A biologically active molecule

It has been a basic principle that one fluorine atom or trifluoromethyl group in a biologically active molecule enhances its lipophilicity. Smart3 argues that this rule holds only for fluorinated aromatics and fluorine adjacent to 7r-bonded systems. 

In a biologically active molecule the replacement of an atom or a group of atoms by another one presenting the same physiochemical properties is based on the concept of isosterism. The notion of isosterism was introduced in 1919 by Langmuir who was mainly focused in the similarities of electronic and steric arrangement of atoms, groups, radicals, and molecules. 

Dimerization of a biologically active molecule represents an alternative approach in the optimization process of a lead compound. Generally, the duplication of the pharmacophore leads to an equivalent or more active derivative which exhibits different selectivity profile and pharmacokinetic properties. Enzyme inhibition will be improved when using homodimer inhibitors. Antagonists and agonists of specific receptors could be transformed respectively into agonists and antagonists of another receptor subtype. Several examples will be reported and discussed below. 

The Hammett constant, functional group on the acidity or basicity of a neighboring site, as already discussed in Section 1.4.2. It determines the distribution of partial charges over the surface of a biologically active molecule, modulating its binding behavior toward a target structure. 

Biological activity is mainly determined by the surface of the molecule (Figure 6.38, lower left). A biologically active molecule docks to an active center (e.g., a protein). The shape of the active center and the distribution of electrostatic fields along the surface determine whether a molecule fits or not. This representation is calculated by special software and is colored according to electronic properties of the surface. 

Mayer, G., Heckel, A., Biologically Active Molecules with a Light Switch , Angew. Chem. Int. Ed. 2006, 45, 4900 4921. 

The specific replacement of a carboxylic acid in a biologically active molecule by a phosphonic acid moiety is a useful reaction for substrate modification. This can be accomplished very simply by the reaction sequence shown in Scheme 14. 

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