Thio Ethers. Thio ethers are commonly oxidized to a sulfoxide or sulfone. The
conversion of chlorpromazine to chlorpromazine sulfoxide is a good example of this.
Sulfonic Acids. Drugs that contain sulfonic acids are quite acidic. They have high
water solubility and are rapidly excreted, leading to a rather short half-life. They can
also be irritating to the gastrointestinal tract during the pharmaceutical phase.
Sulfonamides.In drug design, sulfonamides are frequently attached to aromatic
rings. Thus many drugs are constructed around a benzenesulfonamide nucleus. This
nucleus is quite stable to acid-, base-, or enzyme-catalyzed hydrolysis.
Epoxides. Epoxides or oxiranes are quite reactive metabolically. These three-
membered rings will readily open in the presence of most nucleophiles. They will react
with most biopolymers, including proteins and nucleic acids. Compounds with epox-
ides have very short half-lives and tend to be toxic.
Aziridines. These are similar to epoxides. They are extremely reactive to most nucle-
ophiles and open readily. Aziridines tend to behave as alkylating agents and thus have
carcinogenic effects. In harmony with this, drugs containing aziridines have been used
to treat cancer.
Tetrahydrofuran and Furan. Some drugs containing tetrahydrofurans (oxalanes)
tend to be readily air oxidized, and thus have a poor shelf life and are unstable even
prior to being administered; other tetrahydrofuran-containing drugs are metabolically
stable. Furans (oxoles) behave more like aromatic compounds than ethers; accordingly,
they undergo aromatic hydroxylation.
Pyrrole and Pyrrolidine. Pyrroles (azoles) undergo aromatic hydroxylation; pyrro-
lidines (azolidines) undergo conjugation with either glucuronic acid or sulfuric acid.
Thiophenes and Tetrahydrothiophenes.Thiophenes (thioles) are subject to aro-
matic hydroxylation; tetrahydrothiophenes (thiolanes) undergo oxidation of the sulfur
to give sulfoxides or sulfones.
Oxazole and Isoxazole.These are five-membered ring heterocycles containing
oxygen and a nitrogen. Two common forms are oxazole (1,3-oxazole) and isoxazole
(1,2-oxazole), both of which undergo aromatic hydroxylation.
Pyrazole and Imidazole.These are five-membered ring heterocycles containing two
nitrogens, one basic and one neutral. Two common forms are pyrazole (1,2-diazole) and
imidazole (1,3-diazole); both are prone to aromatic hydroxylation.
Pyridine and Piperidine.These are six-membered heterocyclic rings containing one
nitrogen. Piperidine (azine) is aromatic and undergoes aromatic hydroxylation. Piperidine
functions as a secondary amine and undergoes hydroxylation with either glucuronic
acid or sulfuric acid.
152 MEDICINAL CHEMISTRY