Electrostatic potentials and average electron densities of bioisosteres in methylsquarate and acetic acid.

Background: The bioisosterism in -CO2H and -C4HO3 is exploited using the quantum theory of atoms in molecules and molecular electrostatic potentials (ESP).

Results & Discussion: Bioisosteres in methylsquarate and acetic acid, in the neutral/anionic forms, have average electron densities that differ by less than 2% (i.e., ∼0.01 atomic units) while irrespective of the capping group. The topography of the ESP reveals similarities in the case of the neutral species but not in the anionic forms.

Conclusion: The nonclassical bioisosteres in methylsquarate and acetic acid have average electron densities that are similar and relatively insensitive to the ionization state (neutral or anionic) or its studied capping group (H, CH3, Cl or phenyl). The ESP reveals similarities in the topography of neutral molecules.