Design e sintesi di inibitori dell'uridina monofosfato sinteasi umana (hUMPS) basati sullo scaffold idrossitriazolico

Human uridine monophosphate synthetase (hUMP) is a bifunctional enzyme that catalyses the last two steps of de novo pyrimidine biosynthesis, a pathway associated both to restore myeloid differentiation in Acute Myelogenous Leukaemia (AML) as well as to block viral replication in infected cells. This biological target could play an important role in AML as well in diseases associated to the presence of a virus (SARS-CoV-2, ….). Starting from the screening of a MEDSynth library based on hydroxyazoles, compounds MEDS449 and MEDS450 characterized by the presence of the 4-hydroxytriazole scaffold, were identified as weak inhibitors of hUMPS with around 30 – 40 % of inhibition at 100 μM. Using MEDS449 and MEDS450 as starting point, new molecules were designed using the support of molecular modelling. In this occasion, we present two new inhibitors candidates based on hydroxy-triazole scaffold, substituted with chain that mimicking ribose in both Nb and Nc position. Theoretical design, modelling, synthesis, and biological assays are here presented and discussed.