Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors

Thirteen new -aryl 1,2,3,4-tetrahydroquinoline compounds (–, –, and –) were synthesized and evaluated for antitumor activity and drug-like properties. Compound exhibited high inhibitory potency with low nanomolar GI values of 16–20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound inhibited colchicine binding to tubulin and tubulin assembly with an IC value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, also exhibited highly improved water solubility (75 μg/mL) and a suitable log value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site