Replacing triazole with diazole to optimize physicochemical properties of a click-based lead compound

摘要

This work mainly demonstrated how the physicochemical properties of a click-based lead compound would be affected by the replacement of its triazole ring with a pyrazole or an imidazole ring. Compound A1, a click-based lead from our previous work, was a selective and moderate inhibitor against VEGFR2. Eight new derivatives of A1 were synthesized, from which a pyrazole derivative B2 was selected as a new lead. B2 maintained the in vitro activity of A1. The solubilities of B2 at pH 2.0 and pH 7.4 were enhanced to 1310 and 1.7 mu g/mL, respectively. Its log D value of 3.4 would favor B2 to be modified with hydrophilic fragments to further improve intestinal solubility in our future work.