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
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 rational...
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ftdoajarticles:oai:doaj.org/article:5dbb82913dc34a5d862083d04bc41b3c 2024-01-07T09:42:55+01:00 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 2021-01-01T00:00:00Z https://doi.org/10.3390/molecules26020330 https://doaj.org/article/5dbb82913dc34a5d862083d04bc41b3c EN eng MDPI AG https://www.mdpi.com/1420-3049/26/2/330 https://doaj.org/toc/1420-3049 doi:10.3390/molecules26020330 1420-3049 https://doaj.org/article/5dbb82913dc34a5d862083d04bc41b3c Molecules, Vol 26, Iss 2, p 330 (2021) multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking Organic chemistry QD241-441 article 2021 ftdoajarticles https://doi.org/10.3390/molecules26020330 2023-12-10T01:47:06Z 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. Article in Journal/Newspaper DML Directory of Open Access Journals: DOAJ Articles Molecules 26 2 330 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking Organic chemistry QD241-441 |
spellingShingle |
multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking Organic chemistry QD241-441 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 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 |
topic_facet |
multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking Organic chemistry QD241-441 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
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 |
author_facet |
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 |
author_sort |
Rosaria Ottanà |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
MDPI AG |
publishDate |
2021 |
url |
https://doi.org/10.3390/molecules26020330 https://doaj.org/article/5dbb82913dc34a5d862083d04bc41b3c |
genre |
DML |
genre_facet |
DML |
op_source |
Molecules, Vol 26, Iss 2, p 330 (2021) |
op_relation |
https://www.mdpi.com/1420-3049/26/2/330 https://doaj.org/toc/1420-3049 doi:10.3390/molecules26020330 1420-3049 https://doaj.org/article/5dbb82913dc34a5d862083d04bc41b3c |
op_doi |
https://doi.org/10.3390/molecules26020330 |
container_title |
Molecules |
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26 |
container_issue |
2 |
container_start_page |
330 |
_version_ |
1787424181968699392 |