Novel 4- nitroimidazole analogues: Synthesis, in vitro biological evaluation, in silico studies and molecular dynamics simulation

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 ?M against the Z-138-non Hodgkin lymphoma cancer cell line, and 10 showed IC50 of 7.40 ?M against the DND-41 acute lymphoblastic leukemia cancer cell line. However, all compounds demonstrated IC50 values ranging from 22.0 to > 100 ?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?, 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.