When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Abstract

ABSTRACT:In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorinecontaining aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures.

Possible Origin of Modified EAG Activity by Point‐Fluorination of the Insect Pheromone Eldanolide

“…Liljefos proposed a bioactive conformation of a pheromone component using a 3D-QSAR study, [13] and Hoffmann and Rychlewski reported that the substitution of hydrogen by fluorine caused a significant modification of the favored conformer. [14] Here we report the results of our computational study and show that the modified conformational preference caused by the pointfluorination of eldanolide is consistent with a loss of EAG activity (Figure 1). …”

CD22-Antagonists with nanomolar potency: The synergistic effect of hydrophobic groups at C-2 and C-9 of sialic acid scaffold

“…One important advantage of introducing fluoride is to render the compound relatively resistant to metabolic transformation due to the high energy of carbon-fluorine bond. 16 Unexpectedly, we found that compound 7 has significantly lower activity for CD22 (IC 50 5 μM; 50-fold less potent than 5 ). Obviously, a fluorine atom cannot donate hydrogen bonds, but it is electronegative and can accept them.…”

“…The rationale for such strategy stems from similarities between fluorine and oxygen in polarity and close isosteric relationship. 16 Consequently, a F atom is considered as a good substitute of a OH group. One important advantage of introducing fluoride is to render the compound relatively resistant to metabolic transformation due to the high energy of carbon-fluorine bond.…”

Fluoro-substitution effects in deoxyfluoro-d-glucose derivatives: random conformational search and quantum chemical calculation

“…[20][21][22] The effect of substituting an F atom for an OH group has been widely studied by Hoffmann et al using the quantum chemical calculation. [23][24][25] In the case of L L-tartaric acid, replacement of an OH group by an F atom results in important conformational changes and ends up with greater conformational diversity, 23 while for D D-glucose, substitution of an F atom for an OH group does not change much the shape and the electrostatic properties of the molecule. Hence, potential drugs obtained by replacing an OH group by an F atom are more 0008 likely to be discovered with cyclic compounds than aliphatic ones.…”