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...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
2021
|
Subjects: | |
Online Access: | https://refubium.fu-berlin.de/handle/fub188/30419 https://doi.org/10.17169/refubium-30160 https://doi.org/10.3390/molecules26020330 |
id |
ftfuberlin:oai:refubium.fu-berlin.de:fub188/30419 |
---|---|
record_format |
openpolar |
spelling |
ftfuberlin:oai:refubium.fu-berlin.de:fub188/30419 2023-05-15T16:02:04+02:00 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 Ottanà, Rosaria Paoli, Paolo Cappiello, Mario Nguyen, Trung Ngoc Adornato, Ilenia Del Corso, Antonella Genovese, Massimo Nesi, Ilaria Moschini, Roberta Naß, Alexandra Wolber, Gerhard Maccari, Rosanna 2021 32 Seiten application/pdf https://refubium.fu-berlin.de/handle/fub188/30419 https://doi.org/10.17169/refubium-30160 https://doi.org/10.3390/molecules26020330 eng eng https://refubium.fu-berlin.de/handle/fub188/30419 http://dx.doi.org/10.17169/refubium-30160 doi:10.3390/molecules26020330 https://creativecommons.org/licenses/by/4.0/ CC-BY multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking ddc:616 ddc:615 doc-type:article 2021 ftfuberlin https://doi.org/10.17169/refubium-30160 https://doi.org/10.3390/molecules26020330 2022-05-15T20:50:51Z 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 Freie Universität Berlin: Refubium (FU Berlin) |
institution |
Open Polar |
collection |
Freie Universität Berlin: Refubium (FU Berlin) |
op_collection_id |
ftfuberlin |
language |
English |
topic |
multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking ddc:616 ddc:615 |
spellingShingle |
multi-target ligands diabetes mellitus aldose reductase protein tyrosine phosphatase 1B 4-thiazolidinones molecular docking ddc:616 ddc:615 Ottanà, Rosaria Paoli, Paolo Cappiello, Mario Nguyen, Trung Ngoc Adornato, Ilenia Del Corso, Antonella Genovese, Massimo Nesi, Ilaria Moschini, Roberta Naß, Alexandra Wolber, Gerhard Maccari, Rosanna 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 ddc:616 ddc:615 |
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 |
Ottanà, Rosaria Paoli, Paolo Cappiello, Mario Nguyen, Trung Ngoc Adornato, Ilenia Del Corso, Antonella Genovese, Massimo Nesi, Ilaria Moschini, Roberta Naß, Alexandra Wolber, Gerhard Maccari, Rosanna |
author_facet |
Ottanà, Rosaria Paoli, Paolo Cappiello, Mario Nguyen, Trung Ngoc Adornato, Ilenia Del Corso, Antonella Genovese, Massimo Nesi, Ilaria Moschini, Roberta Naß, Alexandra Wolber, Gerhard Maccari, Rosanna |
author_sort |
Ottanà, Rosaria |
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 |
publishDate |
2021 |
url |
https://refubium.fu-berlin.de/handle/fub188/30419 https://doi.org/10.17169/refubium-30160 https://doi.org/10.3390/molecules26020330 |
genre |
DML |
genre_facet |
DML |
op_relation |
https://refubium.fu-berlin.de/handle/fub188/30419 http://dx.doi.org/10.17169/refubium-30160 doi:10.3390/molecules26020330 |
op_rights |
https://creativecommons.org/licenses/by/4.0/ |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.17169/refubium-30160 https://doi.org/10.3390/molecules26020330 |
_version_ |
1766397696852099072 |