Systematic Study of Effects of Structural Modifications on the Aqueous Solubility of Drug-like Molecules
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- 作者：José A. Cisneros ; Michael J. Robertson ; Brandon Q. Mercado ; William L. Jorgensen
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2017
- 出版时间：January 12, 2017
- 年：2017
- 卷：8
- 期：1
- 页码：124-127
- 全文大小：322K
- ISSN：1948-5875
文摘
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.