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Article

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

1
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, Polo Universitario Annunziata, 98168 Messina, Italy
2
Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134 Firenze, Italy
3
Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy
4
Molecular Design Lab, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, 14195 Berlin, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: George Kokotos
Molecules 2021, 26(2), 330; https://doi.org/10.3390/molecules26020330
Received: 18 December 2020 / Revised: 5 January 2021 / Accepted: 7 January 2021 / Published: 10 January 2021
(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)
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. View Full-Text
Keywords: multi-target ligands; diabetes mellitus; aldose reductase; protein tyrosine phosphatase 1B; 4-thiazolidinones; molecular docking multi-target ligands; diabetes mellitus; aldose reductase; protein tyrosine phosphatase 1B; 4-thiazolidinones; molecular docking
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MDPI and ACS Style

Ottanà, R.; Paoli, P.; Cappiello, M.; Nguyen, T.N.; Adornato, I.; Del Corso, A.; Genovese, M.; Nesi, I.; Moschini, R.; Naß, A.; Wolber, G.; Maccari, R. 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. Molecules 2021, 26, 330. https://doi.org/10.3390/molecules26020330

AMA Style

Ottanà R, Paoli P, Cappiello M, Nguyen TN, Adornato I, Del Corso A, Genovese M, Nesi I, Moschini R, Naß A, Wolber G, Maccari R. 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. Molecules. 2021; 26(2):330. https://doi.org/10.3390/molecules26020330

Chicago/Turabian Style

Ottanà, Rosaria, Paolo Paoli, Mario Cappiello, Trung Ngoc Nguyen, Ilenia Adornato, Antonella Del Corso, Massimo Genovese, Ilaria Nesi, Roberta Moschini, Alexandra Naß, Gerhard Wolber, and Rosanna Maccari. 2021. "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" Molecules 26, no. 2: 330. https://doi.org/10.3390/molecules26020330

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