IMPDH from Pseudomonas aeruginosa (see Inosine-5′-monophosphate dehydrogenase project) was found to be allosterically regulated by MgATP (Labesse et al., 2013). The discovery of this mode of regulation of the catalytic activity, never described before for any IMPDH, opens the way for the development of allosteric inhibitors, targeting a much less conserved domain (i.e. the CBS modules) than the catalytic sites (i.e. IMP and NAD binding sites). The screening of part of our compound collection has led to the identification of several families of P. aeruginosa IMPDH inhibitors. Among them, four pyranopyrimidine derivatives were characterized as allosteric inhibitors of P. aeruginosa IMPDH, or in other words as competitive inhibitors of MgATP with IC50 in the micromolar range.
Efficient synthetic strategies have been developed to explore three potential modification sites on the pyranopyrimidine scaffold. The syntheses were performed via microwave-assisted reaction by an initial Knoevenagel reaction of aryl aldehyde and malonitrile, subsequent Michael reaction with barbituric acid derivatives and a final heterocyclisation reaction. More than 200 compounds were synthesized and evaluated on the recombinant P. aeruginosa IMPDH, increasing the inhibitory potency to nanomolar range. Moreover, these modifications improved the stability of inhibitors in aqueous media.
These original molecules would provide a good starting point for lead optimization and further development of new antibacterial compounds.
These compounds have been added to the french chemical library “Chimiothèque Nationale” .