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Investigation of novel malaria parasite enzyme (DHODH) inhibitors based on 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin scaffolds

Galleano, Iacopo LU (2013) KEMP31 20131
Department of Chemistry
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... (More)
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. (Less)
Abstract
Abstract
Plasmodium falciparum is the causative agent of the most serious and fatal malarial infections, and it has developed resistance to commonly employed chemotherapeutics. The de novo pyrimidine biosynthesis enzymes 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 antimalarials, modifications of original 4-aminocoumarin scaffold were synthesized. 4-Amino-3-benzylcoumarin derivatives are inactive against the recombinant enzyme, while results for the 4-Amino-8-azacoumarin derivatives are still not available. These results demonstrate that position-3 in the coumarin scaffold... (More)
Abstract
Plasmodium falciparum is the causative agent of the most serious and fatal malarial infections, and it has developed resistance to commonly employed chemotherapeutics. The de novo pyrimidine biosynthesis enzymes 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 antimalarials, modifications of original 4-aminocoumarin scaffold were synthesized. 4-Amino-3-benzylcoumarin derivatives are inactive against the recombinant enzyme, while results for the 4-Amino-8-azacoumarin derivatives are still not available. These results demonstrate that position-3 in the coumarin scaffold cannot be expanse most likely due to the steric hindrance in the hydrophobic subsite of the binding site. (Less)
Please use this url to cite or link to this publication:
author
Galleano, Iacopo LU
supervisor
organization
course
KEMP31 20131
year
type
L3 - Miscellaneous, Projetcs etc.
subject
keywords
organisk kemi, Organic Chemistry
language
English
id
4295194
date added to LUP
2014-02-14 13:40:35
date last changed
2014-02-14 13:40:35
@misc{4295194,
  abstract     = {Abstract
Plasmodium falciparum is the causative agent of the most serious and fatal malarial infections, and it has developed resistance to commonly employed chemotherapeutics. The de novo pyrimidine biosynthesis enzymes 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 antimalarials, modifications of original 4-aminocoumarin scaffold were synthesized. 4-Amino-3-benzylcoumarin derivatives are inactive against the recombinant enzyme, while results for the 4-Amino-8-azacoumarin derivatives are still not available. These results demonstrate that position-3 in the coumarin scaffold cannot be expanse most likely due to the steric hindrance in the hydrophobic subsite of the binding site.},
  author       = {Galleano, Iacopo},
  keyword      = {organisk kemi,Organic Chemistry},
  language     = {eng},
  note         = {Student Paper},
  title        = {Investigation of novel malaria parasite enzyme (DHODH) inhibitors based on 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin scaffolds},
  year         = {2013},
}