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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/3172 |
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| author | Andrea Galbiati Aureliano Zana Chiara Borsari Marco Persico Stefania Bova Oleh Tkachuk Alexandra Ioana Corfu Lucia Tamborini Nicoletta Basilico Caterina Fattorusso Stefano Bruno Silvia Parapini Paola Conti |
| author_facet | Andrea Galbiati Aureliano Zana Chiara Borsari Marco Persico Stefania Bova Oleh Tkachuk Alexandra Ioana Corfu Lucia Tamborini Nicoletta Basilico Caterina Fattorusso Stefano Bruno Silvia Parapini Paola Conti |
| author_sort | Andrea Galbiati |
| collection | DOAJ |
| 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 (5<i>S</i>, α<i>S</i>) 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 <i>Plasmodium falciparum</i> glyceraldehyde 3-phosphate dehydrogenase (<i>Pf</i>GAPDH) 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 <i>Pf</i>GAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (<b>1a</b>–<b>d</b> and <b>4a</b>–<b>d</b>), 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 (5<i>S</i>, α<i>S</i>) isomers. |
| first_indexed | 2024-03-11T05:29:41Z |
| format | Article |
| id | doaj.art-640877a73467454187830b2b5472f319 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:29:41Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-640877a73467454187830b2b5472f3192023-11-17T17:14:35ZengMDPI AGMolecules1420-30492023-04-01287317210.3390/molecules28073172Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and DerivativesAndrea Galbiati0Aureliano Zana1Chiara Borsari2Marco Persico3Stefania Bova4Oleh Tkachuk5Alexandra Ioana Corfu6Lucia Tamborini7Nicoletta Basilico8Caterina Fattorusso9Stefano Bruno10Silvia Parapini11Paola Conti12Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, ItalyDepartment of Medicine and Surgery, University of Parma, 43124 Parma, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyDepartment of Biomedical, Surgical and Dental Sciences, University of Milan, Via Pascal 36, 20133 Milan, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, ItalyFood and Drug Department, University of Parma, 43124 Parma, ItalyDepartment of Biomedical Sciences for Health, University of Milan, Via Pascal 36, 20133 Milan, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, ItalyChiral 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 (5<i>S</i>, α<i>S</i>) 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 <i>Plasmodium falciparum</i> glyceraldehyde 3-phosphate dehydrogenase (<i>Pf</i>GAPDH) 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 <i>Pf</i>GAPDH, leading to covalent irreversible binding and enzyme inactivation. While stereochemistry affects the target binding only for two subclasses (<b>1a</b>–<b>d</b> and <b>4a</b>–<b>d</b>), 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 (5<i>S</i>, α<i>S</i>) isomers.https://www.mdpi.com/1420-3049/28/7/3172stereochemistry3-Br-acivicin<i>Plasmodium falciparum</i>glyceraldehyde 3-phosphate dehydrogenasemultitargetcovalent inhibitors |
| spellingShingle | Andrea Galbiati Aureliano Zana Chiara Borsari Marco Persico Stefania Bova Oleh Tkachuk Alexandra Ioana Corfu Lucia Tamborini Nicoletta Basilico Caterina Fattorusso Stefano Bruno Silvia Parapini Paola Conti Role of Stereochemistry on the Biological Activity of Nature-Inspired 3-Br-Acivicin Isomers and Derivatives Molecules stereochemistry 3-Br-acivicin <i>Plasmodium falciparum</i> glyceraldehyde 3-phosphate dehydrogenase multitarget covalent inhibitors |
| 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 | stereochemistry 3-Br-acivicin <i>Plasmodium falciparum</i> glyceraldehyde 3-phosphate dehydrogenase multitarget covalent inhibitors |
| url | https://www.mdpi.com/1420-3049/28/7/3172 |
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