Discovery and kinetic evaluation of 6-substituted 4-benzylthio-1,3,5-triazin-2(1 H)-ones as inhibitors of cathepsin B

• Published in: European journal of medicinal chemistry Vol. 46; no. 9; pp. 4648 - 4656
• Main Authors: Sosič, Izidor, Mirković, Bojana, Turk, Samo, Štefane, Bogdan, Kos, Janko, Gobec, Stanislav
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-09-2011; Elsevier
• Subjects: 1,3,5-Triazine-2(1 H)-ones; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cathepsin B; Cathepsin B - antagonists & inhibitors; Cysteine protease; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Kinetics; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Models, Molecular; Noncovalent inhibitors; Partial mixed-type inhibition; Pharmacology. Drug treatments; Spectrometry, Mass, Electrospray Ionization; Triazines - chemistry; Triazines - pharmacology; 1,3,5-Triazine-2(1 H)-ones; catB; Cysteine protease; EI; AMC; Cathepsin B; Z; ESI; Noncovalent inhibitors; Partial mixed-type inhibition; ES; Enzyme; Nitrogen heterocycle; Cysteine endopeptidases; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Selectivity; Cycloalkane; In vitro; Modeling; Peptidases; Structure activity relation; Six membered ring; 1,3,5-Triazine-2(1H)-ones; Molecular model; Non covalent binding; Hydrolases; Kinetics; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.08.005

Cathepsin B is a lysosomal cysteine protease that has various physiological and pathophysiological functions. We present here the discovery of 6-substituted 4-benzylthio-1,3,5-triazin-2(1
H)-ones as inhibitors of cathepsin B, starting from screening of a library of variously 2,4,6-trisubstituted 1,3,5-triazines and 1,3,5-triazin-2(1
H)-ones on three different human cathepsins. The synthesis and enzymatic evaluation of a focused library of new 1,3,5-triazin-2(1
H)-ones is also described. The detailed kinetics analyses have shown that these compounds can act as reversible, partial mixed-type inhibitors of cathepsin B, with
K
i and
K
i′ values in the low micromolar range. The inhibitory activities of selected compounds were also assessed against two related cysteine proteases, cathepsin H and cathepsin L, to estimate their selectivity; these compounds have a selective profile for catB and catL over catH.
A focused library of 6-substituted 4-benzylthio-1,3,5-triazin-2(1
H)-ones was synthesized. We present new reversible, partial mixed-type inhibitors of cathepsin B, with
K
i and
K
i′ values in the low micromolar range.
[Display omitted]
► A focused library of 6-substituted 4-benzylthio-1,3,5-triazin-2(1
H)-ones was synthesized. ► The compounds inhibited cathepsin B in the low micromolar range. ► The detailed kinetics analyses showed that these compounds act as reversible, partial mixed-type inhibitors of cathepsin B. ► Molecular docking predicted binding in the S1′ and S2′ subsites of the enzyme.