Developing drugs for the central nervous system (CNS) requires fine chemical modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogues represent valuable heterocycles, due to their conformational and physicochemical properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pK a value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic−hydrophilic interactions, and to improve blood solubility and brain permeability of the overall structure. In CNS-active compounds, morpholines are used (1) to enhance the potency through molecular interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/ pharmacodynamic (PK/PD) properties. In this perspective, selected morpholinecontaining CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathology of CNS tumors. The medicinal chemistry/pharmacological activity of morpholine derivatives is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.
The development of molecules able to target protein–protein
interactions (PPIs) is of interest for the development of novel therapeutic
agents. Since a high percentage of PPIs are mediated by α-helical
structure at the interacting surface, peptidomimetics that reproduce
the essential conformational components of helices are useful templates
for the development of PPIs inhibitors. In this work, the synthesis
of a constrained dipeptide isostere and insertion in the short peptide
epitope EDLFYQ of the angiotensin-converting enzyme 2 (ACE2) α1
helix domain resulted in the identification of a molecule capable
of inhibiting the SARS-CoV-2 ACE2/spike interaction in the micromolar
range. Moreover, inhibition of SARS-CoV-2 3CLPro main protease activity
was assessed as an additional inhibitory property of the synthesized
peptidomimetics, taking advantage of the C-terminal Q amino acid present
in both the ACE2 epitope and the Mpro recognizing motif (APSTVxLQ),
thus paving the way to the development of multitarget therapeutics
toward coronavirus infections.
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