Heterocycles as nonclassical bioisosteres of α-amino acids

Bioisosterism of α-amino acids is often accomplished by replacing the α-carboxylate with one of the many known carboxylic acid bioisosteres. However, bioisosterism of the whole α-amino acid moiety is accomplished with heterocyclic bioisosteres that often display an acidic function. In this Minireview, we summarized the reported heterocycles as nonclassical bioisosteres of α-amino acids, which include quinoxaline-2,4(1H)-dione, quinoxaline-2,3(1H)-dione and quinolin-2(1H)-one, azagrevellin and azepine-derived structures. The binding mode of the crystalized bioisosteres were compared with those of the crystalized α-amino acids that bind in the same domain, and where no data on the crystal structure were available, the displacement studies of known orthosteric ligands were used. The reported bioisosteres share the following essential structural features for mimicking α-amino acids: an aromatic ring system joined to a lactam ring system with an acidic feature next to the lactam carbonyl, where this acidic feature together with the lactam carbonyl can mimic the α-carboxylate, and the lactam nitrogen together with the aromatic ring system can mimic the α-ammonium. The majority of these heterocycles can be prepared from three common corresponding starting materials: the corresponding anilines, isatins or anthranilic esters. The data collected here show the potential of this class of bioisosteres in the design of glutamate receptor ligands and beyond.