New antibacterials for the treatment of toxoplasmosis; A patent review

Expert Opinion on Therapeutic Patents

Volumn 22, Issue 3, 2012, Pages 311-333

  Rodriguez, Juan Bautista ^a   Szajnman, Sergio Hernán ^a  

^a UNIVERSIDAD DE BUENOS AIRES   (Argentina)

Author keywords

Calcium dependent protein kinases; Dihydrofolate reductase; Farnesyl pyrophosphate synthase; Macrolides; Squalene synthase; T. gondii adenosine kinase; T. gondii histone deacetylase; Toxoplasma gondii; Toxoplasmosis

Indexed keywords

1 ALKYL BISPHOSPHONATE DERIVATIVE; 1 AMINO BISPHOSPHONATE DERIVATIVE; 1 HYDROXY BISPHOSPHONATE DERIVATIVE; 1H BENZO[D]IMIDAZOL 2(3H) ONE; 4 PHENOXYPHENOXY ETHYL THIOCYANATE; 6 N BENZYLADENOSINE; ALENDRONIC ACID; ALPHA FLUORO 1,1 BISPHOSPHONATE DERIVATIVE; ANTIINFECTIVE AGENT; APICIDIN; ARTEMETHER; ARTEMISIN; ARTEMISININ DERIVATIVE; ARTEMISONE; AZASTEROL DERIVATIVE; AZITHROMYCIN; BISPHOSPHONIC ACID DERIVATIVE; DEOXYARTEMISININ; ERYTHROMYCIN; IBANDRONIC ACID; MACROLIDE; N[4 [(2 AMINO 6 METHYL 4 OXO 3,4 DIHYDROTHIENO[2,3 D]PYRIMIDIN 5 YL)SULFANYL]BENZOYL]GLUTAMICACID; PAMIDRONIC ACID; PIRITREXIM; PYRIMETHAMINE SULFADIAZINE; RISEDRONIC ACID; SQUALENE SYNTHASE INHIBITOR; TACROLIMUS; TRIMETHOPRIM; UNCLASSIFIED DRUG; UNINDEXED DRUG; WC 9;

AMINO ACID SEQUENCE; ANTIPROLIFERATIVE ACTIVITY; BRAIN MALARIA; CELL DEATH; CELL INVASION; DRUG MECHANISM; DRUG POTENTIATION; DRUG STRUCTURE; DRUG TARGETING; ENZYME INHIBITION; LIFE CYCLE; NONHUMAN; NUCLEIC ACID SYNTHESIS; OSTEOPOROSIS; REVIEW; TOXOPLASMA GONDII; TOXOPLASMOSIS;

ANIMALS; ANTIPROTOZOAL AGENTS; DRUG DESIGN; FEMALE; HUMANS; IMMUNOCOMPROMISED HOST; MOLECULAR TARGETED THERAPY; PATENTS AS TOPIC; PREGNANCY; TOXOPLASMA; TOXOPLASMOSIS; TOXOPLASMOSIS, ANIMAL;

EID: 84858686219     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2012.668886     Document Type: Review

References (152)

