Ullah, Saif El-Gamal, Mohammed, I Zaib, Sumera Anbar, Hanan S. Zaraei, Seyed-Omar Sbenati, Rawan M. Pelletier, Julie Sevigny, Jean Oh, Chang-Hyun Iqbal, Jamshed 2024-01-19T17:31:24Z 2024-01-19T17:31:24Z 2022-01-10 2020-06 0045-2068 https://pubs.kist.re.kr/handle/201004/118553 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. English ACADEMIC PRESS INC ELSEVIER SCIENCE PHOSPHODIESTERASE-I POTENT INHIBITORS CANCER ATP LOCALIZATION PURIFICATION ACTIVATION CLONING DESIGN GROWTH Synthesis, biological evaluation, and docking studies of new pyrazole-based thiourea and sulfonamide derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase Article 10.1016/j.bioorg.2020.103783 1 BIOORGANIC CHEMISTRY, v.99 BIOORGANIC CHEMISTRY 99 scie scopus 000535445400004 2-s2.0-85082418114 Biochemistry & Molecular Biology Chemistry, Organic Biochemistry & Molecular Biology Chemistry Article PHOSPHODIESTERASE-I POTENT INHIBITORS CANCER ATP LOCALIZATION PURIFICATION ACTIVATION CLONING DESIGN GROWTH Cytotoxic studies Molecular docking and simulations Nucleotide pyrophosphatase/phosphodiesterase Pyridine-pyrazole-benzenethiourea Pyridine-pyrazole-benzenesulfonamide