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

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
• molecular dynamics
• furagin
• hydantoin
• synthesis

Disclosure statement

The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.