1. Luder CG, Bohne W, Soldati D. Toxoplasmosis: a persisting challenge. Trends Parasitol 2001;17:460-3 (Pubitemid 32918258)
2. Innes EA. A brief history and overview of Toxoplasma gondii. Zoonoses Public Health 2010;57:1-7
3. Frenkel JK, Remington JS, Wong S-Y. Prevention of toxoplasma infection in pregnant women and their fetuses. Clin Infect Dis 1995;20:727-9
4. Tenter AM, Heckerost AR, Weiss LM. Toxoplasma gondii: from animals to humans. Int J Parasitol 2000;30:1217-58
5. Moreno SNJ, Li Z-H. Targeting the isoprenoid pathway of Toxoplasma gondii. Expert Opin Ther Targets 2008;12:253-63 (Pubitemid 351419420)
6. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;318:1439-48
7. Yolken RH, Bachmann S, Ruslanova I, et al. Antibodies to Toxoplasma gondii in individuals with first-episode schizophrenia. Clin Infect Dis 2001;32:842-4 (Pubitemid 32221950)
8. Nicolle C. Manceaux, sur une infection A corps de leishman (ou organism voisin) du gondi. C R Hebd Seances Acad Sci 1908;147:763-6
9. Levine ND, Corliss JO, Cox FE, et al. A newly revised classification of the protozoa. J Protozool 1980;27:37-58
10. Carruthers V, Boothroyd JC. Pulling together: an integrated model of Toxoplasma cell invasion. Curr Opin Microbiol 2007;10:83-9 (Pubitemid 46223639)
11. Fichera ME, Roos DS. A plastid organelle as a drug target in apicomplexan parasites. Nature 1997;390:407-9 (Pubitemid 28027322)
12. Stokkermans TJW, Schwartzman JD, Keenan K, et al. Inhibition of Toxoplasma gondii replication by dinitroaniline herbicides. Exp Parasitol 1996;84:355-70 (Pubitemid 26412997)
13. Roberts F, Roberts CW, Johnson JJ, et al. Evidence for the shikimate pathway in apicomplexan parasites. Nature 1998;393:801-5 (Pubitemid 28299493)
14. Dubey JP, Linsday DS, Speer CA. Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev 1998;11:267-99 (Pubitemid 28197354)
15. Georgiev V. Management of toxoplasmosis. Drugs 1994;48:179-88 (Pubitemid 24260353)
16. Moreno SNJ, Docampo R. Calcium regulation in protozoan parasites. Curr Opin Microbiol 2003;6:359-64 (Pubitemid 37075353)
17. Sabin AB, Warren J. Therapeutic effect of the sulfonamides on the infection with intracellular protozoa (Toxoplasma), J Bacteriol. 1941;41:80-6
18. Eyles DE, Coleman N. Synergistic effect of sulfadiazine and daraprim against toxoplasmosis in mice. Antibiot Chemother 1953;3:483-90
19. Beverly JKA. A rational approach to the treatment of Toxoplasma uveitis. Trans Ophtalmol Soc UK 1958;78:109-21
20. Chang HR, Pechere J-CF. Effect of roxithromycin on acute toxoplasmosis in mice. Antimicrob Agents Chemother 1987;31:1147-9 (Pubitemid 17099595)
21. Chang HR, Pechere J-CF. In vivo effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,993], and A-56268) on Toxoplasma gondii. Antimicrob Agents Chemother 1988;32:524-9 (Pubitemid 18089359)
22. Garin JP, Eyles DE. Le traitement de la toxoplasmose experimentale de la souris par la spiramycine. Press Med 1958;66:957-8
23. Desmonts G, Couvreur J. Congenital toxoplasmosis. A prospective study of 378 pregnancies. N Engl J Med 1974;290:1110-16
24. Baggish AL, Hill DR. Antiparasitic agent atovaquone. Antimicrob Agents Chemother 2002;46:1163-73 (Pubitemid 34415287)
25. Sun IL, Sun EE, Crane FL, et al. Requirement for coenzyme Q in plasma membrane electron transport. Proc Natl Acad Sci USA 1992;89:11126-30
26. McFadden DC, Tomavo S, Berry EA, Boothroyd JC. Characterization of cytochrome b from Toxoplasma gondii and Q(o) domain mutations as mechanism of atovaquone-resistance. Mol Biochem Parasitol 2000;108:1-12 (Pubitemid 30236311)
27. Harris C, Salgo MP, Tanowitz HB, et al. In vitro assessment of antimicrobial agents against Toxoplasma gondii. J Infect Dis 1988;157:14-22 (Pubitemid 18037446)
28. Rytel MW, Jones TC. Introduction of interferon in mice infected with Toxoplasma gondii. Proc Soc Exp Biol Med 1966;123:859-62
29. Koo L, Young LH. Management of ocular toxoplasmosis. Int Ophtalmol Clin 2006;46:183-93 (Pubitemid 44084843)
