Probing salicylamide bioisosteric replacement in the design of Plasmodium Falciparum dihydroorotate dehydrogenase (pfDHODH) inhibitors

Malaria causes great suffering, with annual mortalities of over 800.000 people, principally in Africa and Asia. To fight the resistance to current drug treatments, several strategies have been employed. Recently we presented Plasmodium Falciparum dihydroorotate dehydrogenase inhibitors based on N-substituted salicylamides scaffold1. (1) showed low micromolar range activity over pfDHODH together with a quite interesting selectivity over human DHODH.1 Since 2006, the DSTF Med Chem group investigate hydroxylated pentatomic heterocyclic systems as iso/bioisoster mimic of carboxylic group2 as well as other acidic systems.3 Here, the salicylamide moiety in (1) is identified as a possible occasion for a bioisosteric modulation. Synthesis, dissociation constant (pKa) as well as preliminary pfDHODH in vitro inhibition assays are presented and discussed.