Evaluation of sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as inhibitors of nucleotide pyrophosphatases/phosphodiesterases and anticancer agents

Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzofuran and benzothiophene as potent and selective inhibitors of NPP1 and NPP3. Compounds 1c, 1g, 1n, and 1s are the most active NPP1 inhibitors (IC₅₀ values in the range 0.12-0.95 µM). Moreover, compounds 1e, 1f, 1j, and 1l are the most potent inhibitors of NPP3 (IC₅₀ ranges from 0.12 to 0.95 µM). Compound 1d, 1f and 1t are highly selective inhibitors of NPP1 over NPP3, whereas compounds 1m and 1s are found to be highly selective towards NPP3 over NPP1. Structure-activity relationship (SAR) study has been discussed in detailed. With the aid of molecular docking studies, a common binding mode of these compounds and suramin (the standard inhibitor) was revealed, where the sulfonate group acts as a cation-binding moiety that comes in close contact with the zinc ion of the active site. Moreover, cytotoxic evaluation against MCF-7 and HT-29 cancer cell lines revealed that compound 1r is the most cytotoxic towards MCF-7 cell line with IC₅₀ value of 0.19 µM. Compound 1r is more potent and selective against cancer cells than normal cells (WI-38) as compared to doxorubicin.

Keywords: Antiproliferative activity; Benzofuran sulfonates and sulfamates; Benzothiophene sulfonates and sulfamates; Enzyme inhibition assay; Human ecto-nucleotide pyrophosphatases/phosphodiesterase-1 and -3; In-silico study.