Design, synthesis and molecular docking of piperidin‐4‐amine linked pyrimidine derivatives as potent anticancer agents

Abstract A series of rationally designed novel hybrid piperidin-4-amine linked pyrimidine derivatives PM(1-19) were synthesized. Compound PM-16 was found to be most potent with (IC50=1.92 µM, 60.94% inhibition), while PM-18 (IC50 of 5.2 µM, 66.45% inhibition), the second most potent among all, against HepG2 human liver cancer cell lines. Compounds PM-18&19 were exhibited excellent inhibition percentages of 66.45 and 68.76 respectively, compared to positive control Paclitaxel (62.12%). In-silico target hunting for the potent compounds (PM-16&18) reveals two possible targets, one is binding with human estrogen receptor and other one is inhibiting tubulin polymerisation. The molecular docking studies suggested that compounds (PM-16&18) with hydrophobic group linked by an alkyl chain may facilitate free access in the Helix 12 domain (in determining potency plays a crucial role) in the human estrogen receptor's active and also inhibiting the tubulin polymerase by binding site at α/β-tubuline interface at colchicine binding site.