A new class of antimalarial dioxanes obtained through a simple two-step synthetic approach: Rational design and structure-activity relationship studies

Journal of Medicinal Chemistry

Volumn 54, Issue 24, 2011, Pages 8526-8540

  Persico, Marco ^a,e   Quintavalla, Arianna ^b   Rondom, Francesca ^a,e   Trombini, Claudio ^b   Lombardo, Marco ^b   Fattorusso, Caterina ^a,e   Azzarito, Valeria ^d   Taramelli, Donatella ^c,e   Parapini, Silvia ^c,e   Corbett, Yolanda ^c,e   Chianese, Giuseppina ^a,e   Fattorusso, Ernesto ^a,e   Taglialatela Scafati, Orazio ^a,e  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c UNIVERSITY OF MILAN   (Italy)

^d UNIVERSITY OF LEEDS   (United Kingdom)

^e UNIVERSITY OF TURIN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; CHLOROQUINE; DIOXANE DERIVATIVE;

ANTIMALARIAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG MECHANISM; HUMAN; HUMAN CELL; PHARMACOPHORE; PLASMODIUM FALCIPARUM; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

ANTIMALARIALS; CELL LINE; CHLOROQUINE; DIOXANES; DRUG DESIGN; DRUG RESISTANCE; ENDOTHELIAL CELLS; FERROUS COMPOUNDS; MICROVESSELS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PARASITIC SENSITIVITY TESTS; PLASMODIUM FALCIPARUM; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84055211802     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201056j     Document Type: Article

References (71)

