Design and synthesis of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHDODH) inhibitors based on an hydroxypyrazole scaffold.

In 2012 Malaria is valued still endemic in 104 countries, with 220 million cases of infection and approximately 1 million deaths per year, with over 2 billion people at risk for the disease. While there are a number of drugs approved for its treatment , drug resistance has compromised most of them, making essential the development of new drugs for the treatments. In 2010 Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was claimed to be one of the hottest malaria drug targets under investigation.1 The malaria parasite relies on de novo pyrimidine biosynthesis and unlike the human host cell is unable to scavenge preformed pyrimidines. PfDHDOH, as the human isoform, is an enzyme involved in the fourth key step of pyrimidine biosynthesis. The studies of modeling developed at Lund University,2,3 combined to the knowledge published by the Phillips's group about it, permit to summarize that the good inhibitors of PfDHODH are characterized by a similar structure-activity relationship. Consist in1) a large aromatic amine derived moieties, that permits the interactions with H185 and with the hydrophobic subsite a group able to interact with R265 and H185 and a group that permit and hydrogen bond between the water-mediation and R235. The study of molecular modeling in silico suggests that hydroxydiazoles scaffolds, Target A and B, should be the good isostere to mimic those models in the PfDHODH binding site. In this Master thesis the synthetic strategies for the preparation of scaffolds type A and B were firstly investigated. References 1) Phillips, M. A.; Rathod, P. K. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy.Infect. Disord.: Drug Targets 2010, 10, 226¿239. 2) Fritzson, I. Inhibitors of human and malaria parasite dihydroorotate dehydrogenase, University of Lund: Sweden, 2011. 3) Walse, B.; Al-Karadaghi, S. The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites. Biochemistry 2008, 47, 8929¿8936.