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Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds.

ABSTRACT: 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 sp³-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.

SUBMITTER: Li Petri G

PROVIDER: S-EPMC8352847 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite the progress made in immunization and drug development, so far there are no prophylactic vaccines and effective therapies for many viral infections, including infections caused by coronaviruses. In this regard, the search for new antiviral substances continues to be relevant, and the enormous potential of marine resources are a stimulus for the study of marine compounds with antiviral activity in experiments and clinical trials. The highly pathogenic human coronaviruses-severe acute respiratory syndrome-related coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) remain a serious threat to human health. In this review, the authors hope to bring the attention of researchers to the use of biologically active substances of marine origin as potential broad-spectrum antiviral agents targeting common cellular pathways and various stages of the life cycle of different viruses, including coronaviruses. The review has been compiled using references from major databases such as Web of Science, PubMed, Scopus, Elsevier, Springer and Google Scholar (up to June 2020) and keywords such as 'coronaviruses', 'marine organisms', 'biologically active substances', 'antiviral drugs', 'SARS-CoV', 'MERS-CoV', 'SARS-CoV-2', '3CLpro', 'TMPRSS2', 'ACE2'. After obtaining all reports from the databases, the papers were carefully analysed in order to find data related to the topic of this review (98 references). Biologically active substances of marine origin, such as flavonoids, phlorotannins, alkaloids, terpenoids, peptides, lectins, polysaccharides, lipids and others substances, can affect coronaviruses at the stages of penetration and entry of the viral particle into the cell, replication of the viral nucleic acid and release of the virion from the cell; they also can act on the host's cellular targets. These natural compounds could be a vital resource in the fight against coronaviruses.

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Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds.

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