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Novel inhibitors of the Plasmodium falciparum electron transport chain

Published online by Cambridge University Press:  08 January 2014

P. A. STOCKS ,
V. BARTON ,
T. ANTOINE ,
G. A. BIAGINI ,
S. A. WARD  and
P. M. O'NEILL
P. A. STOCKS
Affiliation:
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
V. BARTON
Affiliation:
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK
T. ANTOINE
Affiliation:
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
G. A. BIAGINI
Affiliation:
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
S. A. WARD
Affiliation:
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK
P. M. O'NEILL*
Affiliation:
Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK
*
*Corresponding author: Department of Chemistry, University of Liverpool, P.O. Box 147, Liverpool, L69 3BX, UK. Tel: 0151 794 3553. E-mail: p.m.oneill01@liv.ac.uk
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Summary

Due to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.

Keywords

Antimalarialdrug developmentmitochondrialdihydroorotate dehydrogenasecytochrome bc1PfNADH IIstructure-activity relationships
Type
Research Article
Information
Parasitology , Volume 141 , Issue 1: Symposia of the British Society for Parasitology volume 49 Emerging paradigms in anti-infective drug design , January 2014 , pp. 50 - 65
Copyright
Copyright © Cambridge University Press 2014 

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References

REFERENCES

Anthony, M. P., Burrows, J. N., Duparc, S., Moehrle, J. J. and Wells, T. N. C. (2012). The global pipeline of new medicines for the control and elimination of malaria. Malaria Journal 11, 316.Google Scholar
Baldwin, J., Farajallah, A. M., Malmquist, N. A., Rathod, P. K. and Phillips, M. A. (2002). Malarial dihydroorotate dehydrogenase. Journal of Biological Chemistry 277, 41827–41834.Google Scholar
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. Journal of Biological Chemistry 280, 21847–21853.Google Scholar
Barton, V., Fisher, N., Biagini, G. A., Ward, S. A. and O'Neill, P. M. (2010). Inhibiting Plasmodium cytochrome bc 1: a complex issue. Current Opinions in Chemical Biology 14, 440–446.CrossRefGoogle ScholarPubMed
Baumgartner, R., Walloschek, M., Kralik, M., Gotschlich, A., Tasler, S., Mies, J. and Leban, J. (2006). Dual binding mode of a novel series of DHODH inhibitors. Journal of Medicinal Chemistry 49, 1239–1247.CrossRefGoogle ScholarPubMed
Bedingfield, P. T., Cowan, D., Acklam, P., Cunningham, F., Parsons, M. R., Mc Conkey, G. A., Fishwick, C. W. G. and Johnson, A. P. (2012). Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenase. Journal of Medicinal Chemistry 55, 5841.Google Scholar
Berman, J., Brown, L., Miller, R., Andersen, S. L., McGreevy, P., Schuster, B. G., Ellis, W., Ager, A. and Rossan, R. (1994). Antimalarial activity of WR 243251, a dihydroacridinedione. Antimicrobial Agents and Chemotherapy 38, 1753–1756.Google Scholar
Berry, E. A. and Huang, L-S. (2011). Conformationally linked interaction in the cytochrome bc1 complex between inhibitors of the Qo site and the Rieske iron–sulfur protein. Biochimica et Biophysica Acta 1807, 1349–1363.Google Scholar
Biagini, G. A., Fisher, N., Berry, N., Stocks, P. A., Meunier, B., Williams, D., Bonar-Law, R., Bray, P. G., Owen, A., O'Neill, P. M. and Ward, S. A. (2006). Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Molecular Pharmacology 73, 1347–1355.CrossRefGoogle Scholar
