Bile acid-based 1,2,4-trioxanes: Synthesis and antimalarial assessment(1)

Journal of Medicinal Chemistry

Volumn 55, Issue 23, 2012, Pages 10662-10673

  Singh, Chandan ^a   Hassam, Mohammad ^a   Verma, Ved Prakash ^a   Singh, Ajit Shanker ^a   Naikade, Niraj Krishna ^a   Puri, Sunil K ^a   Maulik, Prakas R ^a   Kant, Ruchir ^a  

^a CENTRAL DRUG RESEARCH INSTITUTE   (India)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIOXANE DERIVATIVE; ANTIMALARIAL AGENT; ARTEETHER; BILE ACID;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIASTEREOISOMER; DRUG STRUCTURE; DRUG SYNTHESIS; MALARIA; MOUSE; NONHUMAN; PARASITE CLEARANCE; PARASITEMIA; PLASMODIUM YOELII; STEREOCHEMISTRY;

ANIMALS; ANTIMALARIALS; BILE ACIDS AND SALTS; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, MULTIPLE; HETEROCYCLIC COMPOUNDS; MAGNETIC RESONANCE SPECTROSCOPY; MICE; PLASMODIUM YOELII; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION; SPECTROPHOTOMETRY, INFRARED;

EID: 84871028882     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301323k     Document Type: Article

References (64)

