title: Straightforward synthesis of 2,4,6-trisubstituted 1,3,5-triazine compounds targeting cysteine cathepsins K and S.
abstract: The synthesis and evaluation against various cysteine cathepsins with endopeptidase activity, of two new families of hitherto unknown 1,3,5-triazines, substituted by a nitrile function and either a cyclohexylamine moiety (5-like) or a piperazine moiety (9-like) are described. The structure-activity relationship was discussed; from 16 synthesized novel compounds, 9h was the most active and selectively inhibitor of Cat K (IC50 = 28 nM) and Cat S (IC50 = 23 nM). Molecular docking of 9h to X-ray crystal structure of cathepsins K and S confirmed a common binding mode with a crucial covalent bond with Cys25. We observed for 9h that p-trifluorophenyl group is located in S2 pocket and possess hydrophobic interactions with Tyr67 and Met68. Triazine and piperazine moieties are located in S'1 pocket and interact with Gly23, Cys63, Gly64 and Gly65. Altogether, these results indicate that the new analogs can make them effective agents against some viruses for which the glycoprotein cleavage is mediated by an array of proteases.
authors.affiliation: Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Plebanek
authors.affiliation: Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Chevrier
authors.affiliation: Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Roy
authors.affiliation: INSERM, UMR 1100, Pathologies Respiratoires: protéolyse et aérosolthérapie, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032, Tours Cedex, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Garenne
authors.affiliation: INSERM, UMR 1100, Pathologies Respiratoires: protéolyse et aérosolthérapie, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032, Tours Cedex, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lecaille
authors.affiliation: Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Warszycki
authors.affiliation: Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: INSERM, UMR 1100, Pathologies Respiratoires: protéolyse et aérosolthérapie, Centre d'Etude des Pathologies Respiratoires, Université François Rabelais, F-37032, Tours Cedex, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lalmanach
authors.affiliation: Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067, Orléans, France. Electronic address: luigi.agrofoglio@univ-orleans.fr.
authors.forename: Luigi A
authors.initials: LA
authors.lastname: Agrofoglio
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D014227:Triazines; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C028217:cathepsin S; D056657:Cathepsin K
keywords: 1,3,5-Triazine; Cathepsin inhibitors; Cysteine cathepsin; Microwave irradiation