Inhibitors of Human and Malaria Parasite Dihydroorotate Dehydrogenase

Abstract: In the first part of the PhD work, small chemical entities (fragments) found to inhibit human dihydroorotate dehydrogenase (DHODH), were chemically optimized. As part of an ample program at Active Biotech to find new drugs against autoimmune diseases, expanded fragments were repeatedly designed, synthesized and evaluated in a human DHODH assay. Potent inhibitors were identified within three classes of compounds; fenamic acids, 4-hydroxycoumarins and N-(alkylcarbonyl)anthranilic acids. In each class, compounds with submicromolar IC50 values were found. Co-crystals were obtained for human DHODH in complexes with a fenamic acid and an anthranilic acid. The second half of the project is concerned with the synthesis of new classes of compounds for potential treatment of malaria by selective inhibition of the recently characterized enzyme Plasmodium falciparum DHODH (PfDHODH). The search for malaria-combating compounds acting through novel mechanisms is particularly important in light of the growing resistance against today’s malaria drugs. The PfDHODH has recently been discovered to differ significantly in structure from human DHODH, which opened up possibilities for the development of efficient and selective inhibitors of PfDHODH. A novel chemical class of moderate activity, salicylamides, discovered in the first part dealing with human DHODH, was systematically modified and resulting in the discovery of selective PfDHODH inhibitors with low micromolar IC50 values. Another approach used to find novel compound classes against PfDHODH was the in silico design, which focused on polar key interactions and overall fit in the binding site. A pyranopyrrolone scaffold structure was identified and provided inhibitors of poor-to-moderate activity. The pyranone moiety of the pyranopyrrolones was subsequently used as the basis for the design of new classes of inhibitors. 4-Aminopyranone and 4-aminocoumarin derivatives were discovered to possess submicromolar activity against PfDHODH with selectivity compared to human DHODH and, in addition, they inhibited proliferation of P. falciparum parasites in whole cells.