1. W.H.O.: 10 Facts on Malaria. www.who.int/features/factfiles/malaria.
2. Wahlgren, M.; Bejarano, M. T. A blueprint of 'bad air' Nature 1999, 400, 506-507
3. Wellems, T. E.; Plowe, C. V. Chloroquine-Resistant Malaria J. Infect. Dis 2001, 184, 770-776
4. Hastings, I. M. The origins of antimalarial drug resistance Trends Parasitol. 2004, 20, 512-518
5. Ginsburg, H. Should chloroquine be laid to rest? Acta Trop. 2005, 96, 16-23
6. Klayman, D. L. Qinghaosu (artemisinin): An antimalarial drug from China Science 1985, 228, 1049-1055
7. Luo, X. D.; Shen, C. C. The chemistry, pharmacology and clinical applications of qinghaosu (artemisinin) and its derivatives Med. Res. Rev. 1987, 7, 29-52
8. Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Artemisinin and the antimalarial endoperoxides: From herbal remedy to targeted chemotherapy Microbiol. Rev. 1996, 60, 301-315
9. Cumming, J. N.; Ploypradith, P.; Posner, G. H. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes Adv. Pharmacol. 1997, 37, 253-297
10. Bhattacharya, A. K.; Sharma, R. P. Recent developments on the chemistry and biological activity of artemisinin and related antimalarials Heterocycles 1999, 51, 1681-1745
11. Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Antimalarial chemotherapeutic peroxides: Artemisinin, Yingzhaosu A and related compounds Int. J. Parasitol. 2002, 32, 1661-1667
12. Ploypradith, P. Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs Acta Trop. 2004, 89, 329-342
13. O'Neill, P. M.; Posner, G. H. A Medicinal chemistry perspective on artemisinin and related endoperoxides J. Med. Chem. 2004, 47, 2945-2964
14. Tang, Y.; Dong, Y.; Vennerstrom, J. L. Synthetic Peroxides as Antimalarials Med. Res. Rev. 2004, 24, 425-448
15. Jefford, C. W. New development in synthetic peroxidic drugs as artemisinin mimics Drug Discovery Today 2007, 12, 487-494
16. Muraleedharan, K. M.; Avery, M. A. Progress in the development of peroxide-based antiparasitic agents Drug Discovery Today 2009, 14, 793-803
17. Chaturvedi, D.; Goswami, A.; Pratim Saikia, P.; Barua, N. C.; Rao, P. G. Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents Chem. Soc. Rev. 2010, 39, 435-454
18. Dondrop, A. M.; Yeung, S.; White, L.; Nguon, C.; Day, N. P. J.; Socheat, D.; Seidlein, L. V. Artemisinin resistance: current status and scenarios for containment Nature Rev. Microbiol. 2010, 8, 272-280
19. O' Brien, C.; Henrich, P. P.; Passi, N.; Fidlock, D. Recent clinical and molecular insight into emerging artemisinin resistance in Plasmodium falciparum Curr. Opin. Infect. Dis. 2011, 24, 570-577
20. Slack, R. D.; Jacobine, A. M.; Posner, G. P. Antimalarial peroxides: advances in drug discovery and design Med. Chem. Commun. 2012, 3, 281-297
21. Asthana, O. P.; Srivastava, J. S.; Valecha, N. Current status of the artemisinin derivatives in the treatment of malaria with focus on arteether J. Paras. Dis. 1997, 211, 1-12
22. Jambou., R.; Legrand, E.; Niang, M.; Khim, N.; Lim, P.; Volney, B.; Therese Ekala, M.; Bouchier, C.; Esterre, P.; Fandeur, T.; Mercereau-Puijalon, O. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6 Res. Lett. 2005, 366, 1960-1963
23. Singh, C.; Sharma, U.; Saxena, G.; Puri, S. K. Orally active antimalarials: Synthesis and bioevaluation of a new series of steroid-based 1,2,4-trioxanes against multidrug-resistant malaria in mice Bioorg. Med. Chem. Lett. 2007, 17, 4097-4101
24. Todorovic, N. M.; Stefanovic, M.; Tinant, B.; Declercq, J. P.; Makler, M. T.; Solaja, B. A. Steroidal geminal dihydroperoxides and 1,2,4,5-tetraoxanes: Structure determination and their antimalarial activity Steroids 1996, 61, 688-696
25. Opsenica, D.; Pocsfalvi, G.; Juranic, Z.; Tinant, B.; Declercq, J. P.; Kyle, D. E.; Milhous, W. K.; Solaja, B. A. Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: Structure and antimalarial and antiproliferative activity J. Med. Chem. 2000, 43, 3274-3282
