Malaria remains a globally prevalent infectious disease that leads to 
significant morbidity and mortality. While there are a number of drugs approved 
for its treatment, drug resistance has compromised most of them, making the 
development of new drugs for the treatment and prevention of malaria essential. 
The completion of the Plasmodium falciparum genome and a growing understanding 
of parasite biology are fueling the search for novel drug targets. Despite this, 
few targets have been chemically validated in vivo. The pyrimidine biosynthetic 
pathway illustrates one of the best examples of successful identification of 
anti-malarial drug targets. This review focuses on recent studies to exploit the 
fourth enzyme in the de novo pyrimidine biosynthetic pathway of P. falciparum, 
dihydroorotate dehydrogenase (PfDHODH), as a new target for drug discovery. 
Several chemical scaffolds have been identified by high throughput screening as 
potent inhibitors of PfDHODH and these show strong selectivity for the malarial 
enzyme over that from the human host. Potent activity against parasites in whole 
cell models with good correlation between activity on the enzyme and the 
parasite have also been observed for a number of the identified series. Lead 
optimization of a triazolopyrimidine-based series has identified an analog with 
prolonged plasma exposure, that is orally bioavailable, and which shows good 
efficacy against the in vivo mouse model of the disease. These data provide 
strong evidence that PfDHODH is a validated target for the identification of new 
antimalarial chemotherapy. The challenge remains to identify compounds with the 
necessary combination of potency and metabolic stability to allow identification 
of a clinical candidate.