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 Ki of 14 nM and good solubility, 47 μg/mL, while 4e has both high potency and solubility.