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A series of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives were synthesized via a rapid and facile microwave-assisted synthesis method of building 1,2,4-oxadiazole skeleton using mandelic acid as the starting material. Twenty four target compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HT-1080). Among them, 16b exhibited the most potency against different tumour cell lines, especially A549 cell lines (IC 50 = 87 nM). Structure-activity relationship (SAR) studies revealed the aryl substituent at C-5 position on 1,2,4-oxadiazole ring is superior to that at C-3 position. Oxime as a connector can obviously increase the potency, contrary to that in SMART derivatives. Moreover, 16b significantly induced cell cycle arrest in the G2/M phase and caused microtubule destabilization. Molecular docking studies provide a theoretical binding mode of 16b at the colchicine site in the tubulin dimer. Our work laid the foundation for further structure-guided design of novel tubulin polymerization inhibitors.

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