A Minireview on the Morpholine-Ring-Containing U.S. FDA Approved Drugs: A Medicinal-Chemistry-Based Analysis from 2013 to 2023

Abstract

Heterocyclic scaffolds, especially oxazines, constitute a significant component of clinically pertinent pharmaceuticals. Morpholine enhances the solubility, bioavailability, and metabolic stability of drug molecules because of its structural feature that gives optimum basicity (pK _a = ca. 8.7), hydrogen bonding, and an electron-deficient ring system. Apart from structural features, incorporating morpholine ring systems in drug molecules improved their pharmacokinetic profiles also. It provides optimum lipid solubility as well as aqueous solubility. As a bioisosteric replacement unit for piperazine, piperidine, etc., the morpholine ring provides optimum basicity and lipophilicity. We have examined U.S. FDA approved small-molecule drugs (2012–2023) incorporating morpholine as core ring structures. The analysis identified 14 drugs approved in the past decade that contain morpholine ring systems, with 50% classified as anticancer agents. The CYP3A4 enzyme was identified as the main driver for the metabolism of these drugs, with the majority being excreted via feces. Three morpholine-containing drugs were identified as possessing chiral centers, taking into account stereochemical aspects. In addition to covering drugs with morpholine rings, the perspective offers a comprehensive analysis utilizing molecular descriptors, chemical space parameters, and commentary on these medications’ pharmacokinetic and pharmacodynamic aspects. This enhances the article’s medicinal chemistry dimension and renders it a valuable resource for the medicinal and allied science community.

1 Introduction

2 Insights towards the Chemistry of Morpholine

3 Synthetic Strategies to Develop Morpholine Derivatives

4 Implication of Morpholine in Improvising the Pharmacokinetics and Efficacy of Pharmaceutical Drugs: Case Studies

5 Comparative Analysis of the Pharmacological Class of the Approved Drugs Possessing Morpholine System

6 Delving Deeper into the Approved Drugs Bearing the Morpholine-Based Core Systems

7 Analysis and Conclusion

8 Summary

Keywords

heterocycles - morpholine - drug discovery - U.S. FDA approved - chemical space - molecular descriptors - chemical analysis - metabolism

Publikationsverlauf

Eingereicht: 21. Januar 2025

Angenommen: 27. Februar 2025

Accepted Manuscript online:
27. Februar 2025

Artikel online veröffentlicht:
22. April 2025

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