Rationale design, synthesis, cytotoxicity evaluation, and molecular docking studies of 1,3,4-oxadiazole analogues

We report herein, the synthesis of two new series of oxadiazole analogues, and their cytotoxicity evaluation. The oxadiazole analogues (5a-h and 12a-h) were structurally related to the heterocyclic (1,3,4- oxadiazole) linked aryl core of IMC-038525 (tubulin polymerization inhibitor), NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. The title compounds (5a-h and 12a-h) were synthesized in good yields, and were characterized by IR, NMR, and mass spectral data. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol against NCI-60 human cell lines derived from nine different panels. 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2- yl)phenol (5f) showed maximum cytotoxicity among the first series oxadiazoles (5a-h), while 2-[(2,4- dichlorophenoxy)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity among the second series oxadiazoles (12a-h), with the mean percen growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 μM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c was further screened in five dose assay (0.01, 0.1, 1, 10 and 100 μM), and the results was found to be promising, with GI50 values varies between 1.61 and >100 μM, with comparatively higher selectivity towards the renal cancer cell lines. Furthermore, the compounds, 5f and 12c inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 μM, respectively.