A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

ACS Infectious Diseases

Volumn 2, Issue 12, 2016, Pages 945-957

  Phillips, Margaret A ^a   White, Karen L ^b   Kokkonda, Sreekanth ^c   Deng, Xiaoyi ^a   White, John ^c   El Mazouni, Farah ^a   Marsh, Kennan ^d   Tomchick, Diana R ^a   Manjalanagara, Krishne ^e   Rudra, Kakali Rani ^e   Wirjanata, Grennady ^f   Noviyanti, Rintis ^g   Price, Ric N ^f,h   Marfurt, Jutta ^f   Shackleford, David M ^b   Chiu, Francis C K ^b   Campbell, Michael ^b   Jimenez Diaz, Maria Belen ⁱ   Bazaga, Santiago Ferrer ⁱ   Angulo Barturen, Iñigo ⁱ   Martinez, Maria Santos ⁱ   Lafuente Monasterio, Maria ⁱ   Kaminsky, Werner ^c   Silue, Kigbafori ^j   Zeeman, Anne Marie ^k   Kocken, Clemens ^k   Leroy, Didier ^l   Blasco, Benjamin ^l   Rossignol, Emilie ^l   Rueckle, Thomas ^l   Matthews, Dave ^l   Burrows, Jeremy N ^l   Waterson, David ^l   Palmer, Michael J ^l   Rathod, Pradipsinh K ^c   Charman, Susan A ^b   more..

^a UNIVERSITY OF TEXAS AT DALLAS   (United States)

^b MONASH UNIVERSITY   (Australia)

^c UNIVERSITY OF WASHINGTON   (United States)

^d ABBVIE INC   (United States)

^e SYNGENE INTERNATIONAL LTD   (India)

^f MENZIES SCHOOL OF HEALTH RESEARCH   (Australia)

^g EIJKMAN INSTITUTE FOR MOLECULAR BIOLOGY   (Indonesia)

^h UNIVERSITY OF OXFORD   (United Kingdom)

ⁱ GLAXOSMITHKLINE   (Spain)

^j CENTRE SUISSE DE RECHERCHES SCIENTIFIQUES EN CÔTE D'IVOIRE   (Côte d’Ivoire)

^k BIOMEDICAL PRIMATE RESEARCH CENTRE   (Netherlands)

^l Medicines for Malaria Venture   (Switzerland)

more..

Author keywords

dihydroorotate dehydrogenase; malaria; Plasmodium; pyrimidine biosynthesis

Indexed keywords

ANTIMALARIAL AGENT; DIHYDROOROTATE DEHYDROGENASE INHIBITOR; DSM 265; DSM 421; UNCLASSIFIED DRUG; DIHYDROOROTATE DEHYDROGENASE; ENZYME INHIBITOR; OXIDOREDUCTASE; PROTOZOAL PROTEIN; PYRIMIDINE; PYRIMIDINE DERIVATIVE;

AMINO ACID SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; CROSS RESISTANCE; CYTOTOXICITY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG GLUCURONIDATION; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG SOLUBILITY; DRUG STRUCTURE; EC50; EXPERIMENTAL DOG; HEP-G2 CELL LINE; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; IN VIVO STUDY; INTRINSIC CLEARANCE; LIPOPHILICITY; LIVER MICROSOME; MALARIA; MALARIA CONTROL; MAXIMUM PLASMA CONCENTRATION; METABOLIC STABILITY; MINIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; PARASITE ISOLATION; PLASMA CLEARANCE; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PREDICTION; PRIORITY JOURNAL; PROTEIN BINDING; RAT; SCHIZONT; TIME TO MAXIMUM PLASMA CONCENTRATION; TIME-DEPENDENT INHIBITION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DOG; DRUG EFFECTS; ENZYMOLOGY; GENETICS; MALARIA FALCIPARUM; METABOLISM; PARASITOLOGY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTIMALARIALS; DOGS; ENZYME INHIBITORS; HUMANS; MALARIA, FALCIPARUM; MICE; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS; PLASMODIUM FALCIPARUM; PROTOZOAN PROTEINS; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85003456407     PISSN: None     EISSN: 23738227     Source Type: Journal    
DOI: 10.1021/acsinfecdis.6b00144     Document Type: Article

References (43)

