Synthesis and Nucleotide Pyrophosphatase/Phosphodiesterase Inhibition Studies of Carbohydrazides Based on Benzimidazole-Benzothiazine Skeleton

Abstract

Ecto-nucleotide pyrophosphatases/phosphodiesterases (ENPPs) are important family of ecto-nucleotidases. There are seven members of ENPP family out of which ENPP1 and ENPP3 hydrolyze nucleotides whereas, ENPP2 preferably hydrolyzes phospholipids as compared to nucleotides. Overexpression of ENPP1 and ENPP3 has been reported to be associated with many health disorders such as diabetes, chondrocalcinosis, osteoarthritis, and cancer. Development of ENPP1 and −3 inhibitors might be useful for the treatment of these disorders. This study aimed to investigate the inhibitory potentials of the synthesized benzimidazole-benzothiazine hybrid molecules on ecto-nucleotide pyrophosphatases/phosphodiesterases (ENPPs) enzymes. A series of benzimidazole-benzothiazine hybrid molecules was synthesized by Gabriel–Colman rearrangement of methyl 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)acetate. The successfully synthesized compounds (6 a–6 m) were evaluated for ENPP1 and −3 inhibitory activities. Among the investigated compounds 6 m with an IC50 value of 0.14 μM, and 6 h with an IC50 value of 0.12 μM, were found to be the most potent inhibitors of ENPP1 and −3, respectively. Molecular docking studies of most active and selective inhibitors showed putative mode of binding interactions responsible for highest potency and selectivity of docked inhibitors. The overall in-silico results were found to be highly correlated with in-vitro results showed in Table 1.