Design, synthesis, and biological evaluation of novel furo[3,2-b]pyrrole-benzimidazole series as potential protein tyrosine phosphatase (PTPs) inhibitors.

Abstract

Protein tyrosine phosphatases (PTPs) are essential for regulating cell signaling pathways, and their dysregulation is linked to various human diseases, including cancer and diabetes, making them important therapeutic targets. However, developing PTP inhibitors remains challenging due to the conserved structure and charged active sites. In this study, a series of furo[3,2-b]pyrrole-benzimidazole derivatives was designed and synthesized as potential PTP inhibitors. Structure-activity relationship (SAR) studies showed that extending the aromatic system with the benzimidazole scaffold increased potency, and the carboxylic acid group was essential for inhibitory activity. Among the synthesized compounds, 5a was identified as the lead compound, exhibiting strong inhibitory activity against PTP1B (IC₅₀ = 0.70 ± 0.04 μM) and the oncogenic SHP2-E76K mutant (IC₅₀ = 0.36 ± 0.02 μM). Molecular docking studies suggest that the inhibitory activity of this series may depend on the compounds' ability to bind a putative allosteric site, thereby stabilizing the WPD loop in its inactive, open conformation; kinetic and biophysical validation of this mechanism is planned for future work. Antiproliferative cell tests demonstrated that although compound 5a exhibited superior enzymatic inhibition, smaller analogs, such as 2a, lacking the extended benzimidazole moiety, showed more potent, dose-dependent cytotoxicity in U2OS human osteosarcoma cells (IC₅₀ = 16.25 μM vs. 157.24 μM for 5a), likely due to improved physicochemical properties and membrane permeability. These findings offer a promising scaffold for future development and optimization of potent, broad-drug-like PTP inhibitors with enhanced activity against the full-length SHP2-E76K construct relative to the isolated catalytic domains tested.