Identification of novel chromone based sulfonamides as highly potent and selective inhibitors of alkaline phosphatases

Abstract

A new series of structurally diverse chromone containing sulfonamides has been developed. Crystal structures of three representative compounds (2a, 3a and 4a) in the series are reported. All compounds were screened for their inhibitory potential against alkaline phosphatases (ALPs). Two main classes of ALP isozymes were selected for this study, the tissue non-specific alkaline phosphatase (TNALP) from bovine and porcine source and the tissue-specific intestinal alkaline phosphatases (IALPs) from bovine source. All sulfonamide compounds had a marked preference for IALP (K(i), up to 0.01 ± 0.001 μM) over TNALPs. Kinetics studies of the compounds showed competitive mode of inhibition. Molecular docking studies were carried out in order to characterize the selective inhibition of the compounds. An additional interesting aspect of these chromone sulfonamides is their inhibitory activity against ecto-5'-nucleotidase enzyme.

Keywords: ALP; Alkaline phosphatase inhibitors; Chromones; Ecto-5′-nucleotidase inhibitors; IALP; Molecular docking; Structure activity relationships (SARs); Sulfonamides; TNALP; alkaline phosphatase; ecto-5′-NT; ecto-5′-nucleotidase; intestinal alkaline phosphatase; tissue non specific alkaline phosphatase.