Mononuclear Copper(I) Complexes With Acylthiourea Ligands as Potential Anticancer Agents Against Pancreatic Cancer: Synthesis, Structural Characterization, DFT Calculations, and Docking Studies

Abstract

In this study, two acylthiourea ligands (L1 and L2) were synthesized and coordinated to Cu(I) to afford mononuclear complexes 1 and 2 featuring sulfur-bound ligands that generate a three-coordinate Cu(S)₂Br core. Spectroscopic analyses (FT-IR, UV–Vis, ¹H and ¹³C NMR) together with ESI-MS confirmed successful coordination and analogous coordination environments for both complexes. Single-crystal X-ray diffraction (SCXRD) of complex 1 revealed a distorted trigonal-planar geometry with strong Cu-S interactions and additional stabilization through intermolecular C-H···Br and π···π contacts. Density functional theory (DFT-D3) calculations indicated metal-centered HOMO character, ligand-centered LUMO distribution, and reduced HOMO-LUMO gaps upon coordination, with complex 2 exhibiting higher softness and electrophilicity consistent with enhanced reactivity. Molecular docking studies against PDGFRA predicted stronger binding affinity for the copper complexes than for the free ligands, with complex 2 exhibiting the most favorable interaction profile. In vitro cytotoxicity assessed by the MTT assay against pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1) showed that complex 2 exhibits superior growth inhibition compared with complex 1 and cisplatin, while maintaining better selectivity toward normal cells, with IC₅₀ values of 16.5 ± 0.1 μM for PANC-1 and MIA PaCa-2 and 8.1 ± 0.4 μM for AsPC-1. Collectively, the structural, computational, and biological findings highlight Cu(I)-acylthiourea complexes as promising candidates for further development as anticancer agents.