Design and synthesis of a new series of 3,5-disubstituted-1,2,4-oxadiazoles as potential colchicine binding site inhibitors: antiproliferative activity, molecular docking, and SAR studies

A series of 3,5-disubstituted 1,2,4-oxadiazoles, sharing a common structural feature with colchicine , were designed and synthesized. All Targets were accepted by National Cancer Institute (NCI), USA for antiproliferative screening at 10 M in full NCI 60 cell panel. The screening of the tested compounds showed moderate antiproliferative activities. Among the series, target 5a demonstrated the broadest and most potent antiproliferative activity (positive cytotoxic effect (PCE) = 33/60 and the mean growth inhibition (MGI) for the most sensitive cell lines (33) is 24.9 %. In addition, targets (5a-k) showed selective potency towards renal cancer in particular A498 cell line . The order of potency of the three most potent targets and the standard colchicine (retrieved from NCI database) against A498 is: Colchicine (GI = 84.5%) 5a (GI = 78%) > 5d (GI = 51%) > 5f (32%). Molecular docking studies were performed for the newly synthesized oxadiazole derivatives as colchicine binding site inhibitors (CBSIs) in β-tubulin against the β-tubulin pocket of colchicine .Compound 5a achieved superior binding affinity (-8.06 kcal/mol) to that of colchicine (6) itself which achieved (-7.40 kcal/mol). Also, 5a -as the most active member- was evaluated for its ability to inhibit β-tubulin polymerization against Colchicine 6 as a reference standard. It showed a twofold potent inhibitory activity of tubulin polymerization (IC50: 1.18uM) compared to that of colchicine (IC50: 2.37uM). Our results could be promising for the identification of new CBSIs leads -especially 5a- for further development as selective anticancer CBSIs