Synthesis of novel PfDHODH inhibitors based on 4-aminocoumarin structures

Sammanfattning: Malaria is an infectious disease caused by the protozoan of the genus Plasmodium. It is a major problem in third-world countries, with hundreds of millions of infections and millions of fatalities annually. The extreme challenge in malaria management is the resistance of parasites to traditional chemotherapies like chloroquine and artemisinin. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was claimed to be one of the hottest malaria drug targets under investigation. PfDHDOH is an enzyme involved in the fourth key step of de novo pyrimidine biosynthesis. This way offer potential as targets for drug design, because, unlike the host, the parasite lacks pyrimidine salvage pathway. In search for new Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors as antimalarial drugs, compounds bearing 5-hydroxy/methoxy-4-aminocoumarin scaffold were developed at Lund University. The compounds with 5-methoxy-4-aminocoumarin structures were synthetized from resorcinol and should be act as a prodrugs, further test on microsomes are necessary to determinate that. The 5-hydroxy-4-aminocompound was obtained through a melting reaction between 4,5-dihydroxycoumarin and the desired amine. All compounds will be tested on PfDHODH by Gothenburg University.