bioisostere

Bioisostere refers to a chemical substituent or group that can be interchanged with another in a molecule without markedly altering the compound’s biological activity. The aim of using bioisosteres in medicinal chemistry is to modify properties such as potency, selectivity, metabolism, toxicity, and pharmacokinetics while preserving the essential interactions with a biological target.

The concept encompasses both classical and nonclassical approaches. Classical bioisosterism involves replacements that resemble the original group in size, shape, and electronic distribution, so that receptor binding is retained. Nonclassical bioisosterism uses replacements that mimic the biological properties or binding features of the original group, even if the atoms differ substantially. Designers consider factors such as hydrogen-bonding patterns, acidity, basicity, and overall three‑dimensional geometry to predict preserved activity and improved properties.

Common examples include replacing a carboxylic acid with a tetrazole ring to retain acidity and binding characteristics, or substituting amide groups with heteroaromatic isosteres such as 1,2,4- or 1,3,4-oxadiazoles to improve metabolic stability. Replacing a phenyl ring with a heteroaromatic ring like pyridine can preserve aromatic character while altering electronics and solubility. Other strategies include modest modifications to lipophilicity or steric profile to tune pharmacokinetic behavior, sometimes by introducing halogens or bioisosteric fluorinated groups.

Bioisosterism is widely used in drug discovery and agrochemistry to optimize efficacy and safety. Its success depends on the specific biological context, and replacements may yield unpredictable results, requiring iterative evaluation and validation.