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  • Inhibition of DHODH is reflected by an antiproliferative


    Inhibition of DHODH is reflected by an antiproliferative effect on peripheral blood mononuclear 87 8 (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 87 8 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 ., , , , , Dihydroorotate dehydrogenase (DHODH) is the enzyme which catalyses the rate-limiting fourth step of the de novo pyrimidine biosynthetic pathway. DHODH catalyses the oxidation of dihydroorotate (DHO) to orotate a ‘ping-pong’ mechanism., , , In both human and DHODH, this oxidation is coupled to the reduction of ubiquinone to dihydroubiquinone with flavin mononucleotide acting as an intermediate in the electron transfer (). Leflunomide is used clinically for the treatment of rheumatoid arthritis. The active metabolite of leflunomide, A77 1726 (), is a potent inhibitor of human DHODH (HsDHODH). Additionally, inhibitors of DHODH derived from , and , , , , , , have been identified which inhibit bacterial and parasite growth, respectively. Co-crystal structures of human, rat and DHODH show that A77 1726 binds within the putative ubiquinone binding channel., This binding channel of has previously been the focus of structure-based drug design approaches., , Our initial studies identified -arylaminomethylene malonate inhibitors which show a good level of inhibition against DHODH, with selectivity observed for the target enzyme. It is noteworthy that some of these inhibitors also show good activity against cultures. More recently, Phillips et al. have identified a series of pyrazolopyrimidine inhibitors which are exceptionally potent and selective for DHODH, show excellent activity against cultures and also inhibit the growth of in mice., X-ray crystallographic studies have revealed the structural details involved in the binding of this class of inhibitors to DHODH. In earlier work we presented arguments concerning the structural requirements for DHODH inhibitor selectivity. We now present our findings on the effects of subtle structural variations upon the enzyme affinity and selectivity of a new series of -arylaminomethylene ester DHODH inhibitors. Previously, we and others have reported, that, despite the very similar structures of the human and enzymes, subtle differences in the shapes of the putative ubiquinone binding channels could be utilized in the design of inhibitors capable of differentiating between the two enzymes. As noted earlier, some -aryl-2-aminomethylene malonates are selective inhibitors of DHODH and also display antiplasmodial activity. Inspection of the predicted binding modes of these inhibitors within the ubiquinone binding channel indicated that it may be possible to take advantage of the subtle differences between the two enzymes in order to develop even more selective inhibitors. In particular, we were aware of the presence of regions within the ubiquinone binding channel that feature significant differences in the positioning of substituents between the human and enzymes. We have proposed that a key factor in selective binding to DHODH appears to be the ability of the ligand to form a hydrogen bond to His185, since, for HsDHODH, all X-ray structures of protein–ligand complexes show that the corresponding histidine residue (His56) is intramolecularly hydrogen bonded to Tyr147 and in this conformation is not available for hydrogen bonding to a ligand. Experimental support for this argument comes from X-ray structures of selective ligands bound to DHODH and also studies which show that mutation of His185 to alanine causes a significant reduction in binding affinity. Another differentiating feature is the backbone N–H of Met536 in DHODH, whereas the equivalent residue in HsDHODH is Pro364, which lacks this backbone N–H. Assuming that the -acyl-2-aminomethylene malonate inhibitors bind to DHODH in an analogous fashion to that of A77 1726 (), modelling suggests that incorporation of H-bond acceptors into the aryl (‘tail’) portion of these molecules would increase the selectivity of these inhibitors for DHODH.