Structure-activity relationships of triazole-benzodioxine inhibitors of cathepsin X

Cathepsin X is a cysteine Carboxypeptidase that is involved in various physiological and pathological processes. In particular, highly elevated expression and activity of Cathepsin X has been observed in cancers and neurodegenerative diseases. Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible Cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for Cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced Cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against Cathepsin X compared to Z9, with IC₅₀ values of 7.1 μM-13.6 μM. Additionally, 25 inhibited prostate Cancer cell migration by 21%, which is under the control of Cathepsin X.