Design and synthesis of pyrazole–oxindole conjugates targeting tubulin polymerization as new anticancer agents

•The new pyrazole–oxindole conjugates were synthesized by Knoevenagel condensation.•Investigated for antiproliferative activity on different human cancer cell lines.•The lead congeners were taken for cellular tubulin polymerization assay.•Studies on Zebrafish embryos have been carried out.•Further, lead compounds have been docked against the tubulin structure.

A series of twenty one compounds with pyrazole and oxindole conjugates were synthesized by Knoevenagel condensation and investigated for their antiproliferative activity on different human cancer cell lines. The conjugates are comprised of a four ring scaffold; the structural isomers 12b and 12c possess chloro-substitution in the D ring. Among the congeners 12b, 12c, and 12d manifested significant cytotoxicity and inhibited tubulin assembly. Treatments with 12b, 12c and 12d resulted in accumulation of cells in G2/M phase, disruption of microtubule network, and increase in cyclin B1 protein. Zebrafish screening revealed that 12b, and 12d caused developmental defects. Docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.

Graphical abstractA series of twenty one pyrazole linked oxindole conjugates comprising of a four ring scaffold (A, B, C and D) were synthesized and investigated for their antiproliferative activity.Figure optionsDownload full-size imageDownload as PowerPoint slide