Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents

• Published in: European journal of medicinal chemistry 2017-02, Vol.127, p.840-858
• Main Authors: Ottanà, Rosaria, Paoli, Paolo, Naß, Alexandra, Lori, Giulia, Cardile, Venera, Adornato, Ilenia, Rotondo, Archimede, Graziano, Adriana Carol Eleonora, Wolber, Gerhard, Maccari, Rosanna
• Format: Article
• Language: English
• Subjects: 5-Arylidene-4-thiazolidinone derivatives; Allosteric Regulation - drug effects; Anti-inflammatory activity; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Benzoic Acid - chemistry; Benzoic Acid - metabolism; Benzoic Acid - pharmacology; Computer Simulation; Drug Design; Enzyme inhibitors; Hep G2 Cells; Humans; Insulin - metabolism; Insulinomimetic effects; Kinetics; Molecular docking; Peptidomimetics - chemistry; Peptidomimetics - metabolism; Peptidomimetics - pharmacology; Protein Conformation; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein tyrosine phosphatases
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.10.063

New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signaling. [Display omitted] •Insulin resistance and inflammation are implicated in diabetes mellitus and obesity.•Protein tyrosine phosphatase 1B (PTP1B) inhibitors act as insulin-sensitizing agents.•New 4-thiazolidinone derivatives were found to be potent PTP1B inhibitors.•Several tested compounds exhibited insulinomimetic and/or anti-inflammatory activity.•A new lead compound endowed with a promising cellular activity profile was identified.