meta-Non-flat substituents: a novel molecular design to improve aqueous solubility in small molecule drug discovery

Org Biomol Chem. 2021 Jan 21;19(2):446-456. doi: 10.1039/d0ob02083d.


Aqueous solubility is a key requirement for small-molecule drug candidates. Here, we investigated the regioisomer-physicochemical property relationships of disubstituted benzenes. We found that meta-isomers bearing non-flat substituents tend to possess the lowest melting point and the highest thermodynamic aqueous solubility among the regioisomers. The examination of pharmaceutical compounds containing a disubstituted benzene moiety supported the idea that the introduction of a non-flat substituent at the meta position of a benzene substructure would be a promising approach for medicinal chemists aiming to improve the thermodynamic aqueous solubility of drug candidates, even though it might not be universally effective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • Isomerism
  • Small Molecule Libraries / chemistry*
  • Solubility
  • Structure-Activity Relationship
  • Thermodynamics
  • Transition Temperature
  • Water / chemistry*


  • Small Molecule Libraries
  • Water