Skip to main content Accessibility help
×
Home

Novel inhibitors of the Plasmodium falciparum electron transport chain

  • P. A. STOCKS (a1), V. BARTON (a2), T. ANTOINE (a1), G. A. BIAGINI (a1), S. A. WARD (a1) and P. M. O'NEILL (a2)...

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.

Copyright

Corresponding author

*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

References

Hide All
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.
Baldwin, J., Farajallah, A. M., Malmquist, N. A., Rathod, P. K. and Phillips, M. A. (2002). Malarial dihydroorotate dehydrogenase. Journal of Biological Chemistry 277, 4182741834.
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, 2184721853.
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, 440446.
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, 12391247.
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.
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, 17531756.
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, 13491363.
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, 13471355.
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.
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, 18411851.
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, 19451967.
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, 3305433064.
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.
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, 52145218.
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, 373381.
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, 50145019.
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, 55405561.
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, 43994426.
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, 70767094.
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.
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, 2699927009.
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, 455467.
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.
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.
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, 12731280.
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, 305310.
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, 97319741.
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, 303320.
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, 791798.
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, 498511.
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, 205216.
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, 39353949.
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, 18641872.
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. 157215. Springer, New York, NY, USA.
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.
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, 273289.
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, 45334536.
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, 270273.
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, 3131231318.
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, 34293447.
Kikuth, W. and Mudrowreichenow, L. (1947). Uber Kasualprophylaktish Bei VogelmalariaWirksame Substanzen, Zeitschrift für Hygiene und Infektionskrankheiten 127, 151165.
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.
Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacology and Toxicology Methods 44, 235249.
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, 515522.
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, 2533.
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, 24662475.
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.
Mather, M. W., Henry, K. W. and Vaidya, A. B. (2007). Mitochondrial drug targets in apicomplexan parasites. Current Drug Targets 8, 4960.
McComb, R. B., Bowers, G. N. J. and Posen, S. (1979). Alkaline Phosphatase. Plenum Press, New York, USA and London, UK.
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, 21942200.
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, 12141222.
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, 977985.
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.
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, 8891.
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, 3507835085.
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, 36493653.
Phillips, M. A., Rathod, P. K., Baldwin, J. and Gujjar, R. (2007). Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activity. WO Patent 2007149211 A1.
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.
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.
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, 929956.
Ryley, J. F. and Peters, W. (1970). Antimalarial activity of some quinolone esters. Annals of Tropical Medicine and Parasitology 64, 209222.
Salzer, W., Timmler, H. and Andersag, H. (1948). Uber Einen Neuen, Gegen Vogelmalaria Wirksamen Verbindungstybus. Chemische Berichte-Recueil 81, 1219.
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.
Steck, E. A. (1972). Chemotherapy of Malaria. Division of Medicinal Chemistry, Walter Reed Army Institute of Research, US Government Printing Office, Washington, DC, USA.
The malERA Consultative Group on Drugs (2011). A research agenda for malaria eradication: drugs. PLoS Medicine 8, e1000402. doi: 10.1371/journal.pmed.1000402.
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, 37393747.
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, 11371146.
Willett, P. (2006). Similarity-based virtual screening using 2D fingerprints. Drug Discovery Today 11, 10461053.
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, 30883091.
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, 4756.
Wiselogle, F. Y. (1946). A Survey of Antimalarial Drugs 1941–1945 (ed. Edwards, J. W.), pp. 11921. Ann Harbor, MI, USA.
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, 26572672.
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.

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed