Design and Synthesis of Novel N1-(Phenoxyethyl) Theobromine Derivatives and Evaluation of Their Cytotoxicity by in-vitro Method with Molecular Docking Study: A Laboratory Study

Cancer, one of the global health problems, has been introduced as one of the main death causes worldwide. Xanthine derivatives have been identified as effective compounds for prevention and treatment of cancer. In this study, a series of novel phenoxy ethyl theobromine derivatives were designed with N1 positioning and their cytotoxic activity was evaluated. Also, molecular docking studies were performed to predict the possible action mechanism of these compounds.

In the present laboratory investigation, compounds 2, 3, and 5a-l were initially synthesized. The cytotoxicity of all new synthesized compounds was studied by MTT (methylthiazolyldiphenyl-tetrazolium bromide) -based colorimetric assay against 4 human cancer cell lines. Autodock software was used to determine the binding energies of these structures on human tetrahydrofolate reductase, human octo-5'-nucleotidase (e5NT) and human phosphodiesterase enzymes. The obtained data were analyzed using one-way analysis of variance.

The results of docking studies showed acceptable binding energy (-8.42 kcal/mol) against e5NT. The results of cytotoxicity analysis showed that the greatest effect of cytotoxicity was against A549 and MCF-7 cells (compound 5e with IC50 values of 86.65 μM and 161.09 μM, respectively).

The results of molecular docking studies showed acceptable binding energy against the octo-5'-nucleotidase enzyme. Among the synthesized derivatives, compound 5a with the lowest ΔG level (-8.42 kcal/mol) was selected as the best inhibitor of this enzyme. Appropriate effects of cytotoxicity were observed at different concentrations of the synthesized compounds on MCF7 and A549 cell lines.