Systematic Study of Effects of Structural Modifications on the Aqueous Solubility of Drug-like Molecules

Aqueous solubilities and activities have been measured for 17 members of the quinolinyltriazole series of inhibitors of human macrophage migration inhibitory factor (MIF). Systematic variation of a solvent-exposed substituent provided increases in solubility from 2 μg/mL for the parent compound 3a up to 867 μg/mL. The low solubility of 3a results from its near-planar structure and an intermolecular hydrogen bond, as revealed in a small-molecule X-ray structure. Removal of the hydrogen bond yields a 3-fold increase in solubility, but a 7-fold drop in activity. 5b emerges as the most potent MIF inhibitor with a K_i of 14 nM and good solubility, 47 μg/mL, while 4e has both high potency and solubility.