Modulazione bioisosterica di salicilamidi nella progettazione di inibitori della Diidroorotato deidrogenasi (PfDHODH) del Plasmodium falciparum

Malaria still causes great suffering in Africa, Asia and Latin America, with an estimated annual mortality of around 800,000 people. The fight against malaria is complicated by the rise of resistance to current drug treatments.1 In recent years, the study of PfDHODH for the treatment of malaria has become increasingly important, because of the role of the enzyme in the synthesis of pyrimidines. In fact the parasite can only synthesize de novo and is unable to enzymes through recovery.2 At present there are not commercially available drugs acting by selectively inhibiting this enzyme. DSM265 and Genz-667348 are the only two candidate molecules to become a drug. At the Faculty of Chemistry of Lund (S), new selective inhibitors PfDHODH were designed. N-Substituted salicylamide scaffold 1 has both a micromolar activity and an interesting selectivity.3 Isosteric substitution is a widely used approach in Medicinal Chemistry to improve the properties of a lead compound, such as bioavailability, selectivity and potency. The present study is aimed at the use of systems heterocycles hydroxylated penta-atomic, used in our research group as non-classical isosters of the carboxyl group, such as systems isosterics directed towards other acid groups. The salicylamide portion of these new inhibitors PfDHODH offers opportunities for a bioisosteric modulation. The synthesis, the dissociation constant (pKa) as well as the preliminary PfDHODH in vitro inhibition assays are presented and discussed.