isosterism

Isosterism is a concept in chemistry and drug design that describes the substitution of one part of a molecule with another that has similar electronic properties, size, and shape, in order to achieve comparable physical, chemical, and biological effects. The idea, developed in the mid-20th century and popularized in medicinal chemistry, provides a framework for understanding why different substituents can yield similar activities or binding profiles.

Classical isosteres are atoms or groups that possess similar valence electron counts and comparable steric and electronic characteristics. In practice, researchers look for replacements that preserve important interactions such as hydrogen bonding, electrostatics, and steric fit. Examples commonly cited include replacing a carboxyl group with a tetrazole ring to mimic carboxylate acidity, or substituting a carbonyl group with a thiocarbonyl group to maintain electrophilicity. Aromatic rings can also be exchanged with heteroaromatic rings, such as benzene for pyridine or thiophene, to adjust electronic properties while preserving the planar, conjugated system. A broader, more flexible application includes minor substitutions like replacing a hydrogen with fluorine to modulate metabolic stability and lipophilicity, while maintaining overall shape.

Bioisosterism is a closely related term often used in medicinal chemistry to describe replacements that retain biological activity while potentially altering pharmacokinetic or safety profiles. Isosterism remains a guiding principle rather than an absolute rule, and its success depends on the specific molecular context and biological target.