Medicinal Chemistry of Drugs with N-Oxide Functionalities

Abstract

Molecules with N-oxide functionalities are omnipresent in nature and play an important role in Medicinal Chemistry. They are synthetic or biosynthetic intermediates, prodrugs, drugs, or polymers for applications in drug development and surface engineering. Typically, the N-oxide group is critical for biomedical applications of these molecules. It may provide water solubility or decrease membrane permeability or immunogenicity. In other cases, the N-oxide has a special redox reactivity which is important for drug targeting and/or cytotoxicity. Many of the underlying mechanisms have only recently been discovered, and the number of applications of N-oxides in the healthcare field is rapidly growing. This Perspective article gives a short summary of the properties of N-oxides and their synthesis. It also provides a discussion of current applications of N-oxides in the biomedical field and explains the basic molecular mechanisms responsible for their biological activity. ■ SIGNIFICANCE Relevance of N-oxides for Medicinal Chemistry:• N + −O − bonds are highly polar and form strong hydrogen bonds. They may be inert or reactive in biological systems depending on their substituents.• N-Oxide groups can be used to increase the solubility of drugs and decrease membrane permeability.• Many heteroaromatic and aniline-derived N-oxides are reduced enzymatically in vivo and find applications as hypoxia-activated prodrugs.• Polymeric N-oxides have excellent blood compatibility, are nonimmunogenic and are nonadhesive for microorganisms (stealth materials).