Biagini, G. A., Fisher, N., Shone, A. E., Mubaraki, A., Srivastava, A., Hill, A., Antoine, T., Warman, A. J., Davies, J., Pidathala, C., Amewu, R., Leung, S. C., Sharma, R., Gibbons, P., Hong, D. W., Pacorel, B., Lawrenson, A. S., Charoensutthivarakul, S., Taylor, L., Berger, O., Mbekeani, A., Stocks, P. A., Nixon, G. L., Chadwick, J., Hemingway, J., Delves, M. J., Sinden, R. E., Zeeman, A. M., Kocken, C. H. M., Berry, N. B., O'Neill, P. M. and Ward, S. A. (2012). Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proceedings of the National Academy of Sciences, USA 109, 8298.Google Scholar
Biagini, G. A., Viriyavejakul, P., O'Neill, P. M., Bray, P. G. and Ward, S. A. (2006). Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrobial Agents and Chemotherapy 50, 1841–1851.Google Scholar
Boa, A. N., Canavan, S. P., Hirst, P. R., Ramsey, C., Stead, A. M. W. and McConkey, G. A. (2005). Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase. Bioorganic and Medicinal Chemistry 13, 1945–1967.Google Scholar
Booker, M. L., Bastos, C. M., Kramer, M. L., Barker, R. H. Jr., Skerlj, R., Sidhu, A. B., Deng, X., Celatka, C., Cortese, J. F., Guerrero Bravo, J. E., Crespo Llado, K. N., Serrano, A. E., Angulo-Barturen, I., Jimenez-Diaz, M. B., Viera, S., Garuti, H., Wittlin, S., Papastogiannidis, P., Lin, J-W., Janse, C. J., Khan, S. M., Duraisingh, M., Coleman, B., Goldsmith, E. J., Phillips, M. A., Munoz, B., Wirth, D. F., Klinger, J. D., Wiegand, R. and Sybertz, E. (2010). Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. Journal of Biological Chemistry 285, 33054–33064.Google Scholar
Bueno, J. M., Herreros, E., Angulo- Barturen, I., Ferrer, S., Fiandor, J. M., Gamo, F. J., Gargallo-Viola, D. and Derimanov, G. (2012). Exploration of 4(1H)-pyridones as a novel family of potent antimalarial inhibitors of the plasmodial cytochrome bc1. Future Medicinal Chemistry 4, 2311.CrossRefGoogle ScholarPubMed
Bueno, J. M., Manzano, P., Garcia, M. C., Chicharro, J., Puente, M., Lorenzo, M., Garcia, A., Ferrer, S., Gomez, R. M., Fraile, M. T., Lavandera, J. L., Fiandor, J. M., Vidal, J., Herreros, E. and Gargallo-Viola, D. (2011). Potent antimalarial 4-pyridones with improved physicochemical properties. Bioorganic and Medicinal Chemistry Letters 21, 5214–5218.CrossRefGoogle Scholar
Canfield, C. J., Pudney, M. and Gutteridge, W. E. (1995). Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro. Experimental Parasitology 80, 373–381.CrossRefGoogle ScholarPubMed
Chen, S. F., Ruben, R. L. and Dexter, D. L. (1986). Mechanism of action of the novel anticancer agent 6-fluoro-2-(2′-fluoro-1,1′-biphenyl-4-yl)-3- methyl-4-quinolinecarboxylic acid sodium salt (NSC 368390): inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Research 46, 5014–5019.Google Scholar
Coteron, J. M., Marco, M., Esquivias, J., Deng, X., White, K. L., White, J., Koltun, M., El Mazouni, F., Kokkonda, S., Katneni, K., Bhamidipati, R., Shackleford, D. M., Angulo-Barturen, I., Ferrer, S. B., Jimenez-Diaz, M. B., Gamo, F. J., Goldsmith, E. J., Charman, W. N., Bathurst, I., Floyd, D., Matthews, D., Burrows, J. N., Rathod, P. K., Charman, S. A. and Phillips, M. A. (2011). Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical Candidate potential. Journal of Medicinal Chemistry 54, 5540–5561.Google Scholar
Cross, R. M., Maignan, J. R., Mutka, T. S., Luong, L., Sargent, J., Kyle, D. E. and Manetsch, R. (2011). Optimization of 1,2,3,4-tetrahydroacridin- 9(10H)-ones as antimalarials utilizing structure-activity and structure property relationships. Journal of Medicinal Chemistry 54, 4399–4426.CrossRefGoogle Scholar