1. Miller, L. H., Ackerman, H. C., Su, X. Z., and Wellems, T. E. (2013) Malaria biology and disease pathogenesis: insights for new treatments Nat. Med. 19 (2) 156-67 10.1038/nm.3073
2. White, N. J., Pukrittayakamee, S., Hien, T. T., Faiz, M. A., Mokuolu, O. A., and Dondorp, A. M. (2014) Malaria Lancet 383 (9918) 723-35 10.1016/S0140-6736(13)60024-0
3. WHO. Malaria. Fact Sheet No 94, 10/2015 ed.; WHO: Geneva, 2015.
4. Straimer, J., Gnadig, N. F., Witkowski, B., Amaratunga, C., Duru, V., Ramadani, A. P., Dacheux, M., Khim, N., Zhang, L., Lam, S., Gregory, P. D., Urnov, F. D., Mercereau-Puijalon, O., Benoit-Vical, F., Fairhurst, R. M., Menard, D., and Fidock, D. A. (2015) Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates Science 347 (6220) 428-31 10.1126/science.1260867
5. Mok, S., Ashley, E. A., Ferreira, P. E., Zhu, L., Lin, Z., Yeo, T., Chotivanich, K., Imwong, M., Pukrittayakamee, S., Dhorda, M., Nguon, C., Lim, P., Amaratunga, C., Suon, S., Hien, T. T., Htut, Y., Faiz, M. A., Onyamboko, M. A., Mayxay, M., Newton, P. N., Tripura, R., Woodrow, C. J., Miotto, O., Kwiatkowski, D. P., Nosten, F., Day, N. P., Preiser, P. R., White, N. J., Dondorp, A. M., Fairhurst, R. M., and Bozdech, Z. (2015) Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance Science 347 (6220) 431-5 10.1126/science.1260403
6. Miotto, O., Amato, R., Ashley, E. A., MacInnis, B., Almagro-Garcia, J., Amaratunga, C., Lim, P., Mead, D., Oyola, S. O., Dhorda, M., Imwong, M., Woodrow, C., Manske, M., Stalker, J., Drury, E., Campino, S., Amenga-Etego, L., Thanh, T. N., Tran, H. T., Ringwald, P., Bethell, D., Nosten, F., Phyo, A. P., Pukrittayakamee, S., Chotivanich, K., Chuor, C. M., Nguon, C., Suon, S., Sreng, S., Newton, P. N., Mayxay, M., Khanthavong, M., Hongvanthong, B., Htut, Y., Han, K. T., Kyaw, M. P., Faiz, M. A., Fanello, C. I., Onyamboko, M., Mokuolu, O. A., Jacob, C. G., Takala-Harrison, S., Plowe, C. V., Day, N. P., Dondorp, A. M., Spencer, C. C., McVean, G., Fairhurst, R. M., White, N. J., and Kwiatkowski, D. P. (2015) Genetic architecture of artemisinin-resistant Plasmodium falciparum Nat. Genet. 47, 226 10.1038/ng.3189
7. Menard, D. and Ariey, F. (2015) Towards real-time monitoring of artemisinin resistance Lancet Infect. Dis. 15 (4) 367-8 10.1016/S1473-3099(15)70046-0
8. Wells, T. N., Hooft van Huijsduijnen, R., and Van Voorhis, W. C. (2015) Malaria medicines: a glass half full? Nat. Rev. Drug Discovery 14 (6) 424-42 10.1038/nrd4573
9. Burrows, J. N., Burlot, E., Campo, B., Cherbuin, S., Jeanneret, S., Leroy, D., Spangenberg, T., Waterson, D., Wells, T. N., and Willis, P. (2014) Antimalarial drug discovery-the path towards eradication Parasitology 141 (1) 128-39 10.1017/S0031182013000826
10. Smith, P. W., Diagana, T. T., and Yeung, B. K. (2014) Progressing the global antimalarial portfolio: finding drugs which target multiple Plasmodium life stages Parasitology 141 (1) 66-76 10.1017/S0031182013000747
11. Duparc, S., Lanza, C., Ubben, D., Borghini-Fuhrer, I., and Kellam, L. (2012) Optimal dose finding for novel antimalarial combination therapy Trop. Med. Int. Health 17 (4) 409-13 10.1111/j.1365-3156.2012.02963.x
12. Charman, S. A., Arbe-Barnes, S., Bathurst, I. C., Brun, R., Campbell, M., Charman, W. N., Chiu, F. C., Chollet, J., Craft, J. C., Creek, D. J., Dong, Y., Matile, H., Maurer, M., Morizzi, J., Nguyen, T., Papastogiannidis, P., Scheurer, C., Shackleford, D. M., Sriraghavan, K., Stingelin, L., Tang, Y., Urwyler, H., Wang, X., White, K. L., Wittlin, S., Zhou, L., and Vennerstrom, J. L. (2011) Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria Proc. Natl. Acad. Sci. U. S. A. 108 (11) 4400-5 10.1073/pnas.1015762108
