Deazapurine Analogues Bearing a 1H‐Pyrazolo[3,4‐b]pyridin‐3(2H)‐one Core: Synthesis and Biological Activity

• Published in: European journal of organic chemistry Vol. 2018; no. 20-21; pp. 2629 - 2644
• Main Authors: Supe, Linda, Afzal, Saira, Mahmood, Abid, Ejaz, Syeda Abida, Hein, Martin, Iaroshenko, Viktor O., Villinger, Alexander, Lecka, Joanna, Sévigny, Jean, Iqbal, Jamshed, Langer, Peter
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.06.2018; Wiley Subscription Services, Inc
• Subjects: 1,3‐Diketones; Alkaline phosphatase; Biological activity; Chemistry; Chemistry, Organic; Cyclization; Deazapurine analogues; Diketones; Fluorination; Heterocycles; Molecular chains; Molecular docking; Organofluorine compounds; Phosphatase; Physical Sciences; Regioselectivity; Science & Technology; Synthesis; Heterocycles; 3-Diketones; Regioselectivity; PURINE; Deazapurine analogues; ONE-POT SYNTHESIS; HUMAN NPP1; 1; INTESTINAL ALKALINE-PHOSPHATASE; Organofluorine compounds; Cyclization; REGIOSELECTIVE SYNTHESIS; PYRAZOLE COMPOUNDS; INHIBITORS; STIMULATORS; ANTAGONISTS; DERIVATIVES
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201800163

A new methodology for the synthesis of fluorinated and non‐fluorinated 1H‐pyrazolo[3,4‐b]pyridin‐3‐ones was developed. The reactions proceed by cyclization of electron‐rich 3‐amino‐1H‐pyrazol‐5(4H)‐ones with 1,3‐diketones and the products were obtained in good to excellent yields and with excellent regioselectivity. The products, which can be regarded as deazapurine analogues, were tested for the alkaline phosphatase (h‐TNAP and h‐IAP) and nucleotide pyrophosphatase/phosphodiesterase (h‐NPP1 and h‐NPP3) inhibition profile. Most of the derivatives exhibited selective and potent inhibition on tissue non‐specific and intestinal alkaline phosphatase and nucleotide pyrophosphatase (NPP1 and NPP3) enzymes. Possible binding modes of the most potent inhibitors were studied by molecular docking analysis. New deazapurine analogues were prepared and their bioactivity studied. Most of the derivatives exhibited selective and potent inhibition on tissue non‐specific and intestinal alkaline phosphatase and nucleotide pyrophosphatase enzymes.