Cross, R. M., Monastyrskyi, A., Mutka, T. S., Burrows, J. N., Kyle, D. E. and Manetsch, R. (2010). Endochin optimization: Structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity. Journal of Medicinal Chemistry 53, 7076–7094.Google Scholar
Davies, M., Heikkila, T., Mc Conkey, G., Fishwick, C., Parsons, M. and Johnson, P. (2009). Structure-based design, synthesis and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases. Journal of Medicinal Chemistry 52, 2683.CrossRefGoogle ScholarPubMed
Deng, X. Y., Gujjar, R., El Mazouni, F., Kaminsky, W., Malmquist, N. A., Goldsmith, E. J., Rathod, P. K. and Phillips, M. A. (2009). Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. Journal of Biological Chemistry 284, 26999–27009.Google Scholar
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P., Lindegardh, N., Socheat, D. and White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 361, 455–467.CrossRefGoogle ScholarPubMed
Dong, C. K., Urgaonkar, S., Cortese, F. C., Gamo, F. J., Garcia-Bustos, J. F., Lafuente, M. J., Patel, V., Ross, L., Coleman, B., Derbyshire, E. R., Clish, C. B., Serrano, A. E., Cromwell, M., Barker, R. H. Jr.Dvorin, J. D.Duraisingh, M. T., Wirth, D., Clardy, J. and Mazitschek, R. (2011). Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors. Chemistry and Biology 18, 1602.Google Scholar
Dressman, J. B. and Reppas, C. H. (2000). In vitro–in vivo correlations for lipophilic, poorly water-soluble drugs. European Journal of Pharmaceutical Sciences 11(Suppl. 2), S73.Google Scholar
Durant, J. L., Leland, B. A., Henry, D. R. and Nourse, J. G. (2002). Reoptimization of MDL keys for use in drug discovery. Journal of Chemical Infomatics and Computational Science 42, 1273–1280.CrossRefGoogle ScholarPubMed
Fisher, N., Bray, P. G., Ward, S. A. and Biagini, G. A. (2007). The malaria parasite type II NADH:quinone oxidoreductase: an alternative enzyme for an alternative lifestyle. Trends in Parasitology 23, 305–310.Google Scholar
Fisher, N., Majid, R. A., Antoine, T., Al-Helal, M., Warman, A. J., Johnson, D. J., Lawrenson, A. S., Ranson, H., O'Neill, P. M., Ward, S. A. and Biagini, G. A. (2012). Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc 1 catalytic turnover and protein expression. Journal of Biological Chemistry 287, 9731–9741.Google Scholar
Fisher, N., Warman, A. J., Ward, S. A. and Biagini, G. A. (2009). Chapter 17 Type II NADH: quinone oxidoreductases of Plasmodium falciparum and Mycobacterium tuberculosis kinetic and high-throughput assays. Methods in Enzymology 456, 303–320.Google Scholar
Furfine, E. S., Baker, C. T. and Hale, M. R. (2004). A preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrobial Agents and Chemotherapy 48, 791–798.Google Scholar
Gardner, M., 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., 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., 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. and Barrell, B. (2002). Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511.CrossRefGoogle ScholarPubMed
Geppert, H., Vogt, M. and Bajorath, J. (2010). Current trends in ligand-based virtual screening: molecular representations, data mining methods, new application areas, and performance evaluation. Journal of Chemical Information and Modelling 50, 205–216.Google Scholar
Gujjar, R., El Mazouni, F., White, K. L., White, J., Creason, S., Shackleford, D. M., Deng, X., Charman, W. N., Bathurst, I., Burrows, J., Floyd, D. M., Matthews, D., Buckner, F. S., Charman, S. A., Phillips, M. A. and Rathod, P. K. (2011). Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. Journal of Medicinal Chemistry 54, 3935–3949.CrossRefGoogle ScholarPubMed
