Bioisostère

In medicinal chemistry, bioisosteres are chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties in the same chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. The main use of this term and its techniques are related to pharmaceutical sciences. Bioisosterism is used to reduce toxicity, change bioavailability, or modify the activity of the lead compound, and may alter the metabolism of the lead. Classical bioisosterism was originally formulated by James Moir and refined by Irving Langmuir as a response to the observation that different atoms with the same valence electron structure had similar biological properties. For example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life. Procainamide, an amide, has a longer duration of action than Procaine, an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom. Procainamide is a classical bioisostere because the valence electron structure of a disubstituted oxygen atom is the same as a trisubstituted nitrogen atom, as Langmuir showed. Another example is seen in a series of anti-bacterial chalcones. By modifying certain substituents, the pharmacological activity of the chalcone and its toxicity are also modified. Non-classical bioisosteres may differ in a multitude of ways from classical bioisosteres, but retain the focus on providing similar sterics and electronic profile to the original functional group.