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