13. Moehrle, J. J., Duparc, S., Siethoff, C., van Giersbergen, P. L., Craft, J. C., Arbe-Barnes, S., Charman, S. A., Gutierrez, M., Wittlin, S., and Vennerstrom, J. L. (2013) First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials Br. J. Clin. Pharmacol. 75 (2) 535-548 10.1111/j.1365-2125.2012.04368.x
14. Leong, F. J., Li, R., Jain, J. P., Lefevre, G., Magnusson, B., Diagana, T. T., and Pertel, P. (2014) A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers Antimicrob. Agents Chemother. 58 (10) 6209-14 10.1128/AAC.03393-14
15. Rottmann, M., McNamara, C., Yeung, B. K., Lee, M. C., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., Gonzalez-Paez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H. P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T. H., Fidock, D. A., Winzeler, E. A., and Diagana, T. T. (2010) Spiroindolones, a potent compound class for the treatment of malaria Science 329 (5996) 1175-80 10.1126/science.1193225
16. Spillman, N. J., Allen, R. J., McNamara, C. W., Yeung, B. K., Winzeler, E. A., Diagana, T. T., and Kirk, K. (2013) Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials Cell Host Microbe 13 (2) 227-237 10.1016/j.chom.2012.12.006
17. Kuhen, K. L., Chatterjee, A. K., Rottmann, M., Gagaring, K., Borboa, R., Buenviaje, J., Chen, Z., Francek, C., Wu, T., Nagle, A., Barnes, S. W., Plouffe, D., Lee, M. C., Fidock, D. A., Graumans, W., van de Vegte-Bolmer, M., van Gemert, G. J., Wirjanata, G., Sebayang, B., Marfurt, J., Russell, B., Suwanarusk, R., Price, R. N., Nosten, F., Tungtaeng, A., Gettayacamin, M., Sattabongkot, J., Taylor, J., Walker, J. R., Tully, D., Patra, K. P., Flannery, E. L., Vinetz, J. M., Renia, L., Sauerwein, R. W., Winzeler, E. A., Glynne, R. J., and Diagana, T. T. (2014) KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission Antimicrob. Agents Chemother. 58 (9) 5060-7 10.1128/AAC.02727-13
18. Phillips, M. A., Lotharius, J., Marsh, K., White, J., Dayan, A., White, K. L., Njoroge, J. W., El Mazouni, F., Lao, Y., Kokkonda, S., Tomchick, D. R., Deng, X., Laird, T., Bhatia, S. N., March, S., Ng, C. L., Fidock, D. A., Wittlin, S., Lafuente-Monasterio, M., Benito, F. J., Alonso, L. M., Martinez, M. S., Jimenez-Diaz, M. B., Bazaga, S. F., Angulo-Barturen, I., Haselden, J. N., Louttit, J., Cui, Y., Sridhar, A., Zeeman, A. M., Kocken, C., Sauerwein, R., Dechering, K., Avery, V. M., Duffy, S., Delves, M., Sinden, R., Ruecker, A., Wickham, K. S., Rochford, R., Gahagen, J., Iyer, L., Riccio, E., Mirsalis, J., Bathhurst, I., Rueckle, T., Ding, X., Campo, B., Leroy, D., Rogers, M. J., Rathod, P. K., Burrows, J. N., and Charman, S. A. (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria Sci. Transl. Med. 7 (296) 296ra111 10.1126/scitranslmed.aaa6645
19. Phillips, M. A. and Rathod, P. K. (2010) Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy Infect. Disord.: Drug Targets 10 (3) 226-39 10.2174/187152610791163336
20. 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 J. Med. Chem. 52 (7) 1864-72 10.1021/jm801343r
21. 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 J. Med. Chem. 51, 3649-3653 10.1021/jm8001026
22. 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 J. Med. Chem. 54 (15) 5540-5561 10.1021/jm200592f
23. 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 anti-malarial activity in mice J. Med. Chem. 54 (11) 3935-49 10.1021/jm200265b
