Synthesis, state-of-the-art NMR-binding and molecular modeling study of new benzimidazole core derivatives as Pin1 inhibitors: Targeting breast cancer

New series of benzimidazole ring core conjugated with either dithiocarbamate or thiopropyl linkers, hybridized with different secondary amines were synthesized; 5-15 and 22-31; respectively. The new compounds were characterized by different spectroscopic techniques (¹H, ¹³C 1D & 2D NMR, ESI-MS and IR). They were screened for in vitro Anticancer activity against breast Cancer using MCF7 cell line. The results obtained revealed that compounds 5, 12, 15 and 25 were the most active among the synthesized series exhibiting IC₅₀ < 10 µg/ml against DOX. To characterize targeting breast Cancer on molecular level, binding to ¹⁵N-labeled Pin1 Enzyme was conducted using state-of-the-art 2D NMR binding experiments. Results showed promising binding between compounds 5, 12, and 25 by chemical shift perturbation (peak shifting or peak disappearance). Molecular docking study were quite valuable to explain the binding mode of active derivatives via hydrogen bonding. Additional contact preferences and surface mapping studies stated the similarity pattern between active candidates which may pave the way for more precise anti breast Cancer target optimization.