Nitrile-containing pharmaceuticals play a significant role in various medical treatments, with over 30 such drugs prescribed and more in clinical development. The nitrile group, though not highly electrophilic, is crucial for drug activity, often functioning as a carbonyl or hydroxyl surrogate, facilitating hydrogen bonding and polar interactions. Nitriles are metabolically stable, often passing through the body unchanged, and their metabolism typically occurs away from the nitrile group. Some nitriles can be oxidized in the liver to cyanohydrins, leading to cyanide release, which is a concern in certain drugs. The nitrile group's unique structure allows it to engage in various interactions, including hydrogen bonding and π-stacking, enhancing drug-receptor binding. Nitriles are found in a wide range of pharmaceuticals, including anti-diabetic, anti-osteoporosis, and anti-cancer drugs. For example, vildagliptin, an aminonitrile-containing antidiabetic drug, is metabolized through hydrolysis of the nitrile group. Arylnitriles, such as those in aromatase inhibitors, are effective due to their ability to mimic carbonyl groups and engage in hydrogen bonding. Nitriles are also used in antifungal, antiviral, and anti-inflammatory drugs, where they contribute to binding and activity. The nitrile group can act as a bioisostere for halogens, improving drug properties such as solubility and metabolic stability. In addition, nitriles are used in the development of drugs for conditions like hypertension, heart failure, and diabetes. The review highlights the diverse roles of the nitrile group in pharmaceuticals, emphasizing its importance in drug design and development. The nitrile's ability to engage in various interactions, including hydrogen bonding and π-stacking, makes it a versatile functional group in medicinal chemistry. Understanding these interactions helps in optimizing drug candidates and improving their efficacy and safety.Nitrile-containing pharmaceuticals play a significant role in various medical treatments, with over 30 such drugs prescribed and more in clinical development. The nitrile group, though not highly electrophilic, is crucial for drug activity, often functioning as a carbonyl or hydroxyl surrogate, facilitating hydrogen bonding and polar interactions. Nitriles are metabolically stable, often passing through the body unchanged, and their metabolism typically occurs away from the nitrile group. Some nitriles can be oxidized in the liver to cyanohydrins, leading to cyanide release, which is a concern in certain drugs. The nitrile group's unique structure allows it to engage in various interactions, including hydrogen bonding and π-stacking, enhancing drug-receptor binding. Nitriles are found in a wide range of pharmaceuticals, including anti-diabetic, anti-osteoporosis, and anti-cancer drugs. For example, vildagliptin, an aminonitrile-containing antidiabetic drug, is metabolized through hydrolysis of the nitrile group. Arylnitriles, such as those in aromatase inhibitors, are effective due to their ability to mimic carbonyl groups and engage in hydrogen bonding. Nitriles are also used in antifungal, antiviral, and anti-inflammatory drugs, where they contribute to binding and activity. The nitrile group can act as a bioisostere for halogens, improving drug properties such as solubility and metabolic stability. In addition, nitriles are used in the development of drugs for conditions like hypertension, heart failure, and diabetes. The review highlights the diverse roles of the nitrile group in pharmaceuticals, emphasizing its importance in drug design and development. The nitrile's ability to engage in various interactions, including hydrogen bonding and π-stacking, makes it a versatile functional group in medicinal chemistry. Understanding these interactions helps in optimizing drug candidates and improving their efficacy and safety.