26. Solaja, B. A.; Terzic, N.; Pocsfalvi, G.; Gerena, L.; Tinant, B.; Opsenica, D.; Milhous, W. K. Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity J. Med. Chem. 2002, 45, 3331-3336
27. Opsenica, D.; Angelovski, G.; Pocsfalvi, G.; Juranic, Z.; Zizak, Z.; Kyle, D.; Milhous, W. K.; Solaja, B. A. Antimalarial and antiproliferative evaluation of bis-steroidal tetraoxanes Bioorg. Med. Chem. 2003, 11, 2761-2768
28. Opsenica, D.; Kyle, E.; Milhous, W. K.; Solaja, B. A. Antimalarial, antimycobacterial and antiproliferative activity of phenyl substituted mixed tetraoxanes J. Serb. Chem. Soc. 2003, 68, 291-302
29. Terzic, N.; Opsenica, D.; Milic, D.; Tinant, B.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. Deoxycholic acid-derived tetraoxane antimalarials and antiproliferatives J. Med. Chem. 2007, 50, 5118-5127
30. Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Synthesis of in vivo potent antimalarial 1,2,4-trioxanes Bioorg. Med. Chem. Lett. 1992, 2, 497-500
31. Singh, C.; Misra, D.; Saxena, G.; Chandra, S. In vivo potent antimalarial 1,2,4-trioxanes: Synthesis and activity of 8-(α -arylvinyl)-6,7,10- trioxaspiro[4,5]decanes and 3-(α -arylvinyl)-1,2,5-trioxaspiro[5,5] undecanes against Plasmodium berghei in mice Bioorg. Med. Chem. Lett. 1995, 5, 1913-1916
32. Singh, C.; Gupta, N.; Puri, S. K. Geraniol-derived 1,2,4-trioxanes with potent in vivo antimalarial activity Bioorg. Med. Chem. Lett. 2003, 13, 3447-3450
33. Singh, C.; Malik, H.; Puri, S. K. Synthesis and antimalarial activity of a new series of trioxaquines Bioorg. Med. Chem. 2004, 12, 1177-1182
34. Singh, C.; Gupta, N.; Puri, S. K. Synthesis of new 6-alkylvinyl/ arylalkylvinyl substituted 1,2,4-trioxanes active against multidrugresistant malaria in mice Bioorg. Med. Chem. 2004, 12, 5553-5562
35. Singh, C.; Srivastava, N. C.; Puri, S. K. Synthesis and antimalarial activity of 6-cycloalkylvinyl substituted 1,2,4-trioxanes Bioorg. Med. Chem. 2004, 12, 5745-5752
36. Singh, C.; Malik, H.; Puri, S. K. New orally active spiro 1,2,4-trioxanes with high antimalarial potency Bioorg. Med. Chem. Lett. 2005, 15, 4484-4487
37. Singh, C.; Malik, H.; Puri, S. K. Orally active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5,5]undecanes against multidrug-resistant Plasmodium yoelii nigeriensis in mice J. Med. Chem. 2006, 49, 2794-2803
38. Singh, C.; Verma, V. P.; Naikade, N. K.; Singh, A. S.; Hassam, M.; Puri, S. K. Novel bis- and tris-1,2,4-trioxanes: synthesis and antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice J. Med. Chem. 2008, 51, 7581-7592
39. Singh, C.; Hassam, M.; Naikade, N. K.; Verma, V. P.; Singh, A. S.; Puri, S. K. J. Med. Chem. 2010, 53, 7587-7598
40. Payne, G. B. Tungstic acid catalyzed hydroxylation of cyclohexene in nonaqueous media J. Org. Chem. 1957, 22, 1682-1685
41. Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S. Reaction of bicyclic endoperoxides with carbonyl compounds. A new approach to 1,2,4-trioxanes J. Am. Chem. Soc. 1983, 105, 6497-6498
42. Kepler, J. A.; Philip, A.; Lee, Y. W.; Morey, M. C.; Caroll, F. I. 1,2,4- Trioxanes as potential antimalarial agents J. Med. Chem. 1988, 31, 713-716
43. Avery, M. A.; Chong, W. K. M.; Detre, G. Synthesis of (+)-8a, 9-secoartemisinin and related analogues Tetrahedron Lett. 1990, 31, 1799-1802
44. Bunnelle, W. H.; Isbell, T. A.; Barnes, C. L.; Qualls, S. Cationic ring expansion of an ozonide to a 1,2,4-trioxane J. Am. Chem. Soc. 1991, 113, 8168-8169
45. Posner, G. H.; Milhous, W. K. Olefin oxidative cleavage and dioxetane formation using triethylsilyl hydrotrioxide: applications to preparation of potential antimalarial 1,2,4-trioxanes Tetrahedron Lett. 1991, 32, 4235-4238
46. Bloodworth, A. J.; Shah, A. Synthesis of 1,2,4-trioxanes via intramolecular oxymercuration J. Chem. Soc., Chem. Commun. 1991, 947-948
47. Bloodwarth, A. J.; Johnson, K. A. 6-Hydroxymethyl-1,2,4-trioxanes and derivatives: an alternative 1,2,4-trioxane synthesis from β'γ' -unsaturated β -hydroxyhydroperoxides Tetrahedron Lett. 1994, 35, 8057-8060
