Targeting the human Dihydroorotate Dehydrogenase (hDHODH) by a Scaffold Hopping Bioisosteric approach using Hydroxylated Pentaatomic Heterocycles

Dihydroorotate dehydrogenase (DHODH) has been recognized as a promising target for the treatment of autoimmune diseases and cancer. Due to severe side effects of two of its known inhibitors, leflunomide and brequinar, the discovery of potent hDHODH inhibitors based on novel chemotypes is urgently needed.1 Inside the inhibitor-binding site, conventionally divided into five subsites, two different binding-modes have been described in literature.2 In recent years our group at DSTF has directed its efforts towards the investigation of a general tool able to mimic the carboxyl group. We focused our attention on a pool of over ten acidic hydroxylated pentatomic heterocyclic systems. Starting from structural information from both brequinar and teriflunomide a scaffold hopping approach was applied using our heterocyclic panel affording a new series of products able to establish additional interactions with subsites 3 and 4. The general model of these compounds (1) is a hydroxylated heterocycle linked to a biphenyl system through an amide bond.3 According to molecular modeling studies, the deprotonated acidic moiety should interact with residues Arg136 and Gln47 of subsite 2 (Brequinarlike binding-mode2), while the biphenyl system may establish lipophilic interactions with residues of subsites 1 and 5 (Figure a). New compounds showed inhibitory activity on recombinant hDHODH with IC50 values in the nanomolar range and inhibition of human T-cell proliferation comparable to brequinar and teriflunomide. Our theoretical design, modeling, synthesis, SAR and biological assays, are presented in detail for compounds of first and second generation.