Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1<i>H</i>)-one (<b>2a</b>) by C-ring expansion and isometric replacement of the A/B-ring, successively, aimed at finding new potential alternative drug candidates with different scaffold(s), high antitumor activity, and other improved properties to replace prior, once promising drug candidates that failed in further studies. Two series of new compounds <b>7</b> (<b>a-d</b>) and <b>13</b> (<b>a-j</b>) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds <b>13c</b>, <b>13d</b>, and <b>13e</b> with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI<sub>50</sub> values (4.6-9.6 nM) in cellular assays, comparable to lead <b>2a</b>, clinical drug candidate CA-4, and paclitaxel in the same assays. Further biological evaluations identified new active compounds as tubulin polymerization inhibitors targeting the colchicine binding site. Moreover, <b>13d</b> showed better aqueous solubility than <b>2a</b> and a similar log P value.