Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases

Journal of Medicinal Chemistry

Volumn 52, Issue 9, 2009, Pages 2683-2693

  Davies, Matthew ^a   Heikkilä, Timo ^a   McConkey, Glenn A ^a   Fishwick, Colin W G ^a   Parsons, Mark R ^a   Johnson, A Peter ^a  

^a UNIVERSITY OF LEEDS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; DIHYDROOROTATE DEHYDROGENASE; DIHYDROOROTATE DEHYDROGENASE INHIBITOR; MOLECULAR SCAFFOLD;

ANTIPROTOZOAL ACTIVITY; ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITOR INTERACTION; HUMAN; IC 50; NONHUMAN; PLASMODIUM FALCIPARUM; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; MOLECULAR CONFORMATION; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS; PLASMODIUM FALCIPARUM;

EID: 65649152331     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800963t     Document Type: Article

References (29)

1. Tamta, H.; Mukhopadhyay, A. K. Biochemical targets for malaria chemotherapy. Current Research & Information on Pharmaceutical Science (CRIPS) 2003, 4, 6-9.
2. Copeland, R. A.; Marcinkeviciene, J.; Haque, T. S.; Kopcho, L. M.; Jiang, W.; Wang, K.; Ecret, L. D.; Sizemore, C.; Amsler, K. A.; Foster, L.; Tadesse, S.; Combs, A. P.; Stern, A. M.; Trainor, G. L.; Slee, A.; Rogers, M. J.; Hobbs, F. Helicobacter pylori-selective antibacterials based on inhibition of pyrimidine biosynthesis. J. Biol. Chem. 2000, 275, 33373-33378.
3. Morand, P.; Courtin, O.; Sautes, C.; Westwood, R.; Hercend, T.; Kuo, E. A.; Ruuth, E. Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplant. Proc. 1996, 28, 3088-3091. (Pubitemid 26415405)
4. Palfey, B. A.; Bjornberg, O.; Jensen, K. F. Insight into the chemistry of flavin reduction and oxidation in Escherichia coli dihydroorotate dehydrogenase obtained by rapid reaction studies. Biochemistry 2001, 40, 4381-13290 (Pubitemid 32319583)
5. Norager, S.; Jensen, K. F.; Bjornberg, O.; Larsen, S. E. coli dihydroorotate dehydrogenase reveals structural and functional distinctions between different classes of dihydroorotate dehydrogenases. Structure 2002, 10, 1211-1223. (Pubitemid 35254010)
6. Krungkrai, J. Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim. Biophys. Acta 1995, 1243, 351-360.
7. Liu, S.; Neidhardt, E. A.; Grossman, T. H.; Ocain, T.; Clardy, J. Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure 2000, 8, 25-33. (Pubitemid 30051339)
8. Hurt, D. E.; Widom, J.; Clardy, J. Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr. 2006, D62, 312-323.
9. Loffler, M.; Knecht, W.; Rawls, J.; Ullrich, A.; Dietz, C. Drosophila melanogaster dihydroorotate dehydrogenase: The N-terminus is important for biological function in vivo but not for catalytic properties in vitro. Insect Biochem. Mol. Biol. 2002, 32, 1159-1169.
10. Hansen, M.; Le Nours, J.; Johansson, E.; Antal, T.; Ullrich, A.; Loffler, M.; Larsen, S. Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 2004, 13, 1031-1042.
11. McLean, J. E.; Neidhardt, E. A.; Grossman, T. H.; Hedstrom, L. Multiple inhibitor analysis of the Brequinar and leflunomide binding sites on human dihydroorotate dehydrogenase. Biochemistry 2001, 40, 2194-2200. (Pubitemid 32165690)
12. Fox, R. I.; Herrmann, M. L.; Frangou, C. G.; Wahl, G. M.; Morris, R. E.; Strand, V.; Kirschbaum, B. J. Mechanism of action for leflunomide in rheumatoid arthritis. Clin. Immunol. 1999, 93, 198-208.
13. Peters, G. J.; Sharma, S. L.; Laurensse, E.; Pinedo, H. M. Inhibition of pyrimidine de novo synthesis by DUP-785 (NSC 368390). Invest. New Drugs 1987, 5, 235-244.
14. Leban, J.; Saeb, W.; Garcia, G.; Baumgartner, R.; Kramer, B. Discovery of a novel series of DHODH inhibitors by a docking procedure and QSAR refinement. Bioorg. Med. Chem. Lett. 2004, 14, 55-58. (Pubitemid 38010193)
