Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase

Journal of Medicinal Chemistry

Volumn 50, Issue 2, 2007, Pages 186-191

  Heikkilä, Timo ^a   Ramsey, Christopher ^a   Davies, Matthew ^a   Galtier, Christophe ^b   Stead, Andrew M W ^a   Johnson, A Peter ^a   Fishwick, Colin W G ^a   Boa, Andrew N ^b   McConkey, Glenn A ^a  

^a UNIVERSITY OF LEEDS   (United Kingdom)

^b UNIVERSITY OF HULL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

(3,5 DICHLOROPHENYL) 2 METHYL 3 NITROBENZAMIDE; (4 BROMO 2 METHYLPHENYL) 2 NAPHTHAMIDE; 2 CYANO 3 (9 ETHYL 9H CARBAZOL 3 YLAMINO)ACRYLIC ACID ETHYL ESTER; 3,4 DIMETHYL 1,5 DIHYDROPYRROLO[3,2 B]CARBAZOLE 2 CARBOXYLIC ACID ETHYL ESTER; AMINO ACID; ANTIMALARIAL AGENT; ARGININE; DIHYDROOROTATE DEHYDROGENASE INHIBITOR; HISTIDINE; OROTIC ACID; PHENYLALANINE; PYRIMIDINE; UBIQUINONE; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ARTICLE; BACTERIUM CULTURE; BINDING AFFINITY; BINDING SITE; CONCENTRATION RESPONSE; CULTURE MEDIUM; DRUG BINDING; DRUG DESIGN; DRUG INHIBITION; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME METABOLISM; HYDROPHOBICITY; MUTAGENESIS; NONHUMAN; PLASMODIUM FALCIPARUM; PROTEIN CONFORMATION; PROTEIN PROTEIN INTERACTION; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

AMINOBIPHENYL COMPOUNDS; ANIMALS; ANTIMALARIALS; CARBAZOLES; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; MUTAGENESIS, SITE-DIRECTED; NAPHTHALENES; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS; PLASMODIUM FALCIPARUM; POINT MUTATION; PROTEIN BINDING;

EID: 33846407609     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060687j     Document Type: Article

References (28)

