Original article Synthesis, biological activity and structureeactivity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells Rosaria Ottanà a , Rosanna Maccari a, * , Jérémie Mortier b, c , Anna Caselli d , Simona Amuso a , Guido Camici d, e , Archimede Rotondo f , Gerhard Wolber b , Paolo Paoli d a Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, University of Messina, Polo Universitario dell’Annunziata, Viale SS. Annunziata, 98168 Messina, Italy b Institute of Pharmacy, Department Pharmaceutical & Medicinal Chemistry, Freie Universität Berlin,14195 Berlin, Germany c Institute of Chemistry and Biochemistry, Organic Chemistry, Freie University Berlin,14195 Berlin, Germany d Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy e Center for Research, Transfer and High Education DENOthe, Viale Pieraccini 6, 50139 Firenze, Italy f Dipartimento di Scienze Chimiche, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy article info Article history: Received 25 July 2013 Received in revised form 24 October 2013 Accepted 1 November 2013 Available online 11 November 2013 Keywords: Protein tyrosine phosphatases Enzyme inhibitors Insulinomimetic effects Molecular docking 5-Arylidene-4-thiazolidinone derivatives 4-[(5-Arylidene-4-oxo-2-phenylimino/ oxothiazolidin-3-yl)methyl]benzoic acids abstract Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegen- erative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensi- tivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl] benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested com- pounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IRb phosphorylation and 2-deoxyglucose cellular uptake. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Diabetes mellitus is a serious metabolic disease, which currently affects more than 371 million people worldwide, with a global prevalence of 8.3%. The number of people with diabetes is rapidly growing in every country, correspondingly with the current obesity epidemic, and is predicted to rise to almost 10% of total world population by 2030. More than 90% of diabetic patients suffer from type 2 diabetes (T2DM) [1]. The onset of T2DM is mainly linked to the development of insulin resistance, an altered metabolic con- dition in which the response of target tissues (such as fat tissue, liver and skeletal muscle) to the hormone is significantly impaired. Attenuated insulin signaling results in numerous metabolic and cellular alterations, including diminished cellular glucose uptake, increased liver gluconeogenesis, hyperglycemia and hyperlipid- emia. Increased levels of blood glucose and lipids can induce further deterioration of both insulin action and secretion as well as trigger sequences of tissue and vascular dysfunctions that lead to chronic diabetic complications and increased cardiovascular risk [2,3]. The multiple metabolic and tissue abnormalities induced by insulin resistance can contribute to the development of metabolic syndrome, a cluster of correlated comorbid disorders that, beside Abbreviations: 2-DOG, 2-deoxyglucose; IR, insulin receptor; LMW-PTP, low molecular weight protein tyrosine phosphatase; MALDI-TOF MS, matrix-assisted laser desorption/ionization time-of-flight mass; MTT, 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide; PTP, protein tyrosine phosphatase; STAT, signal transducer and activator of transcription; TCPTP, T cell protein tyrosine phospha- tase; T2DM, type 2 diabetes mellitus. * Corresponding author. Tel.: þ39 090 6766406. E-mail address: rmaccari@unime.it (R. Maccari). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.11.001 European Journal of Medicinal Chemistry 71 (2014) 112e127