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Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds
The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp(...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352847/ https://www.ncbi.nlm.nih.gov/pubmed/34373963 http://dx.doi.org/10.1007/s41061-021-00347-5 |
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author | Li Petri, Giovanna Raimondi, Maria Valeria Spanò, Virginia Holl, Ralph Barraja, Paola Montalbano, Alessandra |
author_facet | Li Petri, Giovanna Raimondi, Maria Valeria Spanò, Virginia Holl, Ralph Barraja, Paola Montalbano, Alessandra |
author_sort | Li Petri, Giovanna |
collection | PubMed |
description | The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp(3)-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles. |
format | Online Article Text |
id | pubmed-8352847 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-83528472021-08-24 Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds Li Petri, Giovanna Raimondi, Maria Valeria Spanò, Virginia Holl, Ralph Barraja, Paola Montalbano, Alessandra Top Curr Chem (Cham) Review The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp(3)-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles. Springer International Publishing 2021-08-10 2021 /pmc/articles/PMC8352847/ /pubmed/34373963 http://dx.doi.org/10.1007/s41061-021-00347-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Review Li Petri, Giovanna Raimondi, Maria Valeria Spanò, Virginia Holl, Ralph Barraja, Paola Montalbano, Alessandra Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title | Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title_full | Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title_fullStr | Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title_full_unstemmed | Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title_short | Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds |
title_sort | pyrrolidine in drug discovery: a versatile scaffold for novel biologically active compounds |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352847/ https://www.ncbi.nlm.nih.gov/pubmed/34373963 http://dx.doi.org/10.1007/s41061-021-00347-5 |
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