Gujjar, R., Marwaha, A., El Mazouni, F., White, J., White, K. L., Creason, S., Shackleford, D. M., Baldwin, J., Charman, W. N., Buckner, F. S., Charman, S., Rathod, P. K. and Phillips, M. A. (2009). Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. Journal of Medicinal Chemistry 52, 1864–1872.Google Scholar
Heimbach, T., Fleisher, D. and Kaddoumi, A. (2007). Overcoming poor aqueous solubility of drugs by oral delivery. In Prodrugs: Challenges and Rewards, Part 1 (ed. Stella, V. J., Borchardt, R. T., Hageman, M. J., Oliyai, R., Maag, H. and Tilley, J. W.), pp. 157–215. Springer, New York, NY, USA.Google Scholar
Heikkila, T., McConkey, A. G., Thirumalairajan, S., Davies, M., Parsons, M. R., McConkey, G. A., Fishwick, E. W. G. and Johnson, A. P. (2006). The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorganic and Medicinal Chemistry Letters 16, 88.Google Scholar
Herrmann, M. L., Schleyerbach, R. and Kirschbaum, B. J. (2004). Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 47, 273–289.Google Scholar
Jimenez-Diaz, M. B., Mulet, T., Viera, S., Gomez, V., Garuti, H., Ibanez, J., Alvarez-Doval, A., Shultz, L. D., Martinez, A., Gargallo-Viola, D. and Angulo-Barturen, I. (2009). Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rgammanull mice engrafted with human erythrocytes. Antimicrobial Agents and Chemotherapy 53, 4533–4536.Google Scholar
Kelly, J. X., Smilkstein, M. J., Brun, R., Wittlin, S., Cooper, R. A., Lane, K. D., Janowsky, A., Johnson, R. A., Dodean, R. A., Winter, R., Hinrichs, D. J. and Riscoe, M. K. (2009). Discovery of dual function acridones as a new antimalarial chemotype. Nature 459, 270–273.Google Scholar
Kessl, J. J., Lange, B. B., Merbitz-Zahradnik, T., Zwicker, K., Hill, P., Meunier, B., Palsdottir, H., Hunte, C., Meshnick, S., Trumpower, B. L. (2003). Molecular basis for atovaquone binding to the cytochrome bc1 complex. Journal of Biological Chemistry 278, 31312–31318.Google Scholar
Kesten, S. J., Degnan, M. J., Hung, J., McNamara, D. J., Ortwine, D. F., Uhlendorf, S. E. and Werbel, L. M. (1992). Antimalarial drugs. 64. Synthesis and antimalarial properties of 1-imino derivatives of 7-chloro-3-substituted-3,4-dihydro-1,9(2H,10H)-acridinediones and related structures. Journal of Medicinal Chemistry 35, 3429–3447.CrossRefGoogle Scholar
Kikuth, W. and Mudrowreichenow, L. (1947). Uber Kasualprophylaktish Bei VogelmalariaWirksame Substanzen, Zeitschrift für Hygiene und Infektionskrankheiten 127, 151–165.Google Scholar
Leung, S. C., Gibbons, P., Amewu, R., Nixon, G., Pidathala, C., Hong, W. D., Pacorel, B., Berry, N. G., Sharma, R., Stocks, P. A., Srivastava, A., Shone, A. E., Charoensutthivarakul, S., Taylor, L., Berger, O., Mbekeani, A., Hill, A., Fisher, N., Warman, A. J., Biagini, G. A., Ward, S. A. and O'Neill, P. M. (2012). Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2). Journal of Medicinal Chemistry 55, 1844.Google Scholar
Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacology and Toxicology Methods 44, 235–249.Google Scholar
Liu, K., Feng, J., Young, S. S. and Power, M. V. (2005). A software environment for molecular viewing, descriptor generation, data analysis and hit evaluation. Journal of Chemical Informatics and Modelling 45, 515–522.CrossRefGoogle ScholarPubMed
Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T. and Clardy, J. (2000). Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure 8, 25–33.CrossRefGoogle ScholarPubMed
