Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B |
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| Institution: | 1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Universitario Annunziata, Viale SS. Annunziata, 98168 Messina, Italy;2. Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy;3. Institute of Pharmacy, Computer-Aided Molecular Design, Freie Universitaet Berlin, Koenigin-Luisestr. 2+4, 14195 Berlin, Germany;1. Division of Applied Life Science (BK21 Plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea;2. Division of Applied Life Science (BK21 Plus), PMBBRC, RINS, Gyeongsang National University, Jinju 52828, Republic of Korea;1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy;2. Department of Pharmaceutical and Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany;3. Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy;4. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d''Alcontres, 31, 98166 Messina, Italy;1. Department of Chemistry, K L University, Green Fields, Vaddeswaram, Guntur 522502, India;2. Department of Pharmaceutical Chemistry, Gurunanak Institutions Technical Campus, School of Pharmacy, Hyderabad, India;3. Department of Animal Biology, University of Hyderabad, Hyderabad 500046, India;4. Department of Pharmaceutical Chemistry, Bharath Institute of Technology-Pharmacy, Hyderabad, India |
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| Abstract: | Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations. Accordingly, molecular docking experiments suggested that these inhibitors can fit an allosteric site of PTP1B that we previously individuated. Moreover, cellular assays demonstrated that compound 7e acts as a potent insulin-sensitizing agent in human liver HepG2 cells. Taken together, our results showed that these non-competitive PTP1B inhibitors can be considered promising lead compounds aimed to enhance druggability of the target enzyme and identify novel antidiabetic drugs. |
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| Keywords: | 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones Protein tyrosine phosphatase 1B Non-competitive inhibitors Insulin-sensitizing agents Cellular assays |
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