30. Avery MA, Alvim-Gaston M, Vroman JA, et al. Structure-activity relationships of the antimalarial agent artemisinin. 7. Direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates. J Med Chem 2002;45:4321-35 (Pubitemid 35025578)
31. Vroman JA, Alvim-Gaston M, Avery MA. Current progress in the chemistry, medicinal chemistry and drug design of artemisinin based antimalarials. Curr Pharm Des 1999;5:101-38 (Pubitemid 29115757)
32. Ou-Yang K, Krug EC, Marr JJ, et al. Inhibition of growth of Toxoplasma gondii by qinghaosu and derivatives. Antimicrob Agents Chemother 1990;34:1961-5 (Pubitemid 20290297)
33. Chang HR, Pechere J-C. Arteether,a qinghaosu derivative in toxoplasmosis. Trans R Soc Trop Med Hyg 1988;82:867
34. Jones-Brando L, D'Angelo J, Posner GH, et al. In Vitro Inhibition of Toxoplasma gondii by four new derivatives of artemisinin. Antimicrob Agents Chemother 2006;50:4206-8 (Pubitemid 44865172)
35. D'Angelo JG, Bordon C, Posner GH, et al. Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle. J Antimicrob Chemother 2009;63:146-50
36. Brando LV, Posner GH, D'Angelo JG, et al. Artemisinin derivatives. WO2008127381A2; 2008
37. Hencken CP, Jones-Brando L, Bordon C, et al. Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii. J Med Chem 2010;53:3594-601
38. Posner GH. Endoperoxidases useful as antiparasitic agents. US5817962; 1998.
39. Haynes RK, Fugmann B, Stetter J, et al. Artemisone-A highly active antimalarial drug of the artemisinin class. Angew Chem Int Ed 2006;45:2082-8 (Pubitemid 44105182)
40. Schmeer K, Wollborn U. Antiparasitic artemisinin derivatives. EP1714967A1; 2006
41. Posner GH, Woodard LE, Levine DR, et al. Tioxane monomers and dimmers. WO2010135427; 2010
42. Woodard LE, Chang W, Chen X, et al. Malaria-infected mice live until at least day 30 after a new monomeric trioxane combined with mefloquine are administered together in a single low oral dose. J Med Chem 2009;52:7458-62
43. Nagamune K, Beatty WL, Sibley DL. Artemisinin induces calcium-dependent protein secretion in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 2007;6:2147-56 (Pubitemid 350221283)
44. Nagamune K, Moreno SNJ, Sibley DL. Artemisinin-resistant mutants of Toxoplasma gondii have altered calcium homeostasis. Antimicrob Agents Chemother 2007;51:3816-23 (Pubitemid 350057776)
45. Kawase O, Nishikawa Y, Bannai H, et al. Proteomic analysis of calcium-dependent secretion in Toxoplasma gondii. Proteomics 2007;7:3718-25 (Pubitemid 350022277)
46. O'Neill PM, Rawe SL, Borstnik K, et al. Enantiomeric 1,2,4-trioxanes display equivalent in vitro antimalarial activity versus Plasmodium falciparum malaria parasites: implications for the molecular mechanism of action of the artemisinins. ChemBioChem 2005;6:2048-54 (Pubitemid 41598181)
47. O'Neill PM, Posner GH. A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem 2004;47:2945-64 (Pubitemid 38702690)
48. Urbina JA. Parasitological cure of Chagas disease: is it possible? Is it releVant? Mem Inst Oswaldo Cruz 1999;94(Suppl 1):349-55 (Pubitemid 129584525)
49. Docampo R, Moreno SN. Bisphosphonates as chemotherapeutic agents against trypanosomatid and apicomplexan parasites. Curr Drug Targets Infect Disord 2001;1:51-61
50. Docampo R, Moreno SNJ. The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites. Curr Pharm Des 2008;14:882-8 (Pubitemid 351736420)
51. Gelb MH, Van Voorhis WC, Buckner FS, et al. Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry targets for the development of antitrypanosomatid and antimalarial therapeutics. Mol Biochem Parasitol 2003;726:155-63 (Pubitemid 36255614)
52. Eberl M, Hintz M, Reichenberg A, et al. Microbial isoprenoid biosynthesis and human gammadelta T cell activation. FEBS Lett 2003;544:4-10 (Pubitemid 36628027)
53. Garcia Linares G, Ravaschino EL, Rodriguez JB. Progresses in the field of drug design to combat tropical protozoan Parasitic diseases. Curr Med Chem 2006;13:335-60
54. Dantas-Leite L, Urbina JA, De Souza W, et al. Selective anti-Toxoplasma gondii activities of azasterols. Int J Antimicrob Agents 2004;23:620-6 (Pubitemid 38765163)
