Synthesis, biological evaluation, and docking studies of new pyrazole-based thiourea and sulfonamide derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase

A series of six compounds (1a-f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzene-sulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and -3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e were the most potent inhibitors of ENPP1 with sub-micromolar IC50 values (0.69, 0.18, and 0.40 mu M, respectively. Moreover, compound 1b was the most potent inhibitor of ENPP3 (IC50 = 0.21 mu M). They were much more potent than the reference standard inhibitor, suramin (IC50 values against ENPP1 and -3 were 7.77 and 0.89 mu M, respectively). Furthermore, all the six compounds were investigated for cytotoxic effect against cancerous cell lines (HeLa, MCF-7, and 1321N1) and normal cell line (BHK-21). Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC50 = 16.05 mu M), which is comparable to the potency of cisplatin. All the tested compounds exhibited low or negligible cytotoxic effect against the normal cells. They have the merit of superior selectivity towards cancer cells than normal cells compared to cisplatin. The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes.