations

Affiliations

  • 1 Center of Advanced Research in Bionanoconjugates and Biopolymers, "Petru Poni" Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda Alley, Iasi 700487, Romania.
  • 2 Research Institute of the University of Bucharest-ICUB, 90 Sos. Panduri, 050663 Bucharest, Romania.
  • 3 NMR Laboratory "Petru Poni" Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda Alley, Iasi 700487, Romania.
  • 4 Physics of Polymers and Polymeric Materials Department, "Petru Poni" Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania.
  • 5 Department of Chemical and Geological Sciences, University of Cagliari, 09124 Cagliari, Italy.
  • 6 Sezione di Scienze Farmaceutiche, NeuroFarba Department, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
  • 7 Dipartimento di Chimica "Ugo Schiff", University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence Italy.
  • 8 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy.
  • 9 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze Italy.
PMID: 38301036 DOI: 10.1021/acs.jmedchem.3c02190
Abstract

New dihydro-pyrrol-2-one compounds, featuring dual sulfonamide groups, were synthesized through a one-pot, three-component approach utilizing trifluoroacetic acid as a catalyst. Computational analysis using density functional theory (DFT) and condensed Fukui function explored the structure-reactivity relationship. Evaluation against human Carbonic Anhydrase isoforms (hCA I, II, IX, XII) revealed potent inhibition. The widely expressed cytosolic hCA I was inhibited across a range of concentrations (KI 3.9-870.9 nM). hCA II, also cytosolic, exhibited good inhibition as well. Notably, all compounds effectively inhibited tumor-associated hCA IX (KI 1.9-211.2 nM) and hCA XII (low nanomolar). Biological assessments on MCF7 Cancer cells highlighted the compounds' ability, in conjunction with doxorubicin, to significantly impact tumor cell viability. These findings underscore the potential therapeutic relevance of the synthesized compounds in Cancer treatment.

Figures
Products