A mini review on the morpholine ring containing UDFDA approved drugs: A medicinal chemistry-based analysis from 2013-23

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 (pKa ~8.7), hydrogen bonding, and an electron-deficient ring system. Apart from structural features, 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 USFDA-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.