3-(5-(Benzylideneamino)thiazol-3-yl)-2H-chromen-2-ones: a new class of alkaline phosphatase and ecto-5′-nucleotidase inhibitors

Abstract

A new series of 3-(2-(benzylideneamino)thiazol-4-yl)-2H-chromen-2-ones has been synthesized. The structures of the compounds were established by means of ¹H and ¹³C NMR spectroscopy. All compounds were evaluated for their potential to inhibit human recombinant ecto-nucleotidases, including human tissue-nonspecific alkaline phosphatase (h-TNAP), tissue specific human intestinal alkaline phosphatase (h-IAP), human and rat ecto-5′-nucleotidase (h-e5′NT & r-e5′NT). All the compounds were found to be potent and selective inhibitors of h-e5′NT, the most active h-e5′NT inhibitors were compounds 7a (IC₅₀ = 0.25 ± 0.07 μM) and 7g (IC₅₀ = 0.28 ± 0.05 μM). Most of the compounds were found to selectively inhibit h-TNAP over h-IAP, with inhibitory activities in the lower micromolar range. The most active h-TNAP inhibition was exhibited by compounds 7h and 7c (IC₅₀ = 0.21 ± 0.04 μM and 0.22 ± 0.03, respectively), which is ≈91 times greater than the inhibitory activity of the standard inhibitor levamisole. Compound 7i was found to be the most potent h-IAP inhibitor (IC₅₀ = 0.05 ± 0.001 μM), exhibiting ≈11 times greater selectivity for h-IAP over h-TNAP. Homology modeling, molecular docking and dynamics studies were carried out to determine the most plausible binding site interactions of potent inhibitors with ecto-nucleotidases.