Recent insights about pyrrolidine core skeletons in pharmacology

Abstract

To overcome numerous health disorders, heterocyclic structures of synthetic or natural origin are utilized, and notably, the emergence of various side effects of existing drugs used for treatment or the resistance of disease-causing microorganisms renders drugs ineffective. Therefore, the discovery of potential therapeutic agents that utilize different modes of action is of utmost significance to circumvent these constraints. Pyrrolidines, pyrrolidine-alkaloids, and pyrrolidine-based hybrid molecules are present in many natural products and pharmacologically important agents. Their key roles in pharmacotherapy make them a versatile scaffold for designing and developing novel biologically active compounds and drug candidates. This review aims to provide an overview of recent advancements (especially during 2015–2023) in the exploration of pyrrolidine derivatives, emphasizing their significance as fundamental components of the skeletal structure. In contrast to previous reviews that have predominantly focused on a singular biological activity associated with these molecules, this review consolidates findings from various investigations encompassing a wide range of important activities (antimicrobial, antiviral, anticancer, anti-inflammatory, anticonvulsant, cholinesterase inhibition, and carbonic anhydrase inhibition) exhibited by pyrrolidine derivatives. This study is also anticipated to serve as a valuable resource for drug research and development endeavors, offering significant insights and guidance.

Targeting miRNA for Colorectal Cancer:In SilicoIdentification and Physics-basedDe NovoModeling of Oncogenic miR-135b for Small Molecule RNA Therapy

“…Specifically, we identify ZINC97784705 as a potential miR-135b-targeted colorectal cancer therapeutic strategy, containing a pyrrolidine group observed in pacritinib and futibatinib, both FDA-approved anticancer drugs. 51…”

Identification of BACE-1 inhibitors through directed C(sp3)–H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives

“…Among the many different N -containing heterocycles, 5-oxopyrrolidines is a privileged structure in medicinal chemistry. 19,20 In particular, fully substituted 5-oxopyrrolidines bearing a carbonyl moiety in position 3 are found in many bioactive molecules and natural products involved in the treatment of CNS diseases. Just to give some examples, different Endothelin Receptor Antagonists 21 and Glutaminyl-Peptide CycloTransferase-Like (QPCTL) inhibitors, 22 used for the treatment of Alzheimer's Disease, contain a fully substituted 5-oxopyrrolidines.…”

“…Several methods have been developed for the preparation of densely functionalized 5-oxopyrrolidines, including cyclization, [3 + 2] or [4 + 1] cycloaddition, 25 cascade reactions, or related transformations. 20,26 However, to the best of our knowledge, short and convenient synthesis of fully substituted 5-oxo-pyrrolidines, containing appendages in each available positions and bearing a carbonyl moiety in position 3 were not reported in the literature. In our previous synthetic efforts in the field of CNS drug discovery, 27–29 we reported the exploitation of the Castagnoli–Cushman reaction (CCR) to generate C -2 substituted morpholinone scaffolds as BACE-1 inhibitors.…”

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition

“…Azepino/cycloheptaindoles and pyrrolidines are common structural motifs in natural products (Scheme a). − While the specific combination of those two moieties is rarely found in nature, , it could embody a new scaffold for pseudonatural products (Scheme b). In this regard, 1,3-dipolar cycloadditions, − and in particular azomethine ylide cycloadditions, have been widely applied to the construction of pyrrolidine-fused rings through cycloaddition. − In the context of a drug discovery program, we were interested in the combination of the aforementioned natural product fragments in an efficient manner.…”