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.

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

“…In another study, two molecules, 1,3-disubstituted-benzimidazole-2-imine ( 433 ) and 1,3-thiazolo[3,2- a ]benzimidazolone derivative ( 434 ), exerted dual effects against dipeptidyl peptidase-IV (DPP-IV) and xanthine oxidase (XO) enzymes with IC 50 values less than 200 μM ( Tomovic et al, 2020 ). Finally, Kanwal et al ( Kanwal et al, 2020 ) prepared a library of benzimidazole-benzothiazine hybrid molecules by Gabriel–Colman rearrangement of methyl 2-(1,1-dioxido-3-oxobenzo[ d ]isothiazol-2(3 H )-yl) acetate, and reported that compounds 435–436 exhibited potential antidiabetic property by inhibiting Ecto-nucleotide pyrophosphatases/phosphodiesterases 1 (ENPP1) 1 and -3.…”

Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors

“… 21 In the previous study, we have reported pyrrolo[2,3- b ]pyridine derivatives such as ( N -(pyrrolo[2,3- b ]pyridine-1-carbonyl)benzenesulfonamide), which was found as a selective inhibitor of ENPP1 with an IC 50 value of 4.50 ± 0.16 μM and carbohydrazide-based derivative, which selectively blocked the activity of ENPP3 to half of the maximal value of 0.15 μM. 22 , 23 Various previously reported structures with sulphonate scaffolds including raloxifene sulphonates, benzofuran, and benzothiophene sulphonates exhibited significant enzyme inhibitory activity to sub-micromolar levels, for example, raloxifene sulphonate derivative 3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)-2-(4-(tosyloxy)phenyl)benzo[ b ]thiophen-6-yl-4-methylbenzenesulfonate tabulated selective inhibition of isozyme ENPP1 to an IC 50 value of 0.45 μM, and benzothiophene derivative (4-(benzo[ b ]thiophen-5-yl)phenyl cyclohexanesulfonate) was endowed with IC 50 = 0.12 μM against ENPP1 and 1.89 μM toward ENPP3. 24 , 25 We have also reported sulphonate derivatives mainly based on non-aromatic or saturated cyclic hydrocarbons.…”