Furagin Derivatives-Nitrofuran-Based Hydrazones as Potential Dual Inhibitors of Thioredoxin Reductase and Carbonic Anhydrases.

Cancer remains one of the leading causes of mortality, accounting for millions of deaths worldwide each year and posing a persistent challenge to global health despite advances in diagnosis and treatment. Dual inhibition of thioredoxin reductase (TrxR) and cancer-associated carbonic anhydrase (CA) isoforms IX and XII represents a promising strategy for selective anticancer therapy by simultaneously disrupting cellular redox homeostasis and pH regulation. The antibacterial agent furagin has been previously explored as an inhibitor of cancer-associated carbonic anhydrases; however, its potential as a TrxR inhibitor has not yet been investigated. In this study, a series of furagin derivatives-nitrofuran-based hydrazones (7a-7s)-were designed and synthesized as potential dual TrxR/CA inhibitors. The derivatives were screened for CA inhibition using a stopped-flow CO2 hydration assay and for rTrxR1 inhibition via a 5,5'-Dithiobis(2-nitrobenzoic acid) (DTNB) reduction assay. Most derivatives displayed weak or negligible activity against the cytosolic isoforms hCA I and hCA II while exhibiting moderate and selective inhibition of the cancer-associated isoforms hCA IX and hCA XII, particularly hCA XII. Several compounds also inhibited rTrxR1, with compound 7g emerging as the most potent inhibitor in the series (IC50 = 11 μM).