2. Academic Validation
  3. Synthesis of biphenyl oxazole derivatives via Suzuki coupling and biological evaluations as nucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors

Synthesis of biphenyl oxazole derivatives via Suzuki coupling and biological evaluations as nucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors

  • Eur J Med Chem. 2020 Dec 15;208:112759. doi: 10.1016/j.ejmech.2020.112759.
Haseen Ahmad 1,  Saif Ullah 2,  Fouzia Rahman 1,  Aamer Saeed 1,  Julie Pelletier 3,  Jean Sévigny 4,  Abbas Hassan 5,  Jamshed Iqbal 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
  • 2 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
  • 3 Centre de Recherche Du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada.
  • 4 Centre de Recherche Du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada; Département de Microbiologie-infectiologie et D'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada.
  • 5 Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan. Electronic address: ahassan@qau.edu.pk.
  • 6 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.
PMID: 32883636 DOI: 10.1016/j.ejmech.2020.112759
Abstract

Oxazole derivatives are important medicinal compounds which are inhibitors of various Enzymes such as NPP1, NPP2, NPP3, tyrosine kinase, dipeptidyl-peptidase IV, cyclooxygenase-2, and protein tyrosine Phosphatase. In this study, an extensive range of new biologically active biphenyl oxazole derivatives was synthesized in high to excellent yields (57-93%) through Suzuki-Miyaura cross-coupling of bromophenyloxazole with different boronic acids. The reaction was carried out in wet toluene under mild conditions. Overexpression of nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and NPP3 has been associated with various health disorders including chondrocalcinosis, Cancer, osteoarthritis, and type 2 diabetes. We evaluated the inhibitory potential and selectivity of the synthesized compounds (3a-3q) towards NPP1 and NPP3 at 100 μM concentrations. We found two compounds that were selective and potent inhibitors of these two Enzymes on the artificial substrate thymidine 5'-monophosphate para-nitrophenyl ester: compound 3n inhibited NPP1 with an IC50 of 0.15 μM, and compound 3f inhibited NPP3 with an IC50 value of 0.17 μM. The compounds with promising inhibitory potential were docked inside the proteins of NPP1 and NPP3 isozymes to get insight into the plausible binding interactions with active site residues.

Keywords

Biphenyl oxazole derivatives; Ecto-nucleotide pyrophosphatases/phosphodiesterases; Molecular docking studies; Suzuki-Miyaura cross-coupling reaction; Thymidine 5′-monophosphate para-nitrophenyl ester.

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