In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B
Rosaria Ottanà,
Paolo Paoli,
Mario Cappiello,
Trung Ngoc Nguyen,
Ilenia Adornato,
Antonella Del Corso,
Massimo Genovese,
Ilaria Nesi,
Roberta Moschini,
Alexandra Naß,
Gerhard Wolber,
Rosanna Maccari
Affiliations
Rosaria Ottanà
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, Polo Universitario Annunziata, 98168 Messina, Italy
Paolo Paoli
Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy
Mario Cappiello
Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy
Trung Ngoc Nguyen
Molecular Design Lab, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, 14195 Berlin, Germany
Ilenia Adornato
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, Polo Universitario Annunziata, 98168 Messina, Italy
Antonella Del Corso
Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy
Massimo Genovese
Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy
Ilaria Nesi
Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy
Roberta Moschini
Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy
Alexandra Naß
Molecular Design Lab, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, 14195 Berlin, Germany
Gerhard Wolber
Molecular Design Lab, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, 14195 Berlin, Germany
Rosanna Maccari
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, Polo Universitario Annunziata, 98168 Messina, Italy
Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.