Malmquist, N. A., Gujjar, R., Rathod, P. K. and Phillips, M. A. (2008). Analysis of flavin oxidation and electron-transfer inhibition in Plasmodium falciparum dihydroorotate dehydrogenase. Biochemistry 47, 2466–2475.Google Scholar
Marwaha, M., White, J., El_Mazouni, F., Creason, S. A., Kokkonda, S., Buckner, F. A., Charman, S. A., Phillips, M. A. and Rathod, P. R. (2012). Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase. Journal of Medicinal Chemistry 55, 7425.CrossRefGoogle ScholarPubMed
Mather, M. W., Henry, K. W. and Vaidya, A. B. (2007). Mitochondrial drug targets in apicomplexan parasites. Current Drug Targets 8, 49–60.Google Scholar
McComb, R. B., Bowers, G. N. J. and Posen, S. (1979). Alkaline Phosphatase. Plenum Press, New York, USA and London, UK.Google Scholar
McLean, J. E., Neidhardt, E. A., Grossman, T. H. and Hedstrom, L. (2001). Multiple inhibitor analysis of the brequinar and leflunomide binding sites on human dihydroorotate dehydrogenase. Biochemistry 40, 2194–2200.CrossRefGoogle ScholarPubMed
Nam, T. G., McNamara, C. W., Bopp, S., Dharia, N. V., Meister, S., Bonamy, G. M. C., Plouffe Kato, N., McCormack, S., Bursulaya, B., Ke, H. J., Vaidya, A. B., Schultz, P. G. and Winzeler, E. A. (2011). A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chemical Biology 6, 1214–1222.Google Scholar
Nixon, G. L., Moss, D. M., Shone, A. E., Lalloo, D. L., Fisher, N., O'Neill, P. M., Ward, S. A. and Biagini, G. A. (2013). Antimalarial pharmacology and therapeutics of atovaquone. Journal of Antimicrobial Chemotherapy 68, 977–985.Google Scholar
Nilsen, A., LaCrue, A. N., White, K. L., Forquer, I. P., Cross, R. M., Marfurt, J., Mather, M. W., Delves, M. J., Shackleford, D. M., Saenz, F. E., Morrisey, J. M., Steuten, J., Mutka, T., Li, Y. X., Wirjanata, G., Ryan, E., Duffy, S., Kelly, J. X., Sebayang, B. F., Zeeman, A. M., Noviyanti, R., Sinden, R. E., Kocken, C. H. M., Price, R. N., Avery, V. M., Angulo-Barturen, I., Jimenez-Diaz, M. B., Ferrer, S., Herreros, E., Sanz, L. M., Gamo, F. J., Bathurst, I., Burrows, J. N., Siegl, P., Guy, R. K., Winter, R. W., Vaidya, A. B., Charman, S. A., Kyle, D. E., Manetsch, R. and Riscoe, M. K. (2013). Quinolone-3-Diarylethers: a new class of antimalarial drug. Science Translational Medicine 5, 177ra37.Google Scholar
Painter, H. J., Morrisey, J. M., Mather, M. W. and Vaidya, A. B. (2007). Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 446, 88–91.CrossRefGoogle ScholarPubMed
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. and Clardy, J. (2008). Identification and characterization of small molecule inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Journal of Biological Chemistry 283, 35078–35085.Google Scholar
Phillips, M. A., Gujjar, R., Malmquist, N. A., White, J., El Mazouni, F., Baldwin, J. and Rathod, P. K. (2008). Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. Journal of Medicinal Chemistry 51, 3649–3653.CrossRefGoogle ScholarPubMed
Phillips, M. A., Rathod, P. K., Baldwin, J. and Gujjar, R. (2007). Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activity. WO Patent 2007149211 A1.Google Scholar
Pidathala, C., Amewu, R., Pacorel, B., Nixon, G. L., Gibbons, P. A., Hong, W. D., Leung, S. C., Berry, N. C., Sharma, R., Stocks, P. A., Srivastava, A., Shone, A. E., Charoensutthivarakul, S., Taylor, L., Berger, O., Mbekeani, A., Hill, A., Fisher, N. E., Warman, A. J., Biagini, G., Ward, S. A. and O'Neill, P. A. (2012). Identification, design and biological evaluation of Bisaryl Quinolones targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2). Journal of Medicinal Chemistry 55, 1831.Google Scholar