24. Deng, X., Kokkonda, S., El Mazouni, F., White, J., Burrows, J. N., Kaminsky, W., Charman, S. A., Matthews, D., Rathod, P. K., and Phillips, M. A. (2014) Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors J. Med. Chem. 57 (12) 5381-94 10.1021/jm500481t
25. Deng, X., 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 J. Biol. Chem. 284, 26999-27009 10.1074/jbc.M109.028589
26. Ganesan, S. M., Morrisey, J. M., Ke, H., Painter, H. J., Laroiya, K., Phillips, M. A., Rathod, P. K., Mather, M. W., and Vaidya, A. B. (2011) Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection Mol. Biochem. Parasitol. 177 (1) 29-34 10.1016/j.molbiopara.2011.01.004
27. Sanz, L. M., Crespo, B., De-Cozar, C., Ding, X. C., Llergo, J. L., Burrows, J. N., Garcia-Bustos, J. F., and Gamo, F. J. (2012) P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action PLoS One 7 (2) e30949 10.1371/journal.pone.0030949
28. Ratcliff, A., Siswantoro, H., Kenangalem, E., Wuwung, M., Brockman, A., Edstein, M. D., Laihad, F., Ebsworth, E. P., Anstey, N. M., Tjitra, E., and Price, R. N. (2007) Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia Trans. R. Soc. Trop. Med. Hyg. 101 (4) 351-9 10.1016/j.trstmh.2006.06.008
29. 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 Antimicrob. Agents Chemother. 53 (10) 4533-4536 10.1128/AAC.00519-09
30. Srivastava, A., Creek, D. J., Evans, K. J., De Souza, D., Schofield, L., Muller, S., Barrett, M. P., McConville, M. J., and Waters, A. P. (2015) Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites PLoS Pathog. 11 (6) e1004882 10.1371/journal.ppat.1004882
31. Booker, M. L., Bastos, C. M., Kramer, M. L., Barker, R. H., Jr., Skerlj, R., Bir Sdhu, A., Deng, X., Celatka, C., Cortese, J. F., Guerrero Bravo, J. E., Krespo Llado, K. N., Serrano, A. E., Angulo-Barturen, I., Belén Jiménez-Díaz, M., Viera, S., Garuti, H., Wittlin, S., Papastogiannidis, P., Lin, J., 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 J. Biol. Chem. 285 (43) 33054-33064 10.1074/jbc.M110.162081
32. Otwinowski, Z. and Minor, W. (1997) Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 276, 307-326 10.1016/S0076-6879(97)76066-X
33. McCoy, A. J. (2007) Solving structures of protein complexes by molecular replacement with Phaser Acta Crystallogr., Sect. D: Biol. Crystallogr. 63 (1) 32-41 10.1107/S0907444906045975
34. Emsley, P. and Cowtan, K. (2004) Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 60 (12) 2126-2132 10.1107/S0907444904019158
35. Adams, P. D., Afonine, P. V., Bunkoczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L. W., Kapral, G. J., Grosse-Kunstleve, R. W., McCoy, A. J., Moriarty, N. W., Oeffner, R., Read, R. J., Richardson, D. C., Richardson, J. S., Terwilliger, T. C., and Zwart, P. H. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 66 (2) 213-221 10.1107/S0907444909052925
36. Vennerstrom, J. L., Arbe-Barnes, S., Brun, R., Charman, S. A., Chiu, F. C., Chollet, J., Dong, Y., Dorn, A., Hunziker, D., Matile, H., McIntosh, K., Padmanilayam, M., Santo Tomas, J., Scheurer, C., Scorneaux, B., Tang, Y., Urwyler, H., Wittlin, S., and Charman, W. N. (2004) Identification of an antimalarial synthetic trioxolane drug development candidate Nature 430 (7002) 900-4 10.1038/nature02779
37. Dembele, L., Gego, A., Zeeman, A. M., Franetich, J. F., Silvie, O., Rametti, A., Le Grand, R., Dereuddre-Bosquet, N., Sauerwein, R., van Gemert, G. J., Vaillant, J. C., Thomas, A. W., Snounou, G., Kocken, C. H., and Mazier, D. (2011) Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery PLoS One 6 (3) e18162 10.1371/journal.pone.0018162
