SUBSTITUTED 4-HYDROXY-1H-1,2,3-TRIAZOLES: SYNTHESIS AND BIOISOSTERIC APPLICATIONS

Bioisosteric replacement is a widely used approach within Medicinal Chemistry for improving properties of a lead compound such as bioavailability, selectivity and potency1. A number of clear bioisosteric relationships have been established for many functional groups, also if only the biological target will be able to answer positively to the bioisosteric hypothesis and cases of bioisosteric replacement need to be evaluated time by time, also if the replacement concern the same function. Since 20062, our group focused its attention in the chemical study of hydroxylated pentatomic heterocyclic systems as possible isoster of carboxylic and phenolic groups. Recently our studies were focalized to bioisosteric applications of the acidic 4-hydroxy-1H-1,2,3-triazole, poorly described in the literature. In this system, the presence of three nitrogen atoms should offer occasions for regiodirect substituents in fixed and specific directions. This property allow us to look for new binding affinity, depending from the target requirement. Here, we describe the chemical synthetic strategies developed to obtain different N-substituted hydroxytriazole isomers and their application as new ligands effective on hot pharmaceutical targets. Inside them, (S)-Glutamate analogues, Dihydroorotate Dehydrogenase (DHODH) and Onchocerca volvulus chitinase (OvCHT1) inhibitors are presented and fully discussed. In all these occasions, the hydroxytriazolic moiety has been used as bioisosteric replacement of an acidic group present in lead compounds: in particular, a carboxylic group in the cases of Glutamate analogues and DHODH inhibitors, and a phenolic group in the case of OvCHT1 inhibitors. The resulted biological activity confirmed the goodness of each bioisosteric substitution.