Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate

Nature Communications

Volumn 6, Issue , 2015, Pages

  Hameed P , Shahul ^a   Solapure, Suresh ^a   Patil, Vikas ^a   Henrich, Philipp P ^b   Magistrado, Pamela A ^c   Bharath, Sowmya ^a   Murugan, Kannan ^a   Viswanath, Pavithra ^a   Puttur, Jayashree ^a   Srivastava, Abhishek ^a   Bellale, Eknath ^a   Panduga, Vijender ^a   Shanbag, Gajanan ^a   Awasthy, Disha ^a   Landge, Sudhir ^a   Morayya, Sapna ^a   Koushik, Krishna ^a   Saralaya, Ramanatha ^a   Raichurkar, Anandkumar ^a   Rautela, Nikhil ^a   Roy Choudhury, Nilanjana ^a   Ambady, Anisha ^a   Nandishaiah, Radha ^a   Reddy, Jitendar ^a   Prabhakar, K R ^a   Menasinakai, Sreenivasaiah ^a   Rudrapatna, Suresh ^a   Chatterji, Monalisa ^a   Jiménez Diáz, Mariá Belén ^d   Martínez, Mariá Santos ^d   Sanz, Laura Mariá ^d   Coburn Flynn, Olivia ^b   Fidock, David A ^b   Lukens, Amanda K ^c   Wirth, Dyann F ^c   Bandodkar, Balachandra ^a   Mukherjee, Kakoli ^a   McLaughlin, Robert E ^a   Waterson, David ^e   Rosenbrier Ribeiro, Lyn ^a   Hickling, Kevin ^a   Balasubramanian, V ^a   Warner, Peter ^a   Hosagrahara, Vinayak ^a   Dudley, Adam ^a   Iyer, Pravin S ^a   Narayanan, Shridhar ^a   Kavanagh, Stefan ^a   Sambandamurthy, Vasan K ^a   more..

^a ASTRAZENECA   (United Kingdom)

^b Department of Medicine   (United States)

^c HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^d GLAXOSMITHKLINE   (Spain)

^e International Center Cointrin   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; BAFILOMYCIN A1; CONCANAMYCIN A; DRUG METABOLITE; N2 (4 CYCLOPROPYL 5 FLUORO 6 METHYLPYRIDIN 2 YL) N4 (1,5 DIMETHYL 1H PYRAZOL 3 YL) 5 (3 METHYLPIPERAZIN 1 YL)PYRAMIDINE 2,4 DIAMINE DIHYDROCHLORIDE; N2 (4 CYCLOPROPYL 5 FLUORO 6 METHYLPYRIDIN 2 YL) N4 (1,5 DIMETHYL 1H PYRAZOL 3 YL) 5 (3,4 DIMETHYLPIPERAZIN 1 YL)PYRAMIDINE 2,4 DIAMINE; N4 (1,5 DIMETHYL 1H PYRAZOL 3 YL) N2 (4 ETHYL 5 FLUORO 6 METHYLPYRIDIN 2 YL) 5 (3 METHYLPIPERAZIN 1 YL)PYRAMIDINE 2,4 DIAMINE DIHYDROCHLORIDE; N4 (1,5 DIMETHYL 1H PYRAZOL 3 YL) N2 (5 FLUORO 6 METHYLPYRIDIN 2 YL) 5 (3 METHYLPIPERAZIN 1 YL)PYRAMIDINE 2,4 DIAMINE; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATE SYNTHASE; PYRIMIDINE DERIVATIVE; TRIAMINOPYRIMIDINE; UNCLASSIFIED DRUG; AMINE;

BLOOD; EMERGENCE; GENOME; MALARIA; OPTIMIZATION; PHENOTYPE; PIG; RODENT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD SAMPLING; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DEVELOPMENT; DRUG EFFICACY; DRUG SAFETY; DRUG SYNTHESIS; FEMALE; GUINEA PIG; HALF LIFE TIME; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; INTRINSIC CLEARANCE; MALE; MOUSE; NEXT GENERATION SEQUENCING; NONHUMAN; PARASITEMIA; PLASMODIUM FALCIPARUM; PLASMODIUM MALARIAE INFECTION; RAT; STRUCTURE ACTIVITY RELATION; ANIMAL; ANTIBIOTIC RESISTANCE; DRUG EFFECTS; PRECLINICAL STUDY;

CAVIA; PLASMODIUM FALCIPARUM; RATTUS;

AMINES; ANIMALS; ANTIMALARIALS; DRUG EVALUATION, PRECLINICAL; DRUG RESISTANCE, MICROBIAL; GUINEA PIGS; HALF-LIFE; PLASMODIUM FALCIPARUM; PYRIMIDINES; RATS;

EID: 84926377660     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms7715     Document Type: Article

References (40)

