2. Academic Validation
  3. The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

  • J Enzyme Inhib Med Chem. 2020 Dec;35(1):1011-1020. doi: 10.1080/14756366.2020.1752201.
Aleksandrs Pustenko 1 2,  Alessio Nocentini 3 4,  Paola Gratteri 4,  Alessandro Bonardi 3 4,  Igor Vozny 1,  Raivis Žalubovskis 1 2,  Claudiu T Supuran 3
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis, Riga, Latvia.
  • 2 Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, Latvia.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Firenze, Italy.
PMID: 32297543 DOI: 10.1080/14756366.2020.1752201
Abstract

The clinically used Antibiotic Furagin and its derivatives possess inhibitory activity on human (h) carbonic anhydrases (CA, EC 4.2.1.1), some of which are highly expressed in various tissues and malignancies (hCA IX/XII). Furagin exhibited good hCA IX and XII inhibition with KIs of 260 and 57 nM, respectively. It does not inhibit off-target CA I and poorly inhibited CA II (KI = 9.6 μM). Some synthesised Furagin derivatives with aminohydantoin moieties as zinc binding group exhibited weak inhibition of CA I/II, and good inhibition of CA IX/XII with KIs ranging from 350 to 7400 and 150 to 5600 nM, respectively. Docking and molecular dynamics simulations suggest that selectivity for the cancer-associated CA IX/XII over CA II is due to strong H-bond interactions in CA IX/XII, involving the tail orientated towards hydrophobic area of the active site. These results suggest a possible drug repurposing of Furagin as anti-cancer agent.

Keywords

Carbonic anhydrase inhibitors; furagin; hydantoin; molecular dynamics; synthesis.

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