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DOI: 10.1055/s-0034-1382826
In Vitro and In Vivo Activity of Benzo[c]phenanthridines against Leishmania amazonensis
Publication History
received 03 October 2013
revised 03 June 2014
accepted 05 June 2014
Publication Date:
16 July 2014 (online)
![](https://www.thieme-connect.de/media/plantamedica/201411/lookinside/thumbnails/10.1055-s-0034-1382826-1.jpg)
Abstract
Seven benzo[c]phenanthridines, synthetic or isolated from Zanthoxylum rhoifolium root bark, were evaluated against Leishmania amazonensis axenic amastigotes. Five of them were considered leishmanicidal, with IC50 values ranging from 0.03 to 0.54 µM, and were evaluated on intramacrophagic amastigotes of L. amazonensis. Chelerythrine displayed the best activity (IC50 = 0.5 µM), which was in the same range as the reference compound amphotericin B (IC50 = 0.4 µM). In vivo studies with chelerythrine, avicine, and fagaridine on a model of mice cutaneous leishmaniasis resulted in the identification of fagaridine as the most active compound. Fagaridine decreased the parasitic burden more than 50 % at the 3rd and 6th weeks after the end of treatment.
Key words
leishmaniasis - Leishmania amazonensis - in vitro - in vivo - leishmanicidal - benzo[c]phenanthridines - Zanthoxylum rhoifolium - Rutaceae-
References
- 1 WHO. Leishmaniasis. Available at:. http://www.who.int/leishmaniasis/en/ Accessed: June 3, 2014
- 2 Dorlo TPC, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 2012; 67: 2576-2597
- 3 Santos D, Coutinho CR, Madeira M, Bottino C, Vieira R, Nascimento S, Bernardino A, Bourguignon S, Corte-Real S, Pinho R, Rodrigues C, Castro H. Leishmaniasis treatment–a challenge that remains: a review. Parasitol Res 2008; 103: 1-10
- 4 Mishra BB, Singh RK, Srivastava A, Tripathi VJ, Tiwari VK. Fighting against leishmaniasis: search of alkaloids as future true potential anti-Leishmanial agents. Mini Rev Med Chem 2009; 9: 107-123
- 5 Hammerová J, Uldrijan S, Táborská E, Slaninová I. Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p 53 status. J Dermatol Sci 2011; 62: 22-35
- 6 Bai LP, Zhao ZZ, Cai Z, Jiang ZH. DNA-binding affinities and sequence selectivity of quaternary benzophenanthridine alkaloids sanguinarine, chelerythrine, and nitidine. Bioorg Med Chem 2006; 14: 5439-5445
- 7 Onda T, Toyoda E, Miyazaki O, Seno C, Kagaya S, Okamoto K, Nishikawa K. NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors. Cancer Lett 2008; 259: 99-110
- 8 Fang SD, Wang LK, Hecht SM. Inhibitors of DNA topoisomerase I isolated from the roots of Zanthoxylum nitidum . J Org Chem 1993; 58: 5025-5027
- 9 de A Gonzaga W, Weber AD, Giacomelli SR, Dalcol II, Hoelzel SC, Morel AF. Antibacterial alkaloids from Zanthoxylum rhoifolium . Planta Med 2003; 69: 371-374
- 10 Jullian V, Bourdy G, Georges S, Maurel S, Sauvain M. Validation of use of a traditional antimalarial remedy from French Guiana, Zanthoxylum rhoifolium Lam. J Ethnopharmacol 2006; 106: 348-352
- 11 Bouquet J, Rivaud M, Chevalley S, Deharo E, Jullian V, Valentin A. Biological activities of nitidine, a potential anti-malarial lead compound. Malaria J 2012; 11: 67
- 12 Rivaud M, Mendoza A, Sauvain M, Valentin A, Jullian V. Short synthesis and antimalarial activity of fagaronine. Bioorg Med Chem 2012; 20: 4856-4861
- 13 Acebey L, Jullian V, Sereno D, Chevalley S, Estevez Y, Moulis C, Beck S, Valentin A, Gimenez A, Sauvain M. Antileishmanial lindenane sesquiterpenes from Hedyosmum angustifolium . Planta Med 2010; 76: 365-368
- 14 Fotie J, Bohle DS, Olivier M, Adelaida Gomez M, Nzimiro S. Trypanocidal and antileishmanial dihydrochelerythrine derivatives from Garcinia lucida . J Nat Prod 2007; 70: 1650-1653
- 15 Fuchino H, Kawano M, Mori-Yasumoto K, Sekita S, Satake M, Ishikawa T, Kiuchi F, Kawahara N. In vitro leishmanicidal activity of benzophenanthridine alkaloids from Bocconia pearcei and related compounds. Chem Pharm Bull 2010; 58: 1047-1050