15. Leban, J.; Kralik, M.; Mies, J.; Gassen, M.; Tentschert, K.; Baumgartner, R. SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 4854-4857. (Pubitemid 41354821)
16. Baumgartner, R.; Walloschek, M.; Kralik, M.; Gotschlich, A.; Tasler, S.; Mies, J.; Leban, J. Dual binding mode of a novel series of DHODH inhibitors. J. Med. Chem. 2006, 49, 1239-1247. (Pubitemid 43271880)
17. Hurt, D. E.; Sutton, A. E.; Clardy, J. Brequinar derivatives and species-specific drug design for dihydroorotate dehydrogenase. Bioorg. Med. Chem. Lett. 2006, 16, 1610-1615. (Pubitemid 43197532)
18. Kremmer, J. M. What I would like to know about leflunomide. J. Rheumatol. 2004, 31, 1029-1031.
19. Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: Confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discovery 2007, 6, 29-40.
20. Bostock, J. M.; Chopra, I.; Johnson, A. P.; Hesse, L.; Horton, J. R.; Fishwick, C. W. G. Macrocyclic Inhibitors of the Bacterial Cell Wall Enzyme MurD. Bioorg. Med. Chem. Lett. 2003, 13, 1557-1560. Ali, M. A.; Bhogal, N.; Findlay, J. B. C.; Fishwick, C. W. G. The first de novo designed antagonists of the human NK2 receptor. J. Med. Chem. 2005, 48, 5655-5658. Besong, G. E.; Bostock, J. M.; Stubbings, W.; Chopra, I.; Roper, D. I.; Lloyd, A. J.; Fishwick, C. W. G.; Johnson, A. P. A novel de novo designed inhibitor of D-Ala-D-Ala ligase from E. coli. Angew. Chem., Int. Ed. 2005, 44, 6403-6406. (Pubitemid 36428559)
21. Heikkila, T.; Thirumalairajan, S.; Davies, M.; Parsons, M. R.; McConkey, G. A.; Fishwick, C. W. G.; Johnson, A. P. The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg. Med. Chem. Lett. 2006, 16, 88-92. (Pubitemid 41625648)
22. Kuo, E. A.; Hambleton, A. B.; Kay, D. P.; Evans, P. L.; Matharu, S. S.; Little, E.; McDowall, N.; Jones, C. B.; Hedgecock, C. J. R.; Yea, C. M.; Chan, A. W. E.; Hairsine, P. W.; Ager, I. R.; Tully, W. R.; Williamson, R. A.; Westwood, R. J. Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-Cyano-3-cyclopropyl-3- hydroxy-N-[3′-methyl- 4′-(trifluoromethyl)phenyl]propenamide and related compounds. J. Med. Chem. 1996, 39, 4608-4621. (Pubitemid 26382846)
23. Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium faliparum. J. Med. Chem. 2008, 51, 3649-3653.
24. Patel, V.; Booker, M.; Kramer, M.; Ross, L.; Celatka, C. A.; Kennedy, L. M.; Dvorin, J. D.; Duraisingh, M. T.; Sliz, P.; Wirth, D. F.; Clardy, J. Identification and Characterization of Small Molecule Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase. J. Biol. Chem. 2008, 283, 35078-35085.
25. Kuo, P. Y.; Shie, T. L.; Chen, Y. S.; Lai, J. T.; Yang, D. Y. Enzyme inhibition potency enhancement by active site metal chelating and hydrogen bonding induced conformation-restricted cyclopropanecarbonyl derivatives. Bioorg. Med. Chem. Lett. 2006, 16, 6024-6027. (Pubitemid 44667806)
26. Baldwin, J.; Michnoff, C. H.; Malmquist, N. A.; White, J.; Roth, M. G.; Rathod, P. K.; Phillips, M. A. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem. 2005, 280, 21847-21853. (Pubitemid 40827835)
27. Heikkila, T.; Ramsey, C.; Davies, M.; Galtier, C.; Stead, A. M. W.; Johnson, A. P.; Fishwick, C. W. G.; Boa, A. N.; McConkey, G. A. Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. J. Med. Chem. 2007, 50, 186-191. (Pubitemid 46147699)
28. Malmquist, N. A.; Gujjar, R.; Rathod, P. K.; Phillips, M. A. Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase. Biochemistry 2008, 47, 2466-2475.
29. Clarke, D.; Ali, M. A.; Clifford, A. A.; Parratt, A.; Rose, P.; Schwinn, D.; Bannwarth, W.; Rayner, C. M. Reactions in unusual media. Curr. Top. Med. Chem. 2004, 4, 729-771.