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

Aleksandrs Pustenko; Alessio Nocentini; Paola Gratteri; Alessandro Bonardi; Igor Vozny; Raivis Žalubovskis; Claudiu T Supuran

doi:10.1080/14756366.2020.1752201

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.

Authors

Aleksandrs Pustenko^{1

2}, Alessio Nocentini^{3

4}, Paola Gratteri⁴, Alessandro Bonardi^{3

4}, Igor Vozny¹, Raivis Žalubovskis^{1

2}, Claudiu T Supuran³

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.

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 K_Is of 260 and 57 nM, respectively. It does not inhibit off-target CA I and poorly inhibited CA II (K_I = 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 K_Is 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.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Furagin / analogs & derivatives
Furagin / chemistry
Furagin / pharmacology*
Humans
Hydrophobic and Hydrophilic Interactions
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Carbonic Anhydrase Inhibitors
Isoenzymes
Carbonic Anhydrases
Furagin