Cathepsin K inhibitors based on 2-amino-1,3,4-oxadiazole derivatives

• Published in: Bioorganic chemistry Vol. 109; p. 104662
• Main Authors: Gontijo, Talita B., Lima, Patrícia S., Icimoto, Marcelo Y., Neves, Raquel Leão, de Alvarenga, Érika C., Carmona, Adriana K., de Castro, Alexandre A., Ramalho, Teodorico C., da Silva Júnior, Eufrânio N., de Freitas, Rossimiriam P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2021
• Subjects: 1,3,4-Oxadiazoles; Cathepsin K; Dipeptides; Dipeptides; 1,3,4-Oxadiazoles; Cathepsin K
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104662

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•A new class of cathepsin K inhibitors was designed and synthesized.•Dipeptide nitriles and 1,3,4-oxadiazoles were evaluated as Cat K inhibitors.•The most active compound acted as enzymatic competitive inhibitor.•The novel compounds interacted with key residues from the enzyme active site.
Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (−134.36 kcal mol−1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.