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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Online Access: | http://hdl.handle.net/11570/3190950 https://doi.org/10.3390/molecules26020330 |
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ftunimessinairis:oai:iris.unime.it:11570/3190950 2024-02-11T10:03:23+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 Ottana 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. Ottana, 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. 2021 http://hdl.handle.net/11570/3190950 https://doi.org/10.3390/molecules26020330 eng eng NLM (Medline) info:eu-repo/semantics/altIdentifier/pmid/33435264 volume:26 issue:2 firstpage:1 lastpage:32 numberofpages:32 journal:MOLECULES http://hdl.handle.net/11570/3190950 doi:10.3390/molecules26020330 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85099997007 multi-target ligand diabetes mellitu aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinone molecular docking info:eu-repo/semantics/article 2021 ftunimessinairis https://doi.org/10.3390/molecules26020330 2024-01-17T17:40:58Z 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 Università degli Studi di Messina: IRIS Molecules 26 2 330 |
institution |
Open Polar |
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Università degli Studi di Messina: IRIS |
op_collection_id |
ftunimessinairis |
language |
English |
topic |
multi-target ligand diabetes mellitu aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinone molecular docking |
spellingShingle |
multi-target ligand diabetes mellitu aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinone molecular docking Ottana 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 |
topic_facet |
multi-target ligand diabetes mellitu aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinone molecular docking |
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. |
author2 |
Ottana, 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. |
format |
Article in Journal/Newspaper |
author |
Ottana 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. |
author_facet |
Ottana 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. |
author_sort |
Ottana R. |
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 |
NLM (Medline) |
publishDate |
2021 |
url |
http://hdl.handle.net/11570/3190950 https://doi.org/10.3390/molecules26020330 |
genre |
DML |
genre_facet |
DML |
op_relation |
info:eu-repo/semantics/altIdentifier/pmid/33435264 volume:26 issue:2 firstpage:1 lastpage:32 numberofpages:32 journal:MOLECULES http://hdl.handle.net/11570/3190950 doi:10.3390/molecules26020330 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85099997007 |
op_doi |
https://doi.org/10.3390/molecules26020330 |
container_title |
Molecules |
container_volume |
26 |
container_issue |
2 |
container_start_page |
330 |
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1790599603055230976 |