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

Autor:	Roberta Moschini, Ilaria Nesi, Trung Ngoc Nguyen, Antonella Del Corso, Rosanna Maccari, Massimo Genovese, Paolo De Paoli, Ilenia Adornato, Gerhard Wolber, Rosaria Ottanà, Mario Cappiello, Alexandra Naß
Rok vydání:	2021
Předmět:	4-thiazolidinones Drug Evaluation Preclinical Pharmaceutical Science Disease Pharmacology Ligands Analytical Chemistry Mice 0302 clinical medicine Drug Discovery Enzyme Inhibitors Non-Receptor Type 1 Aldehyde Reductase Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification 0303 health sciences Chemistry Hep G2 Cells aldose reductase Preclinical Chemistry (miscellaneous) 030220 oncology & carcinogenesis diabetes mellitus Molecular Medicine 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie Therapeutik C2C12 Aldose reductase Diabetes mellitus Molecular docking Multi-target ligands Protein tyrosine phosphatase 1B Animals Diabetes Mellitus Humans Structure-Activity Relationship Hypoglycemic Agents 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten multi-target ligands Article lcsh:QD241-441 03 medical and health sciences lcsh:Organic chemistry medicine Structure–activity relationship Physical and Theoretical Chemistry 030304 developmental biology Organic Chemistry molecular docking medicine.disease Enzyme Cell culture Drug Evaluation Protein Tyrosine Phosphatase protein tyrosine phosphatase 1B
Zdroj:	Molecules Volume 26 Issue 2 Molecules, Vol 26, Iss 330, p 330 (2021)
ISSN:	1420-3049
DOI:	10.3390/molecules26020330
Popis:	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.
Databáze:	OpenAIRE
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