1. Wells, T. N. C. Natural products as starting points for future anti-malarial therapies: going back to our roots? Malaria J. 2011, 10, S1-S3.
2. Arav-Boger, R.; Shapiro, T. A. Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 565-585.
3. Li, Q.; Hickman, M. Toxicokinetic and toxicodynamic (TK/TD) evaluation to determine and predict the neurotoxicity of artemisinins. Toxicology 2011, 279, 1-9.
4. Dondorp, A. M.; Yeung, S.; White, L.; Nguon, C.; Day, N. P. J.; Socheat, D.; von Seidlein, L. Artemisinin resistance: current status and scenarios for containment. Nat. Rev. Microbiol. 2010, 8, 272-280.
5. Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro, A. Metabolites from the sponge Plakortis simplex. Determination of absolute stereochemistry of Plakortin. Isolation and stereostructure of three Plakortin related compounds. Tetrahedron 1999, 55, 7045-7056.
6. Fattorusso, E.; Parapini, S.; Campagnuolo, C.; Basilico, N.; Taglialatela-Scafati, O.; Taramelli, D. Activity against Plasmodium falciparum of cycloperoxide compounds obtained from the sponge Plakortis simplex. J. Antimicrob. Chemother. 2002, 50, 883-888.
7. Campagnuolo, C.; Fattorusso, E.; Romano, A.; Taglialatela-Scafati, O.; Basilico, N.; Parapini, S.; Taramelli, D. Antimalarial polyketide cycloperoxides from the marine sponge Plakortis simplex. Eur. J. Org. Chem. 2005, 5077-5083.
8. Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro, A.; Di Rosa, M. Metabolites from the sponge Plakortis simplex. Part 3: Isolation and stereostructure of novel bioactive cycloperoxides and diol analogues. Tetrahedron 2000, 56, 7959-7967.
9. Fattorusso, C.; Campiani, G.; Catalanotti, B.; Persico, M.; Basilico, N.; Parapini, S.; Taramelli, D.; Campagnuolo, C.; Fattorusso, E.; Romano, A.; Taglialatela-Scafati, O. Endoperoxide derivatives from marine organisms: 1,2-dioxanes of the plakortin family as novel antimalarial agents. J. Med. Chem. 2006, 49, 7088-7094.
10. Haynes, R. K.; Chan, W.-C.; Wong, H.-N.; Li, K.-Y.; Wu, W.-K.; Fan, K.-M.; Sung, H. H. Y.; Williams, I. D.; Prosperi, D.; Melato, S.; Coghi, P.; Monti, D. Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: relationship with flavoenzyme function and antimalarial mechanism of action. ChemMedChem 2010, 5, 1282-1299.
11. Mercer, A. E.; Copple, I. M.; Maggs, J. L.; O'Neill, P. M.; Park, B. K. The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials. J. Biol. Chem. 2011, 286, 987-996.
12. O'Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47, 2945-2964.
13. Posner, G. H.; O'Neill, P. M. Knowledge of the proposed chemical mechanism of action and cytochrome P450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. Acc. Chem. Res. 2004, 37, 379-404.
14. Taglialatela-Scafati, O.; Fattorusso, E.; Romano, A.; Scala, F.; Barone, V.; Cimino, P.; Stendardo, E.; Catalanotti, B.; Persico, M.; Fattorusso, C. Insight into the mechanism of action of plakortins, simple 1,2-dioxane antimalarials. Org. Biomol. Chem. 2010, 8, 846-856.
15. Robert, A.; Benoit-Vical, F.; Meunier, B. The key role of heme to trigger the antimalarial activity of trioxanes. Coord. Chem. Rev. 2005, 249, 1927-1936.
16. Fattorusso, C.; Persico, M.; Calcinai, B.; Cerrano, C.; Parapini, S.; Taramelli, D.; Novellino, E.; Romano, A.; Scala, F.; Fattorusso, E.; Taglialatela-Scafati, O. Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials. J. Nat. Prod. 2010, 73, 1138-1145.
17. Fattorusso, C.; Persico, M.; Basilico, N.; Taramelli, D.; Fattorusso, E.; Scala, F.; Taglialatela-Scafati, O. Antimalarials based on the dioxane scaffold of plakortin. A concise synthesis and SAR studies. Bioorg. Med. Chem. 2011, 19, 312-320.
18. MMV: Medicines for Malaria Venture. http://www.mmv.org.
19. Dembitsky, V. M. Bioactive peroxides as potential therapeutic agents. Eur. J. Med. Chem. 2008, 43, 223-251.
20. Tang, Y.; Dong, Y.; Vennerstrom, J. L. Synthetic peroxides as antimalarials. Med. Res. Rev. 2004, 24, 425-448.
21. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C. K.; 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.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 2004, 430, 900-904.
