title: Systematic Study of Effects of Structural Modifications on the Aqueous Solubility of Drug-like Molecules.
abstract: 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 compound3aup to 867 μg/mL. The low solubility of3aresults 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.5bemerges as the most potent MIF inhibitor with aKiof 14 nM and good solubility, 47 μg/mL, while4ehas both high potency and solubility.
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
authors.forename: José A
authors.initials: JA
authors.lastname: Cisneros
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
authors.forename: Brandon Q
authors.initials: BQ
authors.lastname: Mercado
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
keywords: Aqueous solubility; MIF inhibitors; crystallography