4.7 Article

Exploring chromone sulfonamides and sulfonylhydrazones as highly selective ectonucleotidase inhibitors: Synthesis, biological evaluation and in silico study

Journal

BIOORGANIC CHEMISTRY
Volume 134, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2023.106450

Keywords

Chromone; Ecto-5?-nucleotidase; Alkaline phosphatase; Sulfonamides; Ectonucleotidase inhibitors; Sulfonylhydrazones

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This study describes the synthesis of highly selective inhibitors for human intestinal alkaline phosphatase (h-IAP) and human tissue non-specific alkaline phosphatase (h-TNAP), and evaluates their inhibitory activities against other nucleotidases. These inhibitors hold therapeutic potential and contribute to our understanding of the selective activation and/or inhibition of nucleotidase enzymes in different cells and tissues.
Ectonucleotidases, a well-known superfamily of plasma membrane located metalloenzymes plays a central role in mediating the process of purinergic cell signaling. Major functions performed by these enzymes include the hydrolysis of extracellular nucleosides and nucleotides which are considered as important cell-signaling mole-cules. Any (patho)-physiologically induced disruption in this purinergic cell signaling leads to several disorders, hence these enzymes are important drug targets for therapeutic purposes. Among the major challenges faced in the design of inhibitors of ectonucleotidases, an important one is the lack of selective inhibitors. Access to highly selective inhibitors via a facile synthetic route will not only be beneficial therapeutically, but will also lead to an increase in our understanding of intricate interplay between members of ectonucleotidase enzymes in relation to their selective activation and/or inhibition in different cells and tissues. Herein we describe synthesis of highly selective inhibitors of human intestinal alkaline phosphatase (h-IAP) and human tissue non-specific alkaline phosphatase (h-TNAP), containing chromone sulfonamide and sulfonylhydrazone scaffolds. Compound 1c exhibited highest (and most selective) h-IAP inhibition activity (h-IAP IC50 = 0.51 +/- 0.20 mu M; h-TNAP = 36.5%) and compound 3k showed highest activity and selective inhibition against h-TNAP (h-TNAP IC50 = 1.41 +/- 0.10 mu M; h-IAP = 43.1%). These compounds were also evaluated against another member of ectonucleotidase family, that is rat and human ecto-5 '-nucleotidase (r-e5 ' NT and h-e5 ' NT). Some of the compounds exhibited excellent inhibitory activity against ecto-5 '-nucleotidase. Compound 2 g exhibited highest inhibition against h-e5 ' NT (IC50 = 0.18 +/- 0.02 mu M). To rationalize the interactions with the binding site, molecular docking studies were carried out.

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