Inhibitors of the serine protease furin have been widely studied as antimicrobial
agents due to their ability to block the cleavage and activation of certain viral
surface proteins and bacterial toxins. In this study, the antipseudomonal effects
and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence
quenching studies suggested no relevant binding of the compounds to human serum albumin
and α1-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal
activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low
concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the
two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the
intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even
at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human
hepatocytes also resulted in no changes in cell viability and oxidative stress at
up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both
inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high
concentrations. In conclusion, this study indicates a good safety profile of the furin
inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for
further in vivo investigations, despite some inhibitory effects on CYP3A4.