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.

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

“…Based on the literature survey, it has been suggested that compared to pyrrole analogs, pyrrolidine scaffold will be having more preference to the drug design because of unrestricted conformation of the ring [ 172 ]. Further, pyrrolidine analog has privileged N − 1 position for substitutions which were present in US FDA-approved drugs [ 173 ].…”

Pyrrole as an Important Scaffold of Anticancer Drugs: Recent Advances

“…Initially, pyrrole was identified as a coal tar component in 1834, however it was isolated 23 years later from the pyrolysate of a bone (16). Pyrrole is characterized as an aromatic five membered N-containing heterocycle, differing in several key physicochemical parameters when compared to its saturated analogpyrrolidine (Table 1) (17).…”

Comprehensive analysis of commercial fragment libraries

“…19 The interest in non-planar scaffolds has given rise to numerous developments in synthetic methods. [20][21][22][23][24] In FBDD programs, planar fragments are often avoided, since they tend to bind multiple targets, and therefore are potentially more difficult to develop into a selective drug-like compound. 16 Nonetheless, the successful ligand design from flat fragments has fueled the debate, demonstrating that the flatness of the fragments does not necessarily transfer to the lead.…”