- 16 Arisawa M, Pezzuto JM, Bevelle C, Cordell GA. Potential anticancer agents XXXI. N-demethylation of fagaronine. J Nat Prod 1984; 47: 453-458
- 17 Vermeersch M, da Luz RI, Toté K, Timmermans JP, Cos P, Maes L. In vitro susceptibilities of Leishmania donovani promastigote and amastigote stages to antileishmanial reference drugs: practical relevance of stage-specific differences. Antimicrob Agents Chemother 2009; 53: 3855-3859
- 18 Zhang ZF, Guo Y, Zhang JB, Wei XH. Induction of apoptosis by chelerythrine chloride through mitochondrial pathway and Bcl-2 family proteins in human hepatoma SMMC-7721 cell. Arch Pharm Res 2011; 34: 791-800
- 19 Funakoshi T, Aki T, Nakayama H, Watanuki Y, Imori S, Uemura K. Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine. Toxicol In Vitro 2011; 25: 1581-1587
- 20 Pěnčíková K, Kollár P, Müller Závalová V, Táborská E, Urbanová J, Hošek J. Investigation of sanguinarine and chelerythrine effects on LPS-induced inflammatory gene expression in THP-1 cell line. Phytomedicine 2012; 19: 890-895
- 21 Niu XF, Zhou P, Li WF, Xu HB. Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice. Fitoterapia 2011; 82: 620-625
- 22 Li W, Fan T, Zhang Y, Niu X, Xing W. Effect of chelerythrine against endotoxic shock in mice and its modulation of inflammatory mediators in peritoneal macrophages through the modulation of mitogen-activated protein kinase (MAPK) pathway. Inflammation 2012; 35: 1814-1824
- 23 Houghton PJ, Howes MJ, Lee CC, Steventon G. Uses and abuses of in vitro tests in ethnopharmacology: visualizing an elephant. J Ethnopharmacol 2007; 110: 391-400
- 24 Nakanishi T, Suzuki M, Saimoto A, Kabasawa T. Structural considerations of NK109, an antitumor benzo[c]phenanthridine alkaloid. J Nat Prod 1999; 62: 864-867
- 25 Ishii H, Ishikawa T, Ichikawa YI, Sakamoto M, Ishikawa M, Takahashi T. Studies on the chemical constituents of rutaceous plants. LV. The development of a versatile method for the synthesis of anti-tumour active benzo[c]phenanthridine alkaloids. (5). A new method for the quaternarization of the benzo[c]phenanthridine nucleus. Chem Pharm Bull 1984; 32: 2984-2994
- 26 Marek R, Tousek J, Dostal J, Slavık J, Dommisse R, Sklena V. 1H and 13C NMR study of quaternary benzo[c]phenanthridine alkaloids. Magn Reson Chem 1999; 37: 781-787
- 27 Nakanishi T, Suzuki M. Revision of the structure of fagaridine based on the comparison of UV and NMR data of synthetic compounds. J Nat Prod 1998; 61: 1263-1267
- 28 Sereno D, Lemesre JL. Axenically cultured amastigote forms as an in vitro model for investigation of antileishmanial agents. Antimicrob Agents Chemother 1997; 41: 972-976
- 29 Sauvain M, Dedet JP, Kunesch N, Poisson J, Gayral P, Gantier JC, Kunesch G. In vitro and in vivo leishmanicidal activities of natural and synthetic quinoids. Phytother Res 1993; 7: 167-171
- 30 Castillo D, Arevalo J, Herrera F, Ruiz C, Rojas R, Rengifo E, Vaisberg A, Lock O, Lemesre JL, Gornitza H, Sauvain M. Spirolactone iridoids might be responsible for the antileishmanial activity of a Peruvian traditional remedy made with Himatanthus sucuuba (Apocynaceae). J Ethnopharmacol 2007; 112: 410-414
- 31 Fautz R, Husein B, Hechenberger C. Application of the neutral red assay (NR assay) to monolayer cultures of primary hepatocytes: rapid colorimetric viability determination for the unscheduled DNA synthesis test (UDS). Mutat Res 1991; 253: 173-179
- 32 Sereno D, Lemesre JL. Use of an enzymatic micromethod to quantify amastigote stage of Leishmania amazonensis in vitro . Parasitol Res 1997; 83: 401-403
- 33 Jackson PR, Pappas MG, Hansen BD. Fluorogenic substrate detection of viable intracellular and extracellular pathogenic protozoa. Science 1985; 227: 435-438
- 34 Barreca GS, Matera G, De Majo M, Lamberti A, Liberto MC, Focà A. Early detection of Leishmania promastigotes in dog bone marrow cultures by acridine orange stain. Diagn Microbiol Infect Dis 2000; 37: 247-251