22. Singh, C.; Hassam, M.; Naikade, N. K.; Verma, V. P.; Singh, A. S.; Puri, S. K. Synthesis and antimalarial assessment of a new series of orally active amino-functionalized spiro 1,2,4-trioxanes. J. Med. Chem. 2010, 53, 7587-7598.
23. Bousejra-El Garah, F.; Claparols, C.; Benoit-Vical, F.; Meunier, B.; Robert, A. The antimalarial trioxaquine DU1301 alkylates heme in malaria-infected mice. Antimicrob. Agents Chemother. 2008, 52, 2966-2969.
24. O'Neill, P. M.; Amewu, R. K.; Nixon, G. L.; Bousejra ElGarah, F.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA 182) with superior properties to the semisynthetic artemisinins. Angew. Chem., Int. Ed. 2010, 49, 5693-5697.
25. Dong, Y.; McCullough, K. J.; Wittlin, S.; Chollet, J.; Vennerstrom, J. L. The structure and antimalarial activity of dispiro-1,2,4,5-tetraoxanes derived from (+)-dihydrocarvone. Bioorg. Med. Chem. Lett. 2010, 20, 6359-6361.
26. Muraleedharan, K. M.; Mitchell, A. A. Progress in the development of peroxide-based anti-parasitic agents. Drug Discovery Today 2009, 14, 793-803.
27. Watts, K. R.; Tenney, K.; Crews, P. The structural diversity and promise of antiparasitic marine invertebrate-derived small molecules. Curr. Opin. Biotechnol. 2010, 21, 808-818.
28. Fattorusso, E.; Taglialatela-Scafati, O. Marine antimalarials. Mar. Drugs 2009, 7, 130-152.
29. Tategami, S.; Yamada, T.; Nishino, H.; Korp, J. D.; Kurosawa, K. Formation of 1,2-dioxacyclohexanes by the reaction of alkenes with tris(2,4-pentanedionato)manganese(III) or with β-ketocarbonyl compounds in the presence of manganese(III) acetate. Tetrahedron Lett. 1990, 31, 6371-6374.
30. Yoshida, J.; Nakatani, S.; Sakaguchi, K.; Isoe, S. Formal [2 + 2 + 2] cycloaddition of molecular oxygen, 1,3-diketone, and olefin. Synthesis and reactions of cyclic peroxides. J. Org. Chem. 1989, 54, 3383-3389.
31. Nishino, H. Manganese(III)-based peroxidation of alkenes to heterocycles. Top. Heterocycl. Chem. 2006, 6, 39-76.
32. (a) Snider, B. B. Manganese(III)-based oxidative free-radical cyclizations. Chem. Rev. 1996, 96, 339-363.
33. (b) Linker, T. Selective reactions of transition-metal-generated radicals. J. Organomet. Chem. 2002, 661, 159-167.
34. Posner, G. H.; O'Dowd, H.; Ploypradith, P.; Cumming, J. N.; Xie, S.; Shapiro, T. A. Antimalarial cyclic peroxy ketals. J. Med. Chem. 1998, 41, 2164-2167.
35. Donkers, R. L.; Workentin, M. S. Elucidation of the electron transfer reduction mechanism of anthracene endoperoxides. J. Am. Chem. Soc. 2004, 126, 1688-1698.
36. (a) Arantes, C.; de Araujo, M. T.; Taranto, A. G.; Carneiro, J. W. D. Relative stability of radicals derived from artemisinin: a semiempirical and DFT study. Int. J. Quantum Chem. 2005, 103, 749-762.
37. (b) Drew, M. G. B.; Metcalfe, J.; Dascombe, M. J.; Ismail, F. M. D. De novo identification and stability of the artemisinin pharmacophore: studies of the reductive decomposition of deoxyartemisinins and deoxyarteethers and the implications for the mode of antimalarial action. J. Mol. Struct.: THEOCHEM 2007, 823, 34-46.
38. (a) Posner, G. H.; Wang, D.; Cumming, J. N.; Oh, C. H.; French, A. N.; Bodley, A. L.; Shapiro, T. A. Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin. J. Med. Chem. 1995, 38, 2273-2275.
39. (b) Robert, A.; Benoit-Vical, F.; Dechy-Cabaret, O.; Meunier, B. From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin. Pure Appl. Chem. 2001, 73, 1173-1188.
40. Kawanishi, M.; Kotoku, N.; Itagaki, S.; Horii, T.; Kobayashi, M. Structure-activity relationship of anti-malarial spongean peroxides having a 3-methoxy-1,2-dioxane structure. Bioorg. Med. Chem. 2004, 12, 5297-5307.
41. Posner, G. H.; Oh, C. H.; Wang, D.; Gerena, L.; Milhous, W. K.; Meshnick, S. R.; Asawamahasadka, W. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activity. J. Med. Chem. 1994, 37, 1256-1258.
42. Jefford, C. W. Why artemisinin and certain synthetic peroxides are potent antimalarials. Implications for the mode of action. Curr. Med. Chem. 2001, 8, 1803-1826.
43. (a) Galasso, V.; Kovac, B.; Modellic, A. Theoretical and experimental study on the molecular and electronic structures of artemisinin and related drug molecules. Chem. Phys. 2007, 335, 141-154.