1. WHO. World Malaria Report 2014, http://www. who. int/malaria/publications/world-malaria-report-2014/en/.
2. White, N. J. et al. Malaria. Lancet 383, 723-735 (2014).
3. Ariey, F. et al. A molecular marker of artemisinin resistant Plasmodium falciparum malaria. Nature 505, 50-55 (2014).
4. Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371, 411-423 (2014).
5. Burrows, J. N. et al. Antimalarial drug discovery-the path towards eradication. Parasitology 141, 128-139 (2014).
6. Lee, J. A. et al. Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J. Med. Chem. 55, 4527-4538 (2012).
7. Rottmann, M. et al. Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175-1180 (2010).
8. Hameed, S. P. et al. Aminoazabenzimidazoles, a novel class of orally active antimalarial agents. J. Med. Chem. 57, 5702-5713 (2014).
9. Jiménez-Dáz, M. B. et al. (\+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl Acad. Sci. USA 111, E5455-E5462 (2014).
10. Ramachandran, S. et al. N-Aryl-2-aminobenzimidazoles: Novel, efficacious, antimalarial lead compounds. J. Med. Chem. 57, 6642-6652 (2014).
11. Le Manach, C. et al. Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Malar. J. 16, 424-430 (2013).
12. Angulo-Barturen, I. et al. A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes. PLoS ONE 3, e2252 (2008).
13. White, N. J. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrob. Agents Chemother. 57, 5792-5807 (2013).
14. Winter, K., amp; Hastings, I. M. Development, evaluation, and application of an in silico model for antimalarial drug treatment and failure. Antimicrob. Agents Chemother. 55, 3380-3392 (2011).
15. Simpson, J. A. et al. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob. Agents Chemother. 44, 3414-3424 (2000).
16. Fidock, D. A. et al. Antimalarial drug discovery: efficacy models for compound screening. Nat. Rev. Drug Discov. 3, 509-520 (2004).
17. Dondorp, A. M. et al. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med. 2, e204 (2005).
18. Marchesini, N. et al. A malaria parasite encoded vacuolar H\+-ATPase is targeted to the host erythrocyte. J. Biol. Chem. 280, 36841-36847 (2005).
19. Forgac, M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell. Biol. 8, 917-929 (2007).
20. Saliba, K. J., amp; Kirk, K. pH regulation in the intracellular malaria parasite, Plasmodium falciparum H\+ extrusion via a V-type H\+-ATPase. J. Biol. Chem. 274, 33213-33219 (1999).
21. Saliba, K. J. et al. Acidfication of the malaria parasite's digestive vacuole by a H\+-ATPase and a H\+-pyrophosphatase. J. Biol. Chem. 278, 5605-5612 (2003).
22. Isaka, M. et al. Potent in vitro antimalarial activity of metacycloprodigiosin isolated from Streptomyces spectabilis BCC 4785. Antimicrob. Agents Chemother. 46, 1112-1113 (2002).
23. Auparakkitanon, S., amp; Wilairat, P. Antimalarial activity of concanamycin A alone and in combination with pyronaridine. Southeast Asian J. Trop. Med. Pub Health 37, 619-621 (2006).
24. van Schalkwyk, D. A. et al. Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death. Biochem. Pharmacol. 79, 1291-1299 (2010).
25. Lukens, A. K. et al. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance. Proc. Natl Acad. Sci. USA 111, 799-804 (2014).
26. Lukens, A. K. et al. Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors. J Infect Dis. doi:10. 1093/infdis/jiu565 (21 October 2014).
27. Bennett, T. N. et al. Novel, rapid, and inexpensive cell-based quantification of antimalarial drug efficacy. Antimicrob. Agents Chemother. 48, 1807-1810 (2004).
28. Smilkstein, M. et al. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob. Agents Chemother. 48, 1803-1806 (2004).
29. Flannery, E. L. et al. Using genetic methods to define the targets of compounds with antimalarial activity. J. Med. Chem. 56, 7761-7771 (2013).
30. Rosario, V. Cloning of naturally occurring mixed infections of malaria parasites. Science 212, 1037-1038 (1981).
31. Li, H., amp; Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754-1760 (2009).
32. Van der Auwera, G. A. et al. From FastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline. Curr. Protoc. Bioinformatics 11, 11. 10. 1-11. 10. 33 (2013).
33. Gouet, P. et al. ESPript/ENDscript: extracting and rendering sequences and 3D information from atomic structures of proteins. Nucleic Acids Res. 31, 3320-3323 (2003).
34. Bridgland-Taylor, M. H. et al. Optimisation and validation of a mediumthroughput electrophysiology-based hERG assay using IonWorks HT. J. Pharmacol. Toxicol. Methods 54, 189-199 (2006).
35. McMillian, M. K. et al. An improved resazurin-based cytotoxicity assay for hepatic cells. Cell. Biol. Toxicol. 18, 157-173 (2002).
36. O'Brien, J. et al. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell toxicity. Eur. J. Biochem. 267, 5421-5426 (2000).
37. Hill, A. V. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J. Physiol. 40, iv-vii (1910).
38. Cheng, Y., amp; Prusoff, W. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108 (1973).
39. Marks, L. et al. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds. Toxicol. Appl. Pharm. 263, 171-183 (2012).
40. Mooney, L. et al. Optimising conditions for studying the acute effects of drugs on indices of cardiac contractility and on haemodynamics in anaesthetized guinea pigs. J. Pharmacol. Toxicol. Methods 66, 43-51 (2012).