Work

Investigating the effect of glucosamine conjugation on the inhibitory activity of 2,3-dihydro-1H-perimidine derivatives against protein tyrosine phosphatases

Year: 2026

Type: article

Abstract: This research investigates the impact of attaching glucosamine (GlcN) derivatives to a 2,3-dihydro-1H-perimidine core on the inhibition of protein tyrosine phosphatases (PTPs). A total of twelve novel hybrid compounds (1–12) were synthesized and evaluated against various PTP isoforms. The findings reveal a scaffold-dependent steric-activity relationship: conjugation of GlcN to compound C1, which exhibits high inhibitory activity, resulted in diminished efficacy, likely due to steric hindrance impeding access to the catalytic site. In contrast, attachment of GlcN to a less active compound C2 significantly enhanced potency and selectivity. Compound 9 emerged as the most potent candidate, with an IC50 value of 7.65 ± 0.67 μM against the SHP2-E76K mutant and modest selectivity over PTP1B, TCPTP, SHP1, and SHP2. Molecular docking studies suggested that the deacetylated form of GlcN may form hydrogen bonds with Glu A:200 and Lys A:279, thereby stabilizing the enzyme-ligand complex within the catalytic pocket. Cellular assays demonstrated limited antiproliferative activity of compound 9 against U2OS osteosarcoma cells, possibly attributable to poor membrane permeability that hampers intracellular delivery. These findings imply that conjugation of glucosamine can enhance PTP inhibitory activity, providing a foundational basis for structure-based optimization aimed at the treatment of cancer and metabolic diseases.

Source: Future Medicinal Chemistry

DOI: 10.1080/17568919.2026.2748650