38. Zeeman, A. M., van Amsterdam, S. M., McNamara, C. W., Voorberg-van der Wel, A., Klooster, E. J., van den Berg, A., Remarque, E. J., Plouffe, D. M., van Gemert, G. J., Luty, A., Sauerwein, R., Gagaring, K., Borboa, R., Chen, Z., Kuhen, K., Glynne, R. J., Chatterjee, A. K., Nagle, A., Roland, J., Winzeler, E. A., Leroy, D., Campo, B., Diagana, T. T., Yeung, B. K., Thomas, A. W., and Kocken, C. H. (2014) KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro Antimicrob. Agents Chemother. 58 (3) 1586-95 10.1128/AAC.01927-13
39. Marfurt, J., Chalfein, F., Prayoga, P., Wabiser, F., Wirjanata, G., Sebayang, B., Piera, K. A., Wittlin, S., Haynes, R. K., Mohrle, J. J., Anstey, N. M., Kenangalem, E., and Price, R. N. (2012) Comparative ex vivo activity of novel endoperoxides in multidrug-resistant plasmodium falciparum and P. vivax Antimicrob. Agents Chemother. 56 (10) 5258-63 10.1128/AAC.00283-12
40. Wirjanata, G., Sebayang, B. F., Chalfein, F., Prayoga, Handayuni, I., Trianty, L., Kenangalem, E., Noviyanti, R., Campo, B., Poespoprodjo, J. R., Mohrle, J. J., Price, R. N., and Marfurt, J. (2015) Potent Ex Vivo Activity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax Antimicrob. Agents Chemother. 59 (10) 6117-24 10.1128/AAC.00874-15
41. Jimenez-Diaz, M. B., Mulet, T., Gomez, V., Viera, S., Alvarez, A., Garuti, H., Vazquez, Y., Fernandez, A., Ibanez, J., Jimenez, M., Gargallo-Viola, D., and Angulo-Barturen, I. (2009) Quantitative measurement of Plasmodium-infected erythrocytes in murine models of malaria by flow cytometry using bidimensional assessment of SYTO-16 fluorescence Cytometry, Part A 75A (3) 225-235 10.1002/cyto.a.20647
42. Baragana, B., Hallyburton, I., Lee, M. C., Norcross, N. R., Grimaldi, R., Otto, T. D., Proto, W. R., Blagborough, A. M., Meister, S., Wirjanata, G., Ruecker, A., Upton, L. M., Abraham, T. S., Almeida, M. J., Pradhan, A., Porzelle, A., Martinez, M. S., Bolscher, J. M., Woodland, A., Norval, S., Zuccotto, F., Thomas, J., Simeons, F., Stojanovski, L., Osuna-Cabello, M., Brock, P. M., Churcher, T. S., Sala, K. A., Zakutansky, S. E., Jimenez-Diaz, M. B., Sanz, L. M., Riley, J., Basak, R., Campbell, M., Avery, V. M., Sauerwein, R. W., Dechering, K. J., Noviyanti, R., Campo, B., Frearson, J. A., Angulo-Barturen, I., Ferrer-Bazaga, S., Gamo, F. J., Wyatt, P. G., Leroy, D., Siegl, P., Delves, M. J., Kyle, D. E., Wittlin, S., Marfurt, J., Price, R. N., Sinden, R. E., Winzeler, E. A., Charman, S. A., Bebrevska, L., Gray, D. W., Campbell, S., Fairlamb, A. H., Willis, P. A., Rayner, J. C., Fidock, D. A., Read, K. D., and Gilbert, I. H. (2015) A novel multiple-stage antimalarial agent that inhibits protein synthesis Nature 522 (7556) 315-20 10.1038/nature14451
43. Kokkonda, S., Deng, X., White, K. L., Coteron, J. M., Marco, M., de Las Heras, L., White, J., El Mazouni, F., Tomchick, D. R., Manjalanagara, K., Rudra, K. R., Chen, G., Morizzi, J., Ryan, E., Kaminsky, W., Leroy, D., Martinez-Martinez, M. S., Jimenez Diaz, M. B., Bazaga, S. F., Angulo-Barturen, I., Waterson, D., Burrows, J. N., Matthews, D., Charman, S. A., Phillips, M. A., and Rathod, P. K. (2016) Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidines targeting Plasmodium falciparum dihydroorotate dehydrogenase display potent and selective antimalarial activity J. Med. Chem. 59 (11) 5416-31 10.1021/acs.jmedchem.6b00275