New Synthetic Quinolines as Cathepsin K Inhibitors

Autor(es)

Silva, Taynara L. ^{[1, 2, 3]} ; Bartolomeu, Aloisio de A. ^[1] ; de Jesus, Hugo C. R. ^[1] ; de Oliveira, Kleber T. ^[1] ; Fernandes, Joao B. ^[1] ; Bromme, Dieter ^{[2, 3]} ; Vieira, Paulo C. ^{[4, 1]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, Dept Quim, Km 235, BR-13565905 Sao Carlos, SP - Brazil

^[2] Fac Dent, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3 - Canada

^[3] UBC Ctr Blood Res, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3 - Canada

^[4] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of the Brazilian Chemical Society; v. 31, n. 8, p. 1605-1613, AUG 2020.
• Citações Web of Science: 0

Resumo

Cathepsin K is a papain-like cysteine protease and is responsible for collagen degradation in bone tissue and thus represents an important target for the development of new therapies for treating diseases such as osteoporosis. Quinolines are an important class of heterocyclic molecular leads with a great pharmacological potential and represent a relevant scaffold to explore the chemical space of cathepsin K (CatK) inhibitors. This study presents the synthesis of nine 2,4-diphenylquinolines, including five phthalonitrile quinolines dyads, and the evaluation of their CatK inhibitory activity. Among the evaluated compounds, 4b was the most potent inhibitor with an IC50 (half-maximal inhibitory concentration) value of 1.55 µM (against Z-Phe-Arg-MCA substrate) acting in an uncompetitive inhibition mode. Molecular docking studies provided important information on the interaction of the inhibitor with the enzyme showing that these quinoline derivatives can play an important role as CatK inhibitors. (AU)

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