44. (b) Gu, J.; Chen, K.; Jiang, H.; Ji, R. DFT study of artemisinin and 1,2,4-trioxane. J. Mol. Struct.: THEOCHEM 1999, 459, 103-111.
45. (c) Thomson, C.; Cory, M.; Zerner, M. Theoretical studies of some new anti-malarial drugs. Int. J. Quantum Chem. 1991, 40, 231-245.
46. Haynes, R. K.; Vonwiller, S. C. The behaviour of qinghaosu (artemisinin) in the presence of non-heme iron(II) and (III). Tetrahedron Lett. 1996, 37, 257-260.
47. Avery, M. A.; Gao, F. L.; Chong, W. K. M.; Hendrickson, T. F.; Inman, W. D.; Crews, P. Synthesis, conformational analysis, and antimalarial activity of tricyclic analogs of artemisinin. Tetrahedron 1994, 50, 957-972.
48. Maple, J. R.; Hwang, M. J.; Stockfisch, T. P.; Dinur, U.; Waldman, M.; Ewig, C. S.; Hagler, A. T. Derivation of class II force fields. I. Methodology and quantum force field for the alkyl function group and alkane molecules. J. Comput. Chem. 1994, 15, 162-182.
49. Fletcher, R. Unconstrained Optimization. In Practical Methods of Optimization; John Wiley & Sons: New York, 1980; Vol. 1.
50. Stewart, J. J. P. Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J. Mol. Model. 2007, 13, 1173-1213.
51. MOPAC2009; Stewart Computational Chemistry: Colorado Springs, CO, 2008; http://OpenMOPAC.net.
52. Baker, J. An algorithm for the location of transition states. J. Comput. Chem. 1986, 7, 385-395.
53. Holtje, H. D.; Fattorusso, C. Construction of a model of the Candida albicans lanosterol 14-alpha-demethylase active site using the homology modelling technique. Pharm. Acta Helv. 1998, 72, 271-277.
54. Ding, H. Q.; Karasawa, N.; Goddard, W. A. III. Atomic level simulations on a million particles: the cell multipole method for Coulomb and London non-bond interactions. J. Chem. Phys. 1992, 97, 4309-4315.
55. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.1; Gaussian, Inc.: Wallingford, CT, 2009.
56. Allouche, A. R. A graphical user interface for computational chemistry softwares. J. Comput. Chem. 2011, 32, 174-182.
57. Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648-5652.
58. Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. 1988, B37, 785-789.
59. Frisch, M. J.; Pople, J. A.; Binkley, J. S. Self-consistent molecular orbital methods. 25. Supplementary functions for Gaussian basis sets. J. Chem. Phys. 1984, 80, 3265-3269.
60. Chiodo, S.; Russo, N.; Sicilia, E. Newly developed basis sets for density functional calculations. J. Comput. Chem. 2004, 26, 175-183.
61. Liu, Y.-P. Applications of effective core potentials and density functional theory to the spin states of iron porphyrin. J. Chem. Inf. Comput. Sci. 2001, 41, 22-29.
62. Ruiz, E.; Cirera, J.; Alvarez, S. Spin density distribution in transition metal complexes. Coord. Chem. Rev. 2005, 249, 2469-2660.
63. (a) Peng, C.; Schlegel, H. B. Combining synchronous transit and quasi-Newton methods to find transition states. Isr. J. Chem. 1993, 33, 449-454.
64. (b) Peng, C.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. Using redundant internal coordinates to optimize equilibrium geometries and transition states. J. Comput. Chem. 1996, 17, 49-56.
65. (a) Gonzalez, C.; Schlegel, H. B. An improved algorithm for reaction path following. J. Chem. Phys. 1989, 90, 2154-2161.
66. (b) Gonzalez, C.; Schlegel, H. B. Reaction path following in mass-weighted internal coordinates. J. Phys. Chem. 1990, 94, 5523-5527.
67. Trager, W.; Jensen, J. B. Human malaria parasites in continuous culture. Science 1976, 193, 673-675.
68. (a) Makler, M.; Hinrichs, D. Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. Am. J. Trop. Med. Hyg. 1993, 48, 205-210.
69. (b) Sparatore, A.; Basilico, N.; Parapini, S.; Romeo, S.; Novelli, F.; Sparatore, F.; Taramelli, D. 4-Aminoquinoline quinolizidinyl- and quinolizidinylalkyl-derivatives with antimalarial activity. Bioorg. Med. Chem. 2005, 13, 5338-5345.
70. Ades, E. W.; Candal, F. J.; Swerlick, R. A.; George, V. G.; Summers, S.; Bosse, D. C.; Lawley, T. J. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J. Invest. Dermatol. 1992, 99, 683-690.
71. D'Alessandro, S.; Gelati, M.; Basilico, N.; Parati, E. A.; Haynes, R. K.; Taramelli, D. Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: implications for embryotoxicity. Toxicology 2007, 241, 66-74.