55. Urbina JA, Vivas J, Lazardi K, et al. Antiproliferative effects of Delta24(25) sterol methyl transferase inhibitors on Trypanosoma (Schizotrypanum) cruzi: In vitro and in vivo studies. Chemotherapy 1996;42:294-307
56. Rodrigues JCF, Attias M, Rodriguez C, et al. Ultrastructural and biochemical alterations induced by 22,26-azasterol, a Delta24(25)-sterol methyltransferase inhibitor, on promastigote and amastigote forms of Leishmania amazonensis. Antimicrob Agents Chemother 2002;46:487-99 (Pubitemid 34087200)
57. Urbina JA, Visbal G, Contreras LM., et al. Inhibitors of Delta24(25)-Sterol methyltransferase block sterol synthesis and cell proliferation in Pneumocystis carinii. Antimicrob Agents Chemother 1997;41:1428-32 (Pubitemid 27289662)
58. Dantas-Leite L, Urbina JA, De Souza W, et al. Antiproliferative synergism of azasterols and antifolates against Toxoplasma gondii. Int J Antimicrob Agents 2005;25:130-5 (Pubitemid 40138949)
59. Roelofs AJ, Thompson K, Ebetino FH, et al. Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. Curr Pharm Des 2010;16:2950-60
60. Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem 2004;4:711-17
61. Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep 2003;1:45-52
62. Fleisch H, Russell RGG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 1966;212:901-3
63. Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969;165:1262-4
64. Francis MD, Russell RGG, Fleisch H. Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science 1969;165:1264-6
65. Urbina JA, Moreno B, Vierkotter S, et al. Trypanosoma cruzi contains major pyrophosphate stores, and its growth in vitro and in vivo is blocked by pyrophosphate analogs. J Biol Chem 1999;274:33609-15 (Pubitemid 129511673)
66. Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10:1478-87
67. Rogers MJ, Frith JC, Luckman SP, et al. Molecular mechanisms of action of bisphosphonates. Bone 1999;24:73S-9S (Pubitemid 29202003)
68. KaVanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci 2006;103:7829-34
69. Hosfield DJ, Zhang Y, Dougan DR, et al. Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis. J Biol Chem 2004;279:8526-9 (Pubitemid 38295905)
70. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001;296:235-42 (Pubitemid 32112446)
71. Coxon FP, Thompson K, Rogers MJ. Recent adVances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol 2006;6:307-12 (Pubitemid 43670914)
72. Reddy R, Dietrich E, Lafontaine Y, et al. Bisphosphonated benzoxazinorifamycin prodrugs for the prevention and treatment of osteomyelitis. ChemMedChem 2008;3:1863-8
73. Clezardin P, Massaia M. Nitrogen-containing bisphosphonates and cancer immunotherapy. Curr Pharm Des 2010;16:3007-14
74. Miller K, Erez R, Segal E., et al. Targeting bone metastases with bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate. Angew Chem Int Ed 2009;48:2949-54
75. Coleman RE. Risks and benefits of bisphosphonates. Br J Cancer 2008;98:1736-40 (Pubitemid 351748847)
76. Roth AG, Drescher D, Yang Y, et al. Potent and selective inhibition of acid sphingomyelinase by bisphosphonates. Angew Chem Int Ed 2009;48:7560-3
77. Ghosh S, Chan JMW, Lea CR, et al. Effects of bisphosphonates on the growth of Entamoeba histolytica and plasmodium species in vitro and in vivo. J Med Chem 2004;47:175-87 (Pubitemid 38040501)
78. Martin MB, Grimley JS, Lewis JC, et al. Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donoVani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy. J Med Chem 2001;44:909-16 (Pubitemid 32861615)
79. Yardley V, Khan AA, Martin MB, et al. In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donoVani and Toxoplasma gondii. Antimicrob Agents Chemother 2002;46:929-31 (Pubitemid 34157693)
80. Martin MB, Sanders JM, Kendrick H, et al. Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem 2002;45:2904-14 (Pubitemid 34721514)
81. Rosso VS, Szajnman SH, Malayil L, et al. Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorg Med Chem 2011; 19:2211-17
