Synthesis of indole–quinoline–oxadiazoles: their anticancer potential and computational tubulin binding studies

Abstract: Small hybrid molecules with two or more structural pharmacores having different biological functions and distinct activity have gained a significant role in cancer drug development to combat various types of malignancies. The present study describes an efficient, clean and strategic synthesis of 12 new substituted quinoline–indole–oxadiazole hybrids from substituted 2-(quinolin-8-yloxy)acetohydrazides and indole-3-carboxylic acids by employing T3P^® as a green catalyst. Structures of the newly synthesized compounds were established by IR, ¹H NMR, ¹³C NMR, DEPT C-NMR and MS spectroscopic evidence, as well as CHN analysis data. All indole–quinoline–oxadiazoles were tested for their in vitro cytotoxic potential in breast adenocarcinoma (MCF7) and normal kidney (vero) cell lines using MTT assay. 8-((5-(3-(1H-indol-3-yl)propyl)-1,3,4-oxadiazol-2-yl)methoxy)quinoline (3d) exhibited a low IC50 value and a high selectivity index to MCF7 cells and also displayed a mitotic block in flow cytometric cell cycle progression analysis. Microtubule disruption can induce G₂/M phase cell cycle arrest leading to abnormal mitotic spindle formation. Ligand 3d demonstrated its capability of being a probable tubulin inhibitor when docked in the colchicine domain of tubulin. Graphical Abstract: New series of 8-((5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolines were synthesized using T3P^® as a green catalyst and screened for their cytotoxic and antimitotic potential. The most active 8-((5-(3-(1H-indol-3-yl)propyl)-1,3,4-oxadiazol-2-yl)methoxy)quinoline 3d, displayed good binding interactions with the colchicine binding cavity of microtubule.[Figure not available: see fulltext.]