Design, Synthesis, in Silico Studies and in Vitro Anticancer Activity of 3‐(4‐methoxyphenyl)azetidine Derivatives

A series of 3-(4-methoxyphenyl)azetidine analogues were synthesized and screened for their in vitro anticancer activity against nine different human cancer cell lines using the cell counting kit-8 (CCK-8) assay. The synthesized molecules were characterized by H-1 NMR, C-13 NMR, LCMS and IR analysis. The toxicity, bioavailability and lipophilicity of all the synthesized compounds were predicted by using osiris and molinspiration model. Molecular docking study revealed that, compound 6-(3-(3-(2-aminopyridin-4-yl)-4-methoxyphenyl)azetidin-1-yl)picolinonitrile (4 A-17) and 6-(3-(4-methoxy-3-(2-methoxypyridin-4-yl)phenyl)azetidin-1-yl)picolinonitrile (4 A-19) were found to be potential inhibitor of human topoisomerase II alpha. The cell viability studies exhibited promising antiproliferative activities of the novel synthesized compounds. 4 A-17 (EC50 0.03 mu M) was found to be more potent than standard Doxorubicin (EC50 0.07 mu M) in U251 cancer cell lines. Similarly, 4 A-19 showed considerable potency against four different cancer cell lines (HepG2, U251, A431, 786-O) with EC50 values ranging from 0.46 to 2.13 mu M. These primary findings supported that molecule 4 A-17 and 4 A-19 should be subjected to further studies and lead optimization.