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

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.