Piperidine-containing drugs and recently studied analogs - biological activity, mechanism of action and synthetic cascade access to their scaffolds.

This review provides a comprehensive summary of currently marketed piperidine-containing pharmaceuticals, newly reported bioactive molecules (from 2018 to 2024), and recent advances in domino synthetic strategies focused on the last 7 years. Role of piperidine substitution patterns in modulating biological activity, pharmacokinetics, and molecular recognition (x-ray and cryo-EM structures of drug-target complexes) is discussed. Piperidine is a highly privileged scaffold in medicinal chemistry, present in a wide range of clinically approved drugs and lead compounds, mainly active against cancer, CNS and infective diseases, except for antiviral agents. The piperidine is relatively universal structural motif which offers often relatively high chemical stability, modulation of lipophilicity vs. water solubility, H-bond donor vs. H-bond acceptor properties, or adaptation (via conformation changes) the shape of molecule to steric demands of binding pockets of molecular targets, i.e. crucial physicochemical parameters of considered drugs. From the biological perspective the presence of piperidine motif in structure enhances druggability as this heterocycle is relatively metabolically stable, facilitates drug transport through the natural membranes, improves pharmacokinetic (ADME) properties at often reduced toxicity. Metabolic stability of piperidine scaffold strongly depends on the functionalization at neighboring positions regarding the nitrogen. Hence in order to improve this parameter, using piperidine spirocyclic bioisosteres or spiro-piperidyl systems is often recommended. It is interesting that prodrug but not adjuvant strategy is used to design piperidine-containing drugs. In the synthetic section, green cascade transformations are discussed with complete mechanistic interpretations, including a critical evaluation of proposed pathways and suggestions for more accurate mechanistic alternatives.