ChemMedChem

May 09, 2013

VIP: Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure–Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human Cathepsin L

Veronika Ehmke, Edwin Winkler, David W. Banner,* Wolfgang Haap, W. Bernd Schweizer, Matthias Rottmann, Marcel Kaiser, Céline Freymond, Tanja Schirmeister,* François Diederich*

The cysteine protease rhodesain of Trypanosoma brucei parasites, which cause human African trypanosomiasis (sleeping sickness), has emerged as a target for the development of new drug candidates to address the precarious limitations of chemotherapies in current use.

In collaboration with the group of Tanja Schirmeister at the University of Mainz (Germany), David W. Banner and colleagues at F. Hoffmann-La Roche Ltd., Basel (Switzerland), and scientists at the Swiss Tropical and Public Health Institute, researchers in the group of François Diederich at ETH Zurich (Switzerland) studied the molecular recognition properties of rhodesain and developed a series of triazine nitrile inhibitors as lead compounds using structure-based molecular modeling. The binding preferences of the individual pockets in the active site were systematically analyzed, and inhibitors with affinities (K_i values) down to the single-digit nanomolar range were obtained. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved with inhibitors bearing a basic substituent, which led to a 35-fold increase in antitrypanosomal activity. The introduction of a bioisosteric imidazopyridine nitrile scaffold allowed a decrease in the inherent electrophilicity of the triazine nitrile headgroup, which had been the cause of off-target effects with other nucleophiles present in the cell. X-ray crystal structures of human cathepsin L, a close structural relative of rhodesain, both in complex with a triazine nitrile inhibitor and in the apo form, confirmed the proposed binding mode of the ligand series and gave important insight into the hydration state of the active site.

Received March 13, 2013; published online May 9, 2013, DOI: 10.1002/cmdc.201300112.

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