Dihydroorotate dehydrogenase inhibitors

Leflunomide DMARD dihydroorotate dehydrogenase inhibitor that arrests T cell prolifer-... 

Coteron JM, Marco M, Esquivias J et al (2011) Structure-guided lead optimization of tri-azolopyrimidine-ring substituents identifies potent Plasmocbum falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem 54 5540 5561. doi 10.1021/jm200592f... 

Ren S, Wu S, Lien E (1998) Dihydroorotate dehydrogenase inhibitors quantitative structure-activity relationship analysis. Pharm Res 15 286-295... 

Steric effects and FMO control have been combined in an elegant way to achieve regiospecific synthesis of pyrazole inhibitors of dihydroorotate dehydrogenase <2006SL901>. When the size of the propargylic acid ester 86 is increased from ethyl to diphenylmethyl, pyrazole 87 is formed from compound 85 regiospecifically (Scheme 3 Table 4) <2006H(68)1007>. 

FIGURE 5. (A) Interaction of atovaquone with the Fe-S center (on left) in the cytochrome bc complex via H-bonding with the coordinated His (Plate VIII). (B) The active center of a class 2 dihydroorotate dehydrogenase (PDB ID 1UUM) with a hound inhibitor atovaquone (top baU-and-stick stmcture), orotic acid (green) and riboflavin 5 -(dihydrogen phosphate) (FMN, pink) (Plate IX)... 

Heikkila T, Thirumalairajan S, Davies M et al (2006) The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett 16 88-92... 

Baldwin, J., Michnoff, C. H., Malmquist, N. A., White, J., Roth, M. G., Rathod, P. K., and Phillips, M. A. (2005). High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem. 280,21847-21853. 

Hurt, D. E., Widom, J., and Clardy, J. (2006). Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr. D Biol. Crystallogr. 62,312-323. 

Baldwin J, Michnoflf CH, Malmquist NA et al. High-throughput screening for potent and selective inhibitors of Plasmoduim falciparum dihydroorotate dehydrogenase. J Biol Chem 2005 280 21847-21853. 

Interestingly, the 8-chloro analogues of LY-186054 (18) showed diminished powdery mildew control yet were active against botrytis and other commercially interesting species of fungi. This shift in the biological profile is based on their different MO A 8-haloquinolines are known inhibitors of dihydroorotate dehydrogenase [65]. 

On dihydroorotate dehydrogenases and their inhibitors and uses 13JMC 3148. 

The module which can be used for pharmacophoie generation in this suite is Phase [53], Any number of ligands with their activity value (half maximal inhibitoiy concentration, ICj ) can be used for the generation of common pharmacophore, but always a set of compounds that are studied under similar experimental results will provide good results. For example, we have chosen few compounds which are known inhibitors of dihydroorotate dehydrogenase enzyme in Plasmodium falciparum [54]. This set of compoimds contains active and inactive compoimds (based on the ICjo values). Draw the molecules either in maestro workspace or in any tool like ChemSketch [55] or ChemDraw [56] and save them in. mol format. Now import these molecules into the project table (Fig. 4.56). 

Production of superoxide radical anion (02 ) during oxidation of dihydroorotate in rat hver mitochondria was not affected by antimycin A, thenoyl-trifluoroacetone, or added ubiquinone but was inhibited by orotate, a product inhibitor of dihydroorotate dehydrogenase (Forman and Kennedy 1975). It appears likely that superoxide is generated at the primary dehydrogenase. Dihydroorotate dehydrogenase differs from succinate dehydrogenase both in its utilisation of ubiquinone and in the mechanism of cytochrome b reduction. Formation of orotate is only partially inhibited by thenoyltri-fluoroacetone and the inhibitor does not prevent the reduction of cytochrome by dihydroorotate. 

A series of potentially selective inhibitors of dihydroorotate dehydrogenase (DHODH) were synthesized via interactive, chemoselective Suzuki cross-couplings utilizing biaryl chlorides as key intermediates (Equation 78) [111]. 

Gujjar R, El Mazouni F, White KL, White J, Creason S, Shackleford DM, Deng X, Charman WN, Bathurst 1, Burrows J, Floyd DM, Matthews D, Buckner FS, Charman SA, Phillips MA, Rathod PK (2011) Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J Med Chem 54 3935-3949... 

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