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Antiprotozoal investigation of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Atalantoflavone alters the mitochondrial membrane potential

Published online by Cambridge University Press:  13 February 2019

Layzon Antonio Lemos da Silva ,
Milene Höehr de Moraes ,
Marcus Tullius Scotti ,
Luciana Scotti ,
Rafaela de Jesus Souza ,
Judith L. Nantchouang Ouete ,
Maique Weber Biavatti ,
Mario Steindel  and
Louis Pergaud Sandjo Open the ORCID record for Louis Pergaud Sandjo [Opens in a new window]
Layzon Antonio Lemos da Silva
Affiliation:
Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil
Milene Höehr de Moraes
Affiliation:
Department of Microbiology, Immunology and Parasitology, Universidade Federal de Santa Catarina, 88040-900, Florianópolis-SC, Brazil
Marcus Tullius Scotti
Affiliation:
Post-Graduate Program in Natural and Synthetic Bioactive Products Federal University of Paraíba Cidade Universitária-Castelo Branco III, João Pessoa, PB, Brazil
Luciana Scotti
Affiliation:
Post-Graduate Program in Natural and Synthetic Bioactive Products Federal University of Paraíba Cidade Universitária-Castelo Branco III, João Pessoa, PB, Brazil
Rafaela de Jesus Souza
Affiliation:
Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil
Judith L. Nantchouang Ouete
Affiliation:
Department of Organic Chemistry, University of Yaoundé I, P. O. Box 812, Yaoundé, Cameroon
Maique Weber Biavatti
Affiliation:
Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil
Mario Steindel
Affiliation:
Department of Microbiology, Immunology and Parasitology, Universidade Federal de Santa Catarina, 88040-900, Florianópolis-SC, Brazil
Louis Pergaud Sandjo*
Affiliation:
Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil
*
Author for correspondence: Louis Pergaud Sandjo, E-mail: p.l.sandjo@ufsc.br
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Abstract

The study aims to evaluate the antiprotozoal activities of 20 plant metabolites on Trypanosoma cruzi and Leishmania amazonensis amastigotes. Compounds 1–20 were obtained and identified by using chromatographic and spectroscopic techniques. The antiparasitic assays were performed on the intracellular form of T. cruzi and L. amazonensis using human leukaemic THP-1 cells as the host. The mechanism of action of the most active compounds was explored in silico by molecular docking using T. cruzi trypanothione reductase (TR) as a target, whereas the in vitro studies were performed by enzymatic assay using T. cruzi recombinant TR. In addition, the mitochondrial membrane potential was evaluated by flow cytometry. Two flavonoids, one triterpene and three acetogenins showed from high to moderate trypanocidal activities with IC50 values ranging 3.6–37.2 µm while three of the metabolites were moderately leishmanicidal. The molecular docking study revealed interactions between TR and the most trypanocidal compounds 1 (abyssinone IV) and 2 (atalantoflavone). In contrast, both showed no effect on TR in vitro. For the mitochondrial membrane potential assay, atalantoflavone (2) displayed a dose-dependent depolarization. On the basis of the aforementioned results, this compound's structure could be chemically explored in order to develop more potent trypanocidal derivatives.

Keywords

Antiparasitic evaluationLeishmania amazonensismitochondrial membrane potentialprenylated flavonesTrypanosoma cruzi
Type
Research Article
Information
Parasitology , Volume 146 , Issue 7 , June 2019 , pp. 849 - 856
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Copyright
Copyright © Cambridge University Press 2019 

