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Synthesis of novel PfDHODH inhibitors based on 4-aminocoumarin structures

Valerio, Federico LU (2016) KEMP31 20161
Department of Chemistry
Abstract
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... (More)
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. (Less)
Popular Abstract
Malaria is an infectious disease caused by five species of the genus Plasmodium (P. falciparum, P. vivax,
P. ovale, P. malariae and P. knowlesi) that is transmitted by infected female Anopheles mosquito. The
mosquito bite introduces the parasite into a host’s blood and those parasites travel to the liver where they
multiply before infecting and destroying red blood cells causing anaemia. Plasmodium falciparum is the
deadliest parasite and is responsible for majority of all Malaria cases that occurs mainly in Sub-Saharan
Africa. A vaccine is still not available and malaria treatment depends on chemotherapeutics. It is important
to find new targets and new antimalarial drugs versus Plasmodium parasite because it develops resistance
... (More)
Malaria is an infectious disease caused by five species of the genus Plasmodium (P. falciparum, P. vivax,
P. ovale, P. malariae and P. knowlesi) that is transmitted by infected female Anopheles mosquito. The
mosquito bite introduces the parasite into a host’s blood and those parasites travel to the liver where they
multiply before infecting and destroying red blood cells causing anaemia. Plasmodium falciparum is the
deadliest parasite and is responsible for majority of all Malaria cases that occurs mainly in Sub-Saharan
Africa. A vaccine is still not available and malaria treatment depends on chemotherapeutics. It is important
to find new targets and new antimalarial drugs versus Plasmodium parasite because it develops resistance
against all classes of antimalarial medicines.
Dihydroorotate dehydrogenase (DHODH) is the enzyme that catalyzes the fourth step of de novo pyrimidine
biosynthesis. It is an interesting target because unlike the humane, the parasite has not pyrimidine salvage
pathway and if PfDHODH is inhibited, it will not be able to synthesize DNA so it is growth will be stopped.
In this project we synthetized new 4-amino-5-hydroxy-coumarin and 4-amino-5-methoxy-coumarin
derivatives in search for new Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.
Figure 1. 4-Amino-5-hydroxy-coumarin and 4-amino-5-methoxy-coumarin structures synthesized.
In conclusion we synthetized six compounds which will be tested on the PfDHODH.
Supervisor: Prof. Ulf J. Nilsson and PhD student Maria Luisa Verteramo
Degree project 30 credits, KEMP31, Organic Chemistry (2016)
CAS - Centre for Analysis and Synthesis, Lund University (Less)
Please use this url to cite or link to this publication:
author
Valerio, Federico LU
supervisor
organization
course
KEMP31 20161
year
type
L3 - Miscellaneous, Projetcs etc.
subject
keywords
PfDHODH, coumarins, synthesis, medicinal chemistry, inhibitors, Malaria, organic chemistry, organisk kemi
language
English
id
8891603
date added to LUP
2016-11-14 16:11:22
date last changed
2016-11-14 16:11:22
@misc{8891603,
  abstract     = {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.},
  author       = {Valerio, Federico},
  keyword      = {PfDHODH,coumarins,synthesis,medicinal chemistry,inhibitors,Malaria,organic chemistry,organisk kemi},
  language     = {eng},
  note         = {Student Paper},
  title        = {Synthesis of novel PfDHODH inhibitors based on 4-aminocoumarin structures},
  year         = {2016},
}