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ACS Med Chem Lett. 2016 Dec 1;8(1):124-127. doi: 10.1021/acsmedchemlett.6b00451. eCollection 2017 Jan 12.

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

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Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.


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.


Aqueous solubility; MIF inhibitors; crystallography

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