48. O'Neill, P. M.; Pugh, M.; Davies, J.; Ward, S. A.; Park, B. K. Regioselective Mukaiyama hydroperoxysilylation of 2-alkyl-or 2-aryl-prop-2-en-1-ols: application to a new synthesis of 1,2,4-trioxanes Tetrahedron Lett. 2001, 42, 4569-4571
49. O'Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.; Bachi, M. D.; Stocks, P. A. Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore Org. Lett. 2004, 6, 3035-3038
50. Bartoschek, A.; El-Idreesy, T. T.; Griesbeck, A. G.; Höinck, L.; Lex, J.; Miara, C.; Neudörfl, J. M. A family of new 1,2,4-trioxanes by photooxygenation of allylic alcohols in sensitizerdoped polymers and secondary reactions Synthesis 2005, 2433-2444
51. Griesbeck, A. G.; Blunk, D.; El-Idreesy, T.; Raabe, A. Bicyclic peroxides and perorthoester with 1,2,4-trioxane structures Angew. Chem., Int. Ed. 2007, 46, 8883-8886
52. Ramirez, A. P.; Thomas, A. M.; Woerpel, K. A. Preparation of bicyclic 1,2,4-trioxanes from γ, δ-unsaturated ketones Org. Lett. 2009, 11, 507-510
53. Griesbeck, A. G.; Neudörfl, J.; Hörauf, A.; Specht, S.; Raabe, A. Antimalarial peroxide dyads from natural artemisinin and hydroxyalkylated 1,2,4-trioxanes J. Med. Chem. 2009, 52, 3420-3423
54. Putz, G.; Schmider, W.; Nitschke, R.; Kurz, G.; Blum, H. E. Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes J. Lipid Res. 2005, 46, 2325-2338
55. 2]-enriched bile salts as NMR probes of protein-ligand interaction J. Org. Chem. 2002, 67, 6764-6771
56. Lemos, T. L. G.; McChesney, J. D. Utilization of common natural products as synthons: Preparation of progesterone from lithocholic acid J. Nat. Prod. 1990, 53, 152-156
57. 4-steroids over a palladium-calcium carbonate catalyst J. Chem. Soc.(C) 1967, 2467-2469
58. Singh, C. Preparation of β -hydroxyhydroperoxides by photooxygenation of allylic alcohols and their elaboration into 1,2,4-trioxanes Tetrahedron Lett. 1990, 31, 6901-6902
59. Singh, C.; Gupta, N.; Puri, S. K. Photooxygenation of 3-aryl-2-cyclohexenols: Synthesis of a new series of antimalarial 1,2,4-trioxanes Tetrahedron Lett. 2005, 46, 205-207
60. Peters, W. Techniques for the study of drug response in experimental malaria. In Chemotherapy and drug resistance in malaria; Academic Press: London, 1970; pp 64-136.
61. 6 P. yoelii nigeriensis (MDR) parasites on day zero, and treatment was administered to a group of five mice at each dose, from day 0 to 3, in two divided doses daily. The drug dilutions of compounds 23a-d, 24a-d, 25a-d, 26a, 26b and 26d were prepared in groundnut oil so as to contain the required amount of the drug (1.2 mg for a dose of 96 mg/kg, 0.6 mg for a dose of 48 mg/kg, 0.3 mg for a dose of 24 mg/kg and 0.15 mg for a dose of 12 mg/kg) in 0.1 mL and administered orally for each dose. Parasitaemia level were recorded from thin blood smears on day 4 and subsequently twice a week till day 28. The animals which did not develop patent infection till day 28 were recorded as cured.(17) Mice treated with β -arteether served as positive control.
62. 100% protection means none of the treated mice developed patent infection during the 28 days observation period and hence were recorded as cured. Similarly, 20% protection means only one out of five mice was cured.
63. 100% suppression of parasitemia means no parasites were detected in 50 oil immersion microscopic fields (parasites if at all present are below the detection limit). The parasites present below the detection limit can multiply and eventually can be detected during observation on subsequent days. In such cases, though, the drug is providing near 100% suppression of the parasitaemia on day 4 but will not provide full protection to the treated mice in the 28 day survival assay. Multidrug-resistant Plasmodium yoelii nigeriensis used in this study is resistant to chloroquine, mefloquine, and halofantrine.
64. Puri, S. K.; Singh, N. Azithromycin: antimalarial profile against blood and sporozoite-induced infections in mice and monkeys Expl. Parasitol. 2000, 94, 8-14