Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Novel Benzoxazole Linked 1,3,4-Oxadiazoles.

Abstract

Cancer disease is a serious concern globally. Global cancer occurrence is steadily increasing every year. There is always a persistent need to develop new anticancer drugs with reduced side effects or that act synergistically with the existing chemotherapeutics. Benzoxazoles are fused bicyclic nitrogen and oxygen-containing heterocyclic compounds and are considered biologically privileged scaffolds. We designed a synthetic route to link the benzoxazoles with oxadiazole,s resulting in a better pharmacophore for anticancer activity. A series of novel amide derivatives of benzoxazole linked 1,3,4-oxadiazoles (10 a-j) were synthesized and characterized by 1H NMR, 13C NMR, and mass spectroscopic techniques. The biological properties of the compounds were screened in vitro against four different tumor cell lines. The results suggest that the compound 10b having 3,4,5-trimethoxy substitution on the phenyl ring exhibited potent anticancer activity in three cell lines (A549 = 0.13 ± 0.014 μM, MCF-7 = 0.10 ± 0.013 μM and HT-29 = 0.22 ± 0.017 μM). Notably, among the synthesized derivatives, compounds 10b, 10c, 10f, 10g, and 10i exhibited potent anticancer activity than the control, with IC50 values in the range from 0.11 ± 0.02 to 0.93 ± 0.034 μM. Molecular docking simulation results showed that compounds were stabilized by hydrogen bond and π-π interactions with the protein. The molecules showed comparable binding affinities with standard Combretastatin-A4. The present research work is in a preliminary phase and needs further studies to take the synthesized compounds to the next level in the cancer research field.