82. Szajnman SH, Garcia Linares GE, Li Z-H, et al. Synthesis and biological evaluation of 2-alkylaminoethyl- 1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase. Bioorg Med Chem 2008;16:3283-90 (Pubitemid 351444820)
83. Szajnman SH, Bailey BN, Docampo R, et al. Bisphosphonates derived from fatty acids are potent growth inhibitors of Trypanosoma cruzi. Bioorg Med Chem Lett 2001;11:789-92 (Pubitemid 32230681)
84. Szajnman SH, Montalvetti A, Wang Y, et al. Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. Bioorg Med Chem Lett 2003;13:3231-5 (Pubitemid 37093834)
85. Szajnman SH, Ravaschino EL, Docampo R, et al. Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase. Bioorg Med Chem Lett 2005;15:4685-90 (Pubitemid 41356662)
86. Ling Y, Sahota G, Odeh S, et al. Bisphosphonate inhibitors of Toxoplasma gondii growth: in vitro, QSAR, and in vivo investigations. J Med Chem 2005;48:3130-40 (Pubitemid 40628033)
87. Ling Y, Li Z-H, Miranda K, et al. The farnesyl-diphosphate/ geranylgeranyldiphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and amolecular target of bisphosphonates. J Biol Chem 2007;282:30804-16 (Pubitemid 350035188)
88. Szajnman SH, Rosso VS, Malayil L, et al. Design, synthesis and biological evaluation of 1-(Fluoroalkylidene)-1,1-bisphosphonic Acids against Toxoplasma gondii targeting farnesyl diphosphate synthase. Org Biomol Chem 2012;10:1424-33
89. Jeanmougin F, Thompson JD, Gouy M, et al. Multiple sequence alignment with Clustal X. Trends Biochem Sci 1998;23:403-5 (Pubitemid 28511382)
90. Cinque GM, Szajnman SH, Zhong L, et al. Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi. J Med Chem 1998;41:1540-54 (Pubitemid 28198983)
91. Szajnman SH, Yan W, Bailey BN, et al. Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation. J Med Chem 2000;43:1826-40 (Pubitemid 30305015)
92. Elhalem E, Bailey BN, Docampo R, et al. Design, synthesis and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi. J Med Chem 2002;45:3984-99 (Pubitemid 35024300)
93. Urbina JA, Concepcion JL, Montalvetti A, et al. Mechanism of action of 4-phenoxyphenoxy derivatives against Trypanosoma cruzi, the causative agent of Chagas disease. Antimicrob Agents Chemother 2003;47:2047-50 (Pubitemid 36637844)
94. Martins-Duarte ES, Urbina JA, de Souza W, et al. Antiproliferative activities of two novel quinuclidine inhibitors against Toxoplasma gondii tachyzoites in vitro. J Antimicrob Chemother 2006;58:59-65 (Pubitemid 44294988)
95. Garcia Linares G, Gismondi S, Osa Codesido N, et al. Fluorine-containing aryloxyethyl thiocyanate derivatives are potent inhibitors of Trypanosoma cruzi and Toxoplasma gondii proliferation. Bioorg Med Chem Lett 2007;17:5068-71 (Pubitemid 47259667)
96. Blaney JM, Hansch C, Silipo C, et al. Structure-activity relationships of dihydrofolate reductase inhibitors. Chem Rev 1984;84:333-407 (Pubitemid 15184721)
97. Zuccotto F, Martin ACR, Laskowski RA, et al. Dihydrofolate reductase: a potential drug target in trypanosomes and leishmania. J Comput Aided Mol Des 1998;12:241-57 (Pubitemid 128510954)
98. Gangjee A, Lin X, Queener SF. Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substitutedpyrrolo[ 2,3-d]pyrimidines as dihydrofolate reductase inhibitors. J Med Chem 2004;47:3689-92 (Pubitemid 38822029)
99. Rosowsky A, Forsch RA. 2,4-diamino-5- [5'-substituted-benzyl] pyrimidines and 2,4-diamino-6-[5'-substituted-benzyl] quinazolines. WO2004082613A2; 2004
100. Rosowsky A, Forsch RA, Hopkins Sibley C, et al. New 2,4- Rodriguez & Szajnman diamino-5-(2',5'-substituted benzyl) pyrimidines as potential drugs against opportunistic infections of AIDS and other immune disorders. Synthesis and species-dependent antifolate activity. J Med Chem 2004;47:1475-86 (Pubitemid 38327473)
101. Rosowsky A, Forsch RA, Queener SF. Further studies on 2,4-diamino-5- (2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. J Med Chem 2003;46:1726-36 (Pubitemid 36444225)
102. Chan DC, Fu H, Forsch RA, et al. Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy- 1-alkynyl substitution in the side chain. J Med Chem 2005;48:4420-31 (Pubitemid 40884944)
