Investigation of novel malaria parasite enzyme (DHODH) inhibitors based on 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin scaffolds
Abstract: Popular summery Malaria is a parasitic disease caused by five species of the genus Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi) that affect humans. The most deadly form of Malaria is due to Plasmodium Falciparum and it is mostly spread in African areas. Almost half of the world population is at risk to contract the infection and every year malaria causes around half million deaths. Since an effective vaccine is still not available, malaria treatment relies on chemotherapeutics. It is important to find new targets and new drugs to fight the parasite because it has an inherent ability to develop resistance. Biological background and discussion Dihydroorotate dehydrogenase (DHODH) is the enzyme which catalyzes the fourth and rate limiting step of de novo pyrimidine biosynthesis. It is an interesting target because the parasites rely on this pathway to get pyrimidines, while mammalian cells can also get them from salvage of “used pyrimidines”; if DHODH is inhibited in the parasite (PfDHODH), it will not be able to synthesize DNA so its growth will be impeded. Furthermore, dissimilarities between the human and the parasite enzyme in the primary structure allow the design of species-specific inhibitors. Some 4-aminocoumarin derivatives earlier showed micro molar IC50. In this study we have synthesized new 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin derivatives, after calculations with molecular modeling, trying to optimize the interactions with the protein. Conclusion In the end we got nine derivatives which will be tested on the purified recombinant pfDHODH. These results will aid us towards further optimization of the coumarin scaffold.
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