In this study, synthesis, molecular docking and anticancer screening of new series of substituted heterocycles with trimethoxy phenyl scaffold as Combretastatin analogues were described. Substituted pyridines were synthesized via the reaction of (E)-3-(dimethylamino)-1-(3,4,5- trimethoxyphenyl)prop-2-en-1-one (2) with active methylene reagents. Substituted pyrimidines were prepared by the reaction of the enaminone (2) with heterocyclic amines and 6-amino thiouracil. Furthermore, a series of pyrazoles substituted with trimethoxyphenyl scaffold were prepared by the reaction of the enaminone 2, with selected examples of hydrazonoyl halides. The cytotoxic effect of the newly compounds was evaluated against HePG-2, HCT-116, MCF-7 and PC3 cancer cell lines. Among the new products, compounds 2, 3, 7 and 10 were found to exhibit promising results as anticancer agents. The IC50 values of 2, 3 and 7 were 54.6, 77.4 and 47.4 on PC3 respectively. Also, compound 2 had IC50 28.06 on MCF7. Moreover, the selectivity index indicated that compounds 2 and 3 are safe.