Synthesis, antiproliferative, antioxidant activities, in silico studies, DFT analysis and molecular dynamics simulation of novel 1-(4-chlorobenzhydryl) piperazine derivatives

A series of 1-(4-chlorobenzhydryl) piperazine derivatives 3-10 were synthesized and characterized both spectroscopically and structurally to investigate their antiproliferative activity associated with the piperazine framework. The compounds were screened against seven human cell lines. Analogously, compounds 14-16 were prepared from treatment of 2 with 4-((2-aminothiazol-4-yl)amino)phenol (11), 4-((2-aminothiazol-4-yl)phenol (12) or 2-amino-5-methoxybenzothiazole (13) in the presence of K2CO3 and KI. Compounds 7 and 10 displayed the highest potency, where 7 exhibited an IC50 value of 6.85 mu M against the Z-138-non Hodgkin lymphoma cancer cell line, and 10 showed IC50 of 7.40 mu M against the DND-41 acute lymphoblastic leukemia cancer cell line. However, all compounds demonstrated IC50 values ranging from 22.0 to > 100 mu M against other tested cancer cell lines. These findings suggest that compounds 7 and 10 hold promise as potential lead compounds for the development of novel antiproliferative agents. Furthermore, compounds 3-10, and 14-16 were evaluated for their antioxidant activity. The study encompassed the molecular docking analysis of compound 7 alongside specific amino acids present in Z-138-non-Hodgkin lymphoma (phosphoinositide 3-kinase, protein PI3k delta, PDB: 4XE0), as well as the docking assessment of compound 10 with the amino acids present in DND-41-acute lymphoblastic leukemia (receptor tyrosine phosphatase (PTPRC/CD45, PDB: 1YGR). The molecular dynamics simulation as well as the DFT have been performed.