A Decade of Piperazine-Based Small Molecules Approved by U.S. FDA: Exploring the Medicinal Chemistry Impact of this Versatile Pharmacophore

Abstract Heterocyclic scaffolds, particularly azaheterocycles, are part of numerous clinically relevant drugs. We have explored U.S. FDA approved small-molecule drugs (2012–2023) containing piperazine as a core ring system. The analysis revealed that 36 drugs approved in the last decade possess piperazine ring systems, with 15 drugs falling within the anticancer category. The CYP3A4 was found to be the primary enzyme responsible for the metabolism of these drugs, and most of them undergo fecal excretion. Considering stereochemical aspects, nine piperazine-containing drugs were found to be with chiral centers. The perspective is a concerted effort to cover not only the drugs bearing piperazine rings containing drugs but also provides a thorough discussion and commentaries on their pharmacokinetics and pharmacodynamics aspects. This enriches the article’s medicinal chemistry aspect and makes it a good read for the medicinal and allied science community. 1 Introduction 2 Insights into the Chemistry of Piperazine and Comparative Analysis of Molecular and Chemical Spacing Descriptors 3 Synthetic Strategies to Develop Piperazine Derivative 4 Comparative Analysis of the Pharmacological Class of the Approved Drugs Possessing a Piperazine Ring System 5 Delving Deeper into the Approved Drugs Bearing the Piperazine-Based Core Systems 6 Analysis 7 Conclusion