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Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives
Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095986/ https://www.ncbi.nlm.nih.gov/pubmed/37049935 http://dx.doi.org/10.3390/molecules28073172 |
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author | Galbiati, Andrea Zana, Aureliano Borsari, Chiara Persico, Marco Bova, Stefania Tkachuk, Oleh Corfu, Alexandra Ioana Tamborini, Lucia Basilico, Nicoletta Fattorusso, Caterina Bruno, Stefano Parapini, Silvia Conti, Paola |
author_facet | Galbiati, Andrea Zana, Aureliano Borsari, Chiara Persico, Marco Bova, Stefania Tkachuk, Oleh Corfu, Alexandra Ioana Tamborini, Lucia Basilico, Nicoletta Fattorusso, Caterina Bruno, Stefano Parapini, Silvia Conti, Paola |
author_sort | Galbiati, Andrea |
collection | PubMed |
description | Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3-BA and its ester and amide derivatives were prepared and characterized for their antimalarial activity. Only the (5S, αS) isomers displayed significant antiplasmodial activity, revealing that their uptake might be mediated by the L-amino acid transport system, which is known to mediate the acivicin membrane’s permeability. In addition, we investigated the inhibitory activity towards Plasmodium falciparum glyceraldehyde 3-phosphate dehydrogenase (PfGAPDH) since it is involved in the multitarget mechanism of action of 3-BA. Molecular modeling has shed light on the structural and stereochemical requirements for an efficient interaction with PfGAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (1a–d and 4a–d), it leads to significant differences in the antimalarial activity for all subclasses, suggesting that a stereoselective uptake might be responsible for the enhanced biological activity of the (5S, αS) isomers. |
format | Online Article Text |
id | pubmed-10095986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100959862023-04-13 Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives Galbiati, Andrea Zana, Aureliano Borsari, Chiara Persico, Marco Bova, Stefania Tkachuk, Oleh Corfu, Alexandra Ioana Tamborini, Lucia Basilico, Nicoletta Fattorusso, Caterina Bruno, Stefano Parapini, Silvia Conti, Paola Molecules Article Chiral natural compounds are often biosynthesized in an enantiomerically pure fashion, and stereochemistry plays a pivotal role in biological activity. Herein, we investigated the significance of chirality for nature-inspired 3-Br-acivicin (3-BA) and its derivatives. The three unnatural isomers of 3-BA and its ester and amide derivatives were prepared and characterized for their antimalarial activity. Only the (5S, αS) isomers displayed significant antiplasmodial activity, revealing that their uptake might be mediated by the L-amino acid transport system, which is known to mediate the acivicin membrane’s permeability. In addition, we investigated the inhibitory activity towards Plasmodium falciparum glyceraldehyde 3-phosphate dehydrogenase (PfGAPDH) since it is involved in the multitarget mechanism of action of 3-BA. Molecular modeling has shed light on the structural and stereochemical requirements for an efficient interaction with PfGAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (1a–d and 4a–d), it leads to significant differences in the antimalarial activity for all subclasses, suggesting that a stereoselective uptake might be responsible for the enhanced biological activity of the (5S, αS) isomers. MDPI 2023-04-03 /pmc/articles/PMC10095986/ /pubmed/37049935 http://dx.doi.org/10.3390/molecules28073172 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Galbiati, Andrea Zana, Aureliano Borsari, Chiara Persico, Marco Bova, Stefania Tkachuk, Oleh Corfu, Alexandra Ioana Tamborini, Lucia Basilico, Nicoletta Fattorusso, Caterina Bruno, Stefano Parapini, Silvia Conti, Paola Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title | Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title_full | Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title_fullStr | Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title_full_unstemmed | Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title_short | Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives |
title_sort | role of stereochemistry on the biological activity of nature-inspired 3-br-acivicin isomers and derivatives |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095986/ https://www.ncbi.nlm.nih.gov/pubmed/37049935 http://dx.doi.org/10.3390/molecules28073172 |
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