Design and synthesis of newer 5-aryl-<i>N</i>-(naphthalen-2-yl)-1,3,4-oxadiazol-2-amine analogues as anticancer agents

Cancer is the second leading cause of death and chemotherapy is widely used and well–known for treating cancer, yet it has lots of adverse side effects, making the search for novel compounds imperative. We reported here design, synthesis, DFT analysis, anticancer evaluation and in–silico studies of new 1,3,4–oxadiazoles (4a–e). IMC-038525 and IMC-094332 tubulin inhibitors’ oxadiazole-linked aryl cores inspired the innovative compounds, and synthesis was accomplished in two steps followed by their characterization by spectral data. The HOMO and LUMO energy gap (ΔE) was determined to investigate compounds’ (4a–e) stability followed by their anticancer activity at 10 μM and in-silico studies. 5-(4-Nitrophenyl)-N-(naphthalene-2-yl)-1,3,4-oxadiazol-2-amine (4b) demonstrated substantial anticancer activity against a few cell lines like SR, MDA-MB-435, MOLT-4, K-562, and HL-60(TB). 5-(3,4,5-Trimethoxyphenyl)-N-(naphthalene-2-yl)-1,3,4-oxadiazol-2-amine (4e) demonstrated promising anticancer activity against cell lines, UO–31, NCI–H226, CAKI–1, PC-3, and MCF7. The molecular docking against tubulin’s colchicine binding site (PDB ID: 1AS0), displayed a docking score of –7.295 Kcal/mol and a H–bond interaction with Ala317 residue for the ligand 4e. The ligand 4e was found to interacted 24 amino acids of the tubulin protein in MD simulation investigation with moderate local conformational changes with ligand 4e (&lt; 1 Å).