Synthesis, biological evaluation, and docking studies of novel pyrrolo 2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 +/- 0.04 mM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 +/- 0.01 mM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50 = 4.70 +/- 0.67 mM), and 1h (IC50 = 1.58 +/- 0.20 mM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of sulfonylurea derivatives possessing pyrrolo[2,3-b]pyridine core were synthesized and investigated as inhibitors of NPP1 and NPP3 isozymes. Compound 1c and 1h showed the strongest cytotoxicity against cancer cell lines MCF-7 and HT-29, respectively. These compounds exhibited promising interactions with important binding sites residues of NPP1 and NPP3, making them potential candidates for cancer and diabetes treatment.