Pudney, M., Yeates, C., Pearce, J., Jones, L. and Fry, M. (1992). New 4-pyridone antimalarials which potentiate the activity of atovaquone (566C80). In Abstracts and Programme Vol 2, Proceedings of the 13th International Congress for Tropical Medicine and Malaria, Pattaya, Thailand, November 29–December 4, p. 149.Google Scholar
Rodrigues, T., Lopes, F. and Moreira, R. (2010). Inhibitors of the mitochondrial electron transport chain and the novo pyrimidine biosynthesis as antimalarials: the present status. Current Medicinal Chemistry 17, 929–956.Google Scholar
Ryley, J. F. and Peters, W. (1970). Antimalarial activity of some quinolone esters. Annals of Tropical Medicine and Parasitology 64, 209–222.CrossRefGoogle ScholarPubMed
Salzer, W., Timmler, H. and Andersag, H. (1948). Uber Einen Neuen, Gegen Vogelmalaria Wirksamen Verbindungstybus. Chemische Berichte-Recueil 81, 12–19.CrossRefGoogle Scholar
Shannon, P. V. R., Eichholtz, T., Linstead, D., Masdin, P. and Skinner, R. (1999). Condensed heterocyclic compounds as anti-inflammatory and immunomodulatory agents. International patent number WO 99/45926.Google Scholar
Steck, E. A. (1972). Chemotherapy of Malaria. Division of Medicinal Chemistry, Walter Reed Army Institute of Research, US Government Printing Office, Washington, DC, USA.Google Scholar
The malERA Consultative Group on Drugs (2011). A research agenda for malaria eradication: drugs. PLoS Medicine 8, e1000402. doi: 10.1371/journal.pmed.1000402.CrossRefGoogle Scholar
Vallieres, C., Fisher, N., Antoine, T., Al-Helal, M., Stocks, P., Berry, N. G., Lawrenson, A. S., Ward, S. A., O'Neill, P. M., Biagini, G. A. and Meunier, B. (2012). HDQ, a potent inhibitor of Plasmodium falciparum proliferation, binds to the quinone reduction site of the cytochrome bc1 complex. Antimicrobial Agents and Chemotherapy 56, 3739–3747.Google Scholar
Valkó, K., Du, D. M., Bevan, C. H., Reynolds, D. P. and Abraham, M. H. (2001). Rapid method for the estimation of octanol/water partition coefficient (logpoct) from gradient RP-HPLC retention and hydrogen bond acidity term (sigma alpha2H). Current Medicinal Chemistry 8, 1137–1146.CrossRefGoogle Scholar
Willett, P. (2006). Similarity-based virtual screening using 2D fingerprints. Drug Discovery Today 11, 1046–1053.Google Scholar
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. and Ruuth, E. (1996). Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplantation Proceedings 28, 3088–3091.Google ScholarPubMed
Winter, R. W., Kelly, J. X., Smilkstein, M. J., Dodean, R., Bagby, G. C., Rathbun, R. K., Levin, J. I., Hinrichs, D. and Riscoe, M. K. (2006). Evaluation and lead optimization of anti-malarial acridones. Experimental Parasitology 114, 47–56.Google Scholar
Wiselogle, F. Y. (1946). A Survey of Antimalarial Drugs 1941–1945 (ed. Edwards, J. W.), pp. 1–1921. Ann Harbor, MI, USA.Google Scholar
Xiang, H., McSurdy-Freed, J., Moorthy, G. S., Hugger, E., Bambal, R., Han, C., Ferrer, S., Gargallo, D. and Davis, C. B. (2006). Preclinical drug metabolism and pharmacokinetic evaluation of GW844520, a novel anti-malarial mitochondrial electron transport inhibitor. Journal of Pharmaceutical Sciences 95, 2657–2672.Google Scholar
Zhang, Y., Clark, J. A., Connelly, M., Zhu, F., Min, J., Guiguemde, W. A., Pradhan, A., Iyer, L., Furimsky, A., Gow, J., Parman, T., El Mazouni, F., Phillips, M. A., Kyle, D. E., Mirsalis, J. and Kiplin Guy, R. (2012). Lead optimization of 3-Carboxyl-4(1H)-Quinolones to deliver orally bioavailable antimalarials. Journal of Medicinal Chemistry 55, 4205.CrossRefGoogle ScholarPubMed