Synthesis, in silico investigation and in vitro antiproliferative evaluation of novel imidazole-hydroxyacetamide derivatives

In the present study, imidazole-hydroxyacetamide derivatives (M1-M4) were synthesized by reacting imidazole-2-amine or imidazole-2-thiol derivatives with 2-chloro-N-hydroxyacetamide and validated using different spectroscopic techniques. Network pharmacology predicted BMP1, CA2, EGFR, BRD4, CDK2, ALOX5, ACHE, MAOB, and MAOA as potential targets associated with the antiproliferative activity of the synthesized compounds. Molecular docking analyses were performed against the targets. MD simulations suggested overall stability of the selected protein-ligand complexes, supporting the computational docking predictions. Furthermore, DFT analysis identified M2 as the softest molecule. ADMET analysis showed that all compounds passed Lipinski’s rule, GSK rule, and Golden triangle rule, with no violations or alerts. Antiproliferative activity of the synthesized compounds against SH-SY5Y human neuroblastoma cells demonstrated moderate activity for compound M2. This activity may be associated with the presence of NH group linking the imidazole and hydroxyacetamide in the structure. Overall, M2 may represent a promising preliminary hit for further antiproliferative drug discovery; however, additional mechanistic studies, target validation, and broader biological evaluation are required.