2. Academic Validation
  3. Novel 3-Sulfonamide Dual-Tail Pyrrol-2-one Bridged Molecules as Potent Human Carbonic Anhydrase Isoform Inhibitors: Design, Synthesis, Molecular Modeling Investigation, and Anticancer Activity in MeWo, SK-BR-3, and MG-63 Cell Lines

Novel 3-Sulfonamide Dual-Tail Pyrrol-2-one Bridged Molecules as Potent Human Carbonic Anhydrase Isoform Inhibitors: Design, Synthesis, Molecular Modeling Investigation, and Anticancer Activity in MeWo, SK-BR-3, and MG-63 Cell Lines

  • J Med Chem. 2025 Jan 23;68(2):1863-1882. doi: 10.1021/acs.jmedchem.4c02586.
Cristina M Al-Matarneh 1 2,  Natalia Simionescu 1,  Alina Nicolescu 3,  Mihaela Silion 4,  Andrea Angeli 5,  Niccolò Paoletti 6,  Alessandro Bonardi 6,  Paola Gratteri 6,  Mariana Pinteala 1,  Claudiu T Supuran 5
Affiliations

Affiliations

  • 1 Centre 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, Bucharest 050663, 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, Iasi 700487, Romania.
  • 5 Sezione di Scienze Farmaceutiche, NeuroFarba Department, Universita degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino 50019, Italy.
  • 6 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, Sesto Fiorentino 50019, Firenze Italy.
PMID: 39793971 DOI: 10.1021/acs.jmedchem.4c02586
Abstract

Novel 3-sulfonamide pyrrol-2-one derivatives containing two sulfonamide groups were synthesized via a one-pot, three-component method using trifluoroacetic acid as a catalyst. Structural confirmation was achieved using spectroscopic techniques. The compounds were tested against four selected human Carbonic Anhydrase isoforms (hCA I, hCA II, hCA IX, and hCA XII). Most derivatives showed significant selectivity for hCA II, with 4h, 4i, 4n, 4k, and 4j demonstrating enhanced activity due to methoxy and hydroxy group patterns. Compound 4o exhibited strong dual selectivity for hCA II and hCA IX, while 4l was the most effective inhibitor of hCA XII. Additionally, 4e showed a preference for hCA XII inhibition. Biological evaluation on MeWo, SK-BR-3, and MG-63 Cancer cells showed that compound 4l was cytotoxic for MeWo cells without significantly affecting normal fibroblasts' viability. Compounds 4e, 4l, and 4o were shown to affect tumor cell viability in combination with doxorubicin in additional testing on MeWo Cancer cells.

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