1. Gardner, M. J.; Hall, N.; Fung, E.; White, O.; Berriman, M.; Hyman, R. W.; Carlton, J. M.; Pain, A.; Nelson, K. E.; Bowman, S.; Paulsen, I. T.; James, K.; Eisen, J. A.; Rutherford, K.; Salzberg, S. L.; Craig, A.; Kyes, S.; Chan, M. S.; Nene, V.; Shallom, S. J.; Suh, B.; Peterson, J.; Angiuoli, S.; Pertea, M.; Allen, J.; Selengut, J.; Haft, D.; Mather, M. W.; Vaidya, A. B.; Martin, D. M.; Fairlamb, A. H.; Fraunholz, M. J.; Roos, D. S.; Ralph, S. A.; McFadden, G. I.; Cummings, L. M.; Subramanian, G. M.; Mungall, C.; Venter, J. C.; Carucci, D. J.; Hoffman, S. L.; Newbold, C.; Davis, R. W.; Fraser, C. M.; Barrell, B. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 2002, 419, 498-511.
2. Pink, R.; Hudson, A.; Mouries, M. A.; Bendig, M. Opportunities and challenges in antiparasitic drug discovery. Nat. Rev. Drug Discovery 2005, 4, 727-740.
3. Tamta, H.; Mukhopadhyay, A. K. Biochemical targets for malaria chemotherapy. CRIPS 2003, 4, 6-9.
4. 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, 1211-23.
5. 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.
6. 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, 1031-42.
7. Hurt, D. E.; Widom, J.; Clardy, J. Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta Crystallogr. D 2006, 62, 312-323.
8. 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.
9. Williamson, R. A.; Yea, C. M.; Robson, P. A.; Curnock, A. P.; Gadher, S.; Hambleton, A. B.; Woodward, K.; Bruneau, J. M.; Hambleton, P.; Spinella-Jaegle, S.; 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, 3088-91.
10. 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, 33373-8.
11. Marcinkeviciene, J.; Rogers, M. J.; Kopcho, L.; Jiang, W.; Wang, K.; Murphy, D. J.; Lippy, J.; Link, S.; Chung, T. D.; Hobbs, F.; Haque, T.; Trainor, G. L.; Slee, A.; Stern, A. M.; Copeland, R. A. Selective inhibition of bacterial dihydroorotate dehydrogenases by thiadiazolidinediones. Biochem. Pharmacol. 2000, 60, 339-42.
12. Krungkrai, J. Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim. Biophys. Acta 1995, 1243, 351-60.
13. McRobert, L.; McConkey, G. A. RNA interference (RNAi) inhibits growth of Plasmodium falciparum. Mol. Biochem. Parasitol. 2002, 119, 273-8.
14. Baldwin, J.; Farajallah, A. M.; Malmquist, N. A.; Rathod, P. K.; Phillips, M. A. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J. Biol. Chem. 2000, 277, 41827-34.
15. Kessl, J. J.; Lange, B. B.; Merbitz-Zahradnik, T.; Zwicker, K.; Hill, P.; Meunier, B.; Palsdottir, H.; Hunte, C.; Meshnick, S.; Trumpower, B. L. Molecular basis for atovaquone binding to the cytochrome bel complex. J. Biol. Chem. 2003, 278, 31312-8.
16. Hudson, A. T.; Dickins, M.; Ginger, C. D.; Gutteridge, W. E.; Holdich, T.; Hutchinson, D. B.; Pudney, M.; Randall, A. W.; Latter, V. S. 566C80: A potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp. Clin. Res. 2003. 17, 427-35.
17. Heikkila, T.; Thirumalairajan, S.; Davies, M.; Parsons, M. R.; McConkey, A. G.; Fishwick, C. W.; Johnson, A. P. The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg. Med. Chem. Lett. 2006, 16, 88-92.
18. 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, 21847-53.
19. Shannon, P. V. R.; Eichholtz, T.; Linstead, D.; Masdin, P.; Skinner, R. Condensed heterocyclic compounds as anti-inflammatory and immunomodulatory agents. International patent number WO 99/ 45926, 1999.
20. Boa, A. N.; Canavan, S. P.; Hirst, P. R.; Ramsey, C.; Stead, A. M. W.; McConkey, G. A. Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase. Bioorg. Med. Chem. 2005, 13, 1945-67.
21. 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, 2194-200.
22. Knecht, W.; Henseling, J.; Loffler, M. Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem. Biol. Interact. 2001, 124, 61-76.
23. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.; Olson, A. J. Automated docking using a lamarckian genetic algorithm and empirical binding free energy function. J. Comput. Chem. 1998, 19, 1639-62.
24. Zsoldos, Z.; Szabo, I.; Szabo, Z.; Johnson, A. P. Software tools for structure based rational drug design. J. Mol. Struct.: THEOCHEM 2003, 666-667, 659-65.
25. Gillet, V. J.; Newell, W.; Mata, P.; Myatt, G.; Sike, S.; Zsoldos, Z.; Johnson, A. P. SPROUT: Recent developments in the de novo design of molecules. J. Chem. Inf. Comput. Sci. 1994, 34, 207-17.
26. Wang, R.; Fu, Y.; Lai, L. A new atom-additive method for calculating partition coefficients. J. Chem. Inf. Comput. Sci. 1997, 37, 615-621.
27. Copeland, R. A.; Davis, J. P.; Dowling, R. L.; Lombardo, D.; Murphy, K. B.; Patterson, T. A. Recombinant human dihydroorotate dehydrogenase: Expression, purification, and characterization of a catalytically functional truncated enzyme. Arch. Biochem. Biophys. 1995, 323, 79-86.
28. Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099-108.