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Scaffold hopping-driven lead optimizations were performed based on our prior lead 7-methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1 H )-one ( 2a ) 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 7 ( a-d ) and 13 ( a-j ) were synthesized and evaluated for antitumor activity, leading to the discovery of three highly potent compounds 13c , 13d , and 13e with different scaffolds. They exhibited similar high antitumor activity with single digital low nanomolar GI 50 values (4.6-9.6 nM) in cellular assays, comparable to lead 2a , 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, 13d showed better aqueous solubility than 2a and a similar log P value.

Scaffold Hopping-Driven Optimization of 4-(Quinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-ones as Novel Tubulin Inhibitors