We have previously shown that

We have previously shown that the brequinar-like binding mode leads to a better inhibitory activity, reflecting a high affinity binding mode. Thus, the higher activity of the compounds of the thiophene series as compared to that of the respective representatives of the cyclopentene series can easily be explained by taking into account their possibility for binding in this high affinity mode. Compound represents an exception within the cyclopentene class, as it likewise binds in both modes, resulting in a comparable excellent activity (cf. compound vs ). Furthermore, an increased number of fluoro substituents in the aromatic ring adjacent to the amide bond correlate with an increased tendency toward a ‘brequinar-like’ binding mode, thus with a better inhibitory activity. As can be seen from the furan analogs and , a replacement of sulfur by oxygen in the pentacyclic ring is well tolerated. From the few furan analogs prepared, it can be deduced that this series will have a similar SAR compared with that of the thiophene compounds. A somewhat lower activity can be expected from higher hydrophilicity which results in a hindered diffusion into the hydrophobic environment of the active site, a phenomenon we have encountered with all analogs. Inhibition of DHODH is reflected by an antiproliferative effect on peripheral blood mononuclear WAY-600 receptor (PBMCs), which can be measured by the inhibitory effect on their phytohemagglutinin (PHA) stimulated growth. The test was performed as described in the reference. Data for few selected compounds are presented in . Compounds and displayed potent antiproliferatory activities on PBMCs and suggest the potential of such compounds to have an effect in animal models for autoimmune diseases.
Malaria is a serious health threat affecting more than 40% of the world population, with over 200 million people infected annually, resulting in nearly one million deaths., The disease is caused by intracellular protozoan parasites of the genus and is transmitted the female Anopheline mosquito., is responsible for the majority of mortality due to malaria and is present throughout the tropics. The malaria parasite has developed resistance to the majority of available antimalarial drugs including the recently introduced artemesinin class of antimalarials. As a result of the parasites ability to develop resistance, there is an urgent and continuous need for the development of new treatments to combat the disease. Pyrimidines are a key component of nucleic acids as well as phospholipids and glycoproteins. Humans can acquire pyrimidines via the salvage pathway as well as de novo biosynthesis of pyrimidines via the conserved pathway. However, lacks a salvage pathway for pyrimidines and is therefore totally reliant on the de novo biosynthetic pathway., Therefore, de novo pyrimidine biosynthesis represents an attractive and selective target for the development of new therapeutics against ., , , , ,