103. Popov VM, Yee WA, Anderson AC. Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity. Proteins 2007;66:375-87 (Pubitemid 46053468)
104. Anderson A, Wright DL, Pelphrey PM, et al. Inhibitors of dihydrofolate reductase with antibacterial, antiprotozoal, antifungal and anticancer properties. WO2009025919A2; 2009
105. Pelphrey PM, Popov VM, Joska TM, et al. Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis. J Med Chem 2007;50:940-50 (Pubitemid 46393997)
106. Gangjee A, Qiu Y, Li W, et al. Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo- 5-arylthio-substituted-6-methylthieno [2,3-d]pyrimidine antifolates. J Med Chem 2008;51:5789-97
107. Johnson EF, Hinz W, Atreya CE, et al. Mechanistic characterization of Toxoplasma gondii thymidylate synthase (TS-DHFR)-dihydrofolate reductase. J Biol Chem 2002;277:43126-36
108. Gangjee A, Li W, Kisliuk RL, et al. Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6- ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. J Med Chem 2009;52:4892-902
109. Gangjee A, Matherly LH. Selective proton coupled folate transporter and folate receptor, and garftase inhibitor compounds and methods of using the same. US20100081676A1; 2010
110. Gangjee A. Substituted pyrrolo[2,3-d] pyrimidines for selectively targeting tumor cells with FR type receptors. US7981902 B2; 2011
111. Deligny M, Saidani N, Bonneau A-L, et al. Compounds with antiparasitic activity, applications thereof to the treatment of infectious diseases caused by apicomplexans. WO2008146172A2; 2008
112. El Kouni MH. Adenosine metabolism in Toxoplasma gondii: potential targets for chemotherapy. Curr Pharm Des 2007;13:581-97
113. Krug EC, Marr JJ, Berens BL. Purine metabolism in Toxoplasma gondii. J Biol Chem 1989;264:10601-7 (Pubitemid 19161629)
114. Schumacher MA, Scott DM, Mathews II, et al. Crystal structure of Toxoplasma gondii reveals a novel catalytic mechanism and prodrug binding. J Mol Biol 2000;298:875-93
115. Mathews II, Erion MD, Ealick SE. Structure of human adenosine kinase at 1.5 A resolution. Biochemistry 1998;37:15607-20 (Pubitemid 28524731)
116. Kim YA, Sharon A, Chu CK, et al. Synthesis, biological evaluation and molecular modelling studies of N6-benzyladenosine analogues as potential toxoplasma agents. Biochem Pharmacol 2007;73:1558-72 (Pubitemid 46527543)
117. Kim YA, Sharon A, Chu CK, et al. Structure-activity relationships of 7-deaza-6-benzylthioinosine analogues as ligands of Toxoplasma gondii adenosine kinase. J Med Chem 2008;51:3934-45 (Pubitemid 351956521)
118. Al Safarjalani ON, Rais RH, Kim YA, et al. 7-Deaza-6-benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities. Biochem Pharmacol 2008;76:958-66
119. Al Safarjalani ON, Rais RH, Kim YA, et al. Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: biological activities and selective toxicities. Biochem Pharmacol 2010;80:955-63
120. Kim YA, Rawal RK, Yoo J, et al. Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase. Bioorg Med Chem 2010;18:3403-12
121. El Kouni MH, Guarcello V, Naguib FNM. Treatment of toxoplasmosis. US5773424; 1998
122. Fichera ME, Roos DS. A plastid organelle as a drug target in apicomplexan parasites. Nature 1997;390:407-9 (Pubitemid 28027322)
123. Baird JK. Drugs therapy: effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565-77
124. Pfefferkorn ER, Borotz SE. Comparison of mutants of Toxoplasma gondii selected for resistance to azithromycin, roxithromycin, spiramycin, or clindamycin. Antimicrob Agents Chemother 1994;38:31-7 (Pubitemid 24018153)
125. Araujo FG, Shepard RM, Remington JS. In vivo activity of the macrolide antibiotics azithromycin, roxithromycin, ans spiramycin against Toxoplasma gondii. Eur J Clin Microbiol 1991;10:519-24
126. Lee Y, Choi JY, Fu H, et al. Chemistry and biology of macrolide antiparasitic agents. J Med Chem 2011;54:2792-804
127. Fichera ME, Bophale MK, Roos DS. In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii. Antimicrob Agents Chemother 1995;39:1530-7
