Investigating the potential of pharmacokinetics, chemoselectivity and regioselectivity of triazaspiro[4.4]non-2-en-6-one derivatives for Alzheimer’s disease: A full DFT study on cycloaddition reactions

The cycloaddition of 1,2,7-triazaspiro[4.4]non-2-en-6-one and the dipole 1-benzylidyne-2-phenyl-1,4,2-diazane is described in this work using density functional theory (DFT) methods. The reaction is found to be both chemoselective and regioselective, and the underlying mechanisms are discussed. Furthermore, an in silico approach was employed to examine the pharmacokinetic profiles, drug-likeness, and potential suitability of P1 derivatives as central nervous system (CNS)-active candidates, particularly in the context of Alzheimer’s disease. Based on the prediction of activity spectra for substances (PASS) model, we estimated the biological activity spectrum of analyzed compounds elucidating their strong neuroprotective and anti-inflammatory potential. Docking studies on MAPK-activated protein kinase 2 (MK-2) and acetylcholinesterase (AChE) targets showed that ligand-target complexes were stable, indicating potential strong inhibitory activity of the P1 derivatives. Pharmacokinetic profiling and BOILED-Egg plot analysis revealed good oral absorption, while P1, P1-F, and P1-Cl showed predicted blood–brain barrier (BBB) permeability, suggesting their potential as CNS-targeted agents. Conversely, P1-NH₂ showed good oral bioavailability but lower BBB permeation and was predicted to be substrate of the P-glycoprotein suggesting that structural modifications should be obviously needed in order to optimize its brain distribution. These results lay down a strong background for further experimental investigation and in vitro/in vivo activity of P1 analogs in the search for new therapies against neurodegenerative diseases.