Abstract
In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties. In 1859 the first isocyanide was synthesized by humans and in 1950 the first natural isocyanide was discovered. Now, at the beginning of XXI century, hundreds of isocyanides have been isolated both in prokaryotes and eukaryotes and thousands have been synthesized in the laboratory. For some of them their ecological role is known, and their potent biological activity as antibacterial, antifungal, antimalarial, antifouling, and antitumoral compounds has been described. Notwithstanding, the isocyanides have not gained a good reputation among medicinal chemists who have erroneously considered them either too reactive or metabolically unstable, and this has restricted their main use to technical applications as ligands in coordination chemistry. The aim of this review is therefore to show the richness in biological activity of the isocyanide-containing molecules, to support the idea of using the isocyanide functional group as an unconventional pharmacophore especially useful as a metal coordinating warhead. The unhidden hope is to convince the skeptical medicinal chemists of the isocyanide potential in many areas of drug discovery and considering them in the design of future drugs.
Highlights
In eons of evolution, isocyanides carved out a niche in the ecological systems probably thanks to their metal coordinating properties
Thanks to the discovery of the Ugi reaction in 1959,4 the isocyanide moiety achieved over the following decades the status of an important reactive functional group in organic and combinatorial chemistry, and today it is widely employed in both photocatalysis and transition metal chemistry.[5−7] It is foreseeable that the electro-invisibility of isocyanides in electrochemistry will be surely explored and exploited in the near future.[8]
Our hope is for attentive readers to begin considering the isocyano moiety as a strategic functional group in multicomponent reactions, polymer, and organometallic chemistry, and as a pharmacophoric group in medicinal chemistry
Summary
The isocyanide is the most strange, fascinating, and unique functional group in organic chemistry. It has been shown recently that, after coordination with a metal, both the nitrogen and the carbon atom of isocyanides can act as π-hole acceptors to the electron lone pairs of various kinds of atoms.[33,34] In the same article, the authors propose that the interaction with the nitrogen atom of isocyanide is more electrostatic and longer, while the interaction with the carbon atom of isocyanide is predominantly a charge-transfer complex which requires shorter distance in order to favor the n-π* electron transition This interesting interaction should not be missed in medicinal chemistry, whenever an isocyanide acts as coordinative group with a metal ion present in an active site (Figure 3). As a rule of thumb, it is easy to remember that aromatic isocyanides form stronger bonds with the metal compared to aliphatic ones because of their enhanced backdonation (e.g., phenyisocyanide is a stronger ligand than methylisocyanide; Figure 5).[43]
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