128. Bell A, Monaghan P, Page AP. Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action. Int J Parasitol 2006;36:261-76 (Pubitemid 43376108)
129. Adams B, Musiyenko A, Kumar R, et al. A novel class of dual-family immunophilins. J Biol Chem 2005;280:24308-14 (Pubitemid 40934512)
130. Remington JS, Araujo FG. Treatment for toxoplasmosis with a composition comprising a macrolide antibiotic and aspiropiperidyl derivative of rifamycin S. US5648345; 1997
131. Darkin-Rattray SJ, Gurnett AM, Myers RW, et al. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 1996;93:13143-7 (Pubitemid 26382783)
132. Gissot M, Kelly KA, Ajioka JW, et al. Epigenomic modifications predict active promoters and gene structure in Toxoplasma gondii. PLoS Pathog 2007;3:e77
133. Saksouk N, Bhatti MM, Kieffer S, et al. Histone-modifying complexes regulate gene expression pertinent to the differentiation of the protozoan parasite Toxoplasma gondii. Mol Cell Biol 2005;25:10301-14 (Pubitemid 41681956)
134. Singh SB, Zink DL, Polishook JD, et al. Apicidins: novel cyclic tetrapeptides as coccidiostats and antimalarial agents from fusarium pallidoroseum. Tetrahedron Lett 1996;37:8077-80 (Pubitemid 26366232)
135. Meinke PT, Liberator P. Histone deacetylase: a target for antiproliferative and antiprotozoal agents. Curr Med Chem 2001;8:211-35 (Pubitemid 32416448)
136. Singh SB, Zink DL, Liesch JM, et al. Structure and chemistry of apicidins,a class of novel cyclic tetrapeptides without a terminal alpha-keto epoxide as inhibitors of histone deacetylase with potent antiprotozoal activities. J Org Chem 2002;67:815-25 (Pubitemid 34135683)
137. Singh SB, Zink DL, Liesch JM, et al. Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with praline and valine substitutions. Org Lett 2011;3:2815-18
138. Cannova CL, Dambrowski AW, Goetz MA, et al. Antiprotozoal cyclic tetrapeptides. US5861375; 1999
139. Meinke PT, Schmatz D, Fisher MH, et al. Apicidin-derived cyclic tetrapeptides. WO0107042A1; 2001
140. Liesch JM, Sweely CC, Stafeld GD. Structure of HC-toxin, a cyclic tetrapeptide from Helminthosporium carbonum. Tetrahedron 1982;38:45-8 (Pubitemid 12155708)
141. Mori H, Urano Y, Abe F, et al. FR235222, a fungal metabolite, is a novel immunosuppressant that inhibits mammalian histone deacetylase (HDAC). I. Taxonomy fermentation isolation and biological activities. J Antibiot (Tokyo) 2003;56:72-9 (Pubitemid 36372787)
142. Xie W, Zou B, Pei D, et al. Total synthesis of cyclic tetrapeptide FR235222, a potent immunosuppressant that inhibits mammalian histone deacetylases. Org Lett 2005;7:2775-7 (Pubitemid 43034261)
143. Bougdour A, Maubon D, Baldacci P, et al. Drug inhibition of HDAC3 and epigenetic control of differentiation in apicomplexa parasites. J Exp Med 2009;206:953-66
144. Maubon D, Bougdour A, Wong Y-S, et al. Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. Antimicrob Agents Chemother 2010;54:4843-50
145. Wong Y-S, Hakimi M-A, Bougdour A, et al. Cyclic peptides with anti-parasitic activity. WO2010116985A1; 2010
146. Billker O, Lourido S, Sibley LD. Calcium-dependent signaling and kinases in apicomplexan parasites. Cell Host Microbe 2009;5:612-22
147. Ojo KK, Larson ET, Keyloun KR, et al. Toxoplasma gondii calciumdependent protein kinase 1 is a target for selective kinase inhibitors. Nat Struct Mol Biol 2010;17:602-7
148. Zhang C, Kenski DM, Paulson JL, et al. A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases. Nat Methods 2005;2:435-41 (Pubitemid 40916562)
149. Bishop AC, Kung C-Y, Shah K, et al. Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach. J Am Chem Soc 1999;121:627-31
150. Murphy RC, Ojo KK, Larson ET, et al. Discovery of potent and selective inhibitors of CDPK1 from C. parvum and T. gondii. ACS Med Chem Lett 2010;1:331-5
151. Johnson SM, Murphy RC, Geiger JA, et al. Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. J Med Chem 2012;DOI: 10.1021/jm201713h
152. Van Voorhis WC, Hol WGJ, Larson ET, et al. Composition and methods for treating toxoplasmosis, cryptosporidiosis and other apicomplexan protozoan related diseases. WO2011094628A1; 2011