Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1

Abstract

Cathepsins are known to have many important physiological roles and provide a viable target for inhibition. Fluorobenzoyl dipeptide derivatives were synthesized and tested for biological activity in an effort to find an efficient inhibitor of the cysteine protease cathepsin L. Thirty-six novel inhibitors (1–36) were synthesized from protected amino acids via the standard DCC/HOBt coupling protocol, containing a benzyl ester or a nitrile as an electrophilic warhead. The activity of the inhibitors was evaluated against cathepsin L and IC₅₀ values calculated. Modification of both amino acids and terminal groups afforded compounds with single digit micromolar inhibition. Results utilizing the benzoyl-L-leucine-glycine nitrile backbone are comparable to that for the commercially available inhibitor 39.

Keywords::

• Dipeptide
• fluorine; benzyl ester
• nitrile
• protease inhibition
• cathepsin L

Acknowledgements

We wish to thank the National Institute for Cellular Biotechnology and Dublin City University for grants in aid of research and particularly under the Irish Government PRTLI cycle 3 initiative 2001–2006.

Declaration of interest: The authors report no conflicts of interest.