Coumarin Derivatives as Inhibitors of Pathological Protein Aggregation, Mechanistic Basis of β-Sheet Intercalation, Structure–Activity Relationship, and Multi-Target Therapeutic Design—A Critical Review of the Computational and Biophysical Evidence
Year: 2026
Type: article
Abstract: Natural coumarins are a structurally privileged group of bioactive benzopyranone lactones widely spread across the Apiaceae, Rutaceae, and Leguminosae families, and hold significant potential as inhibitors of pathological protein aggregation in Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes mellitus. The fully planar, rigid bicyclic structure of the coumarin nucleus (~3.4–3.5 Å thickness) is geometrically compatible with intercalative π–π stacking with aggregation-nucleating aromatic residues, including Phe19 of Aβ(1–42), providing a mechanistically coherent pharmacophoric basis for anti-aggregation activity according to computational and indirect biophysical evidence. This review critically evaluates the peer-reviewed literature on naturally occurring coumarins and their synthetic derivatives as candidate β-sheet intercalators, with analysis of SAR at C-3 to C-8 positions; multi-target-directed ligand designs with dual activities of inhibiting AChE, BACE-1, GSK-3β, and MAO-B, and as blood–brain barrier-penetrating neuroprotective agents validated in cellular and rodent models. The critical analysis identifies the translational gap between in vitro IC50 values and attainable brain drug concentrations as the primary pharmacological obstacle. It identifies the absence of systematic investigation of coumarin against IAPP, a directly relevant amyloid target in metabolic neurodegeneration, as the most significant unmet research priority in the field.
Source: Chemistry
Author: Huda Masri
Institution: Arab American University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,172
OpenAlex ID: W7167242578