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References

Abe, F, Nagafuji, S, Okawa, M, Kinjo, J, Akahane, H, Ogura, T, Martinez-Alfaro, MA and Reyes-Chilpa, R (2005) Trypanocidal constituents in plants 5. evaluation of some Mexican plants for their trypanocidal activity and active constituents in the seeds of Persea americana. Biological and Pharmaceutical Bulletin 28, 1314–1317.Google Scholar
Adikaram, NKB, Ewing, DF, Karunaratne, AM and Wijeratne, EMK (1992) Antifungal compounds from immature avocado fruit peel. Phytochemistry 31, 93–96.Google Scholar
Al Musayeib, NM, Mothana, RA, Gamal, AAE, Al-Massarani, SM and Maes, L (2013) In vitro antiprotozoal activity of triterpenoid constituents of Kleinia odora growing in Saudi Arabia. Molecules 18, 9207–9218.Google Scholar
Baell, JB and Nissink, JWM (2017) Seven Year Itch: pan-assay interference compounds (PAINS) in 2017 – utility and limitations. ACS Chemical Biology 13, 36–44.Google Scholar
Borges, A, Cunningham, ML, Tovar, J and Fairlamb, AH (1995) Site-directed mutagenesis of the redox-active cysteines of Trypanosoma cruzi trypanothione reductase. European Journal of Biochemistry 228, 745–752.Google Scholar
Brasil (2010) Ministério da Saúde. Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Assistência Farmacêutica e Insumos Estratégicos. Formulário terapêutico nacional Rename 2010, 2nd edn, Brasília: Ministério da Saúde. Available at http://bvsms.saude.gov.br/bvs/publicacoes/formulario_terapeutico_nacional_2010.pdf.Google Scholar
Cheuka, PM, Mayoka, G, Mutai, P and Chibale, K (2016) The role of natural products in drug discovery and development against neglected tropical diseases. Molecules 22, 58–98.Google Scholar
Da Silva, LAL, Faqueti, LG, Reginatto, FH, Dos Santos, ADC, Barison, A and Biavatti, MW (2015) Phytochemical analysis of Vernonanthura tweedieana and a validated UPLC-PDA method for the quantification of eriodictyol. Brazilian Journal of Pharmacognosy 25, 375–381.Google Scholar
Daina, A, Michielin, O and Zoete, V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports 7, 42717.Google Scholar
Dharmaratne, HRW, Tekwani, BL, Jacob, MR and Nanayakkara, NPD (2012) Anti microbial and antileishmanial active acetogenins from avacado (Persea americana) fruits. Planta Medica 78, P_34.Google Scholar
Djoumessi, AVB, Sandjo, LP, Liermann, JC, Schollmeyer, D, Kuete, V, Rincheval, V, Berhanu, AM, Yeboah, SO, Wafo, P and Ngadjui, BT (2012) Donellanic acids A–C: new cyclopropanic oleanane derivatives from Donella ubanguiensis (Sapotaceae). Tetrahedron 68, 4621–4627.Google Scholar
Feng, T, Wang, RR, Cai, XH, Zheng, YT and Luo, XD (2010) Anti-human immunodeficiency virus-1 constituents of the bark of Poncirus trifoliata. Chemical and Pharmaceutical Bulletin (Tokyo) 58, 971–975.Google Scholar
Fomani, M, Happi, EN, Bisoue, AN, Ndom, JC, Waffo, AFK, Sewald, N and Wansi, JD (2016) Oxidative burst inhibition, cytotoxicity and antibacterial acriquinoline alkaloids from Citrus reticulate (Blanco). Bioorganic & Medicinal Chemistry Letters 26, 306–309.Google Scholar
Fonseca-Silva, F, Inacio, JDF, Canto-Cavalheiro, MM and Almeida-Amaral, EE (2011) Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis. PLoS ONE 6, e14666.Google Scholar
Fru, CG, Sandjo, LP, Kuete, V, Liermann, JC, Schollmeyer, D, Yeboah, SO, Mapitse, R, Abegaz, BM, Ngadjui, BT and Opatz, T (2013) Omphalocarpoidone, a new lanostane-type furano-spiro-γ-lactone from the wood of Tridesmostemon omphalocarpoides Engl.(Sapotaceae). Phytochemistry Letters 6, 676–680.Google Scholar
Goes, GR, Rocha, PS, Diniz, ARS, Aguiar, PHN, Machado, CR and Vieira, LQ (2016) Trypanosoma cruzi needs a signal provided by reactive oxygen species to infect macrophages. PLoS Neglected Tropical Diseases 10, e0004555.Google Scholar
Grecco, SDS, Reimão, JQ, Tempone, AG, Sartorelli, P, Cunha, RLOR, Romoff, P, Ferreira, MJP, Fávero, OA and Lago, JHG (2012) In vitro antileishmanial and antitrypanosomal activities of flavanones from Baccharis retusa DC.(Asteraceae). Experimental parasitology 130, 141–145.Google Scholar
Guedem, AN, Sandjo, LP, Opatz, T, Schollmeyer, D and Ngadjui, BT (2012) (2e, 4R, 5R, 6S)-2-(4, 5, 6-Trihydroxycyclohex-2-en-1-ylidene) acetonitrile. Acta Crystallographica Section E: Structure Reports Online E68, o2737–o2737.Google Scholar
Hamilton, CJ, Saravanamuthu, A, Eggleston, IM and Fairlamb, AH (2003) Ellman's-reagent-mediated regeneration of trypanothione in situ: substrate-economical microplate and time-dependent inhibition assays for trypanothione reductase. Biochemical Journal 369, 529–537.Google Scholar
Izumi, E, Ueda-Nakamura, T, Dias Filho, BP, Júnior, VFV and Nakamura, CV (2011) Natural products and Chagas' disease: a review of plant compounds studied for activity against Trypanosoma cruzi. Natural Product Reports 28, 809–823.Google Scholar
Jain, SK, Sahu, R, Walker, LA and Tekwani, BL (2012) A parasite rescue and transformation assay for antileishmanial screening against intracellular Leishmania donovani amastigotes in THP1 human acute monocytic leukemia cell line. Journal of Visualized Experiments: JoVE 70, 1–14.Google Scholar
Kengap, RT, Kapche, GDWF, Dzoyem, JP, Simo, IK, Ambassa, P, Sandjo, LP, Abegaz, BM and Ngadjui, BT (2011) Isoprenoids and flavonoids with antimicrobial activity from Ficus conraui Warburg (Moraceae). Helvetica Chimica Acta 94, 2231–2238.Google Scholar
Kuete, V, Kamga, J, Sandjo, LP, Ngameni, B, Poumale, HMP, Ambassa, P and Ngadjui, BT (2011) Antimicrobial activities of the methanol extract, fractions and compounds from Ficus polita Vahl. (Moraceae). BMC Complementary and Alternative Medicine 11, 1–6.Google Scholar
Kuete, V, Sandjo, LP, Djeussi, DE, Zeino, M, Kwamou, GMN, Ngadjui, B and Efferth, T (2014) Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells. Investigational New Drugs 32, 1053–1062.Google Scholar
Nagle, AS, Khare, S, Kumar, AB, Supek, F, Buchynskyy, A, Mathison, CJN, Chennamaneni, NK, Pendem, N, Buckner, FS and Gelb, MH (2014) Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chemical Reviews 114, 11305–11347.Google Scholar
Nana, F, Sandjo, LP, Keumedjio, F, Kuete, V and Ngadjui, BT (2012) A new fatty aldol ester from the aerial part of Mimosa invisa (Mimosaceae). Natural Product Research 26, 1831–1836.Google Scholar
Oberlies, NH, Rogers, LL, Martin, JM and McLaughlin, JL (1998) Cytotoxic and insecticidal constituents of the unripe fruit of Persea americana. Journal of Natural Products 61, 781–785.Google Scholar
Persch, E, Bryson, S, Todoroff, NK, Eberle, C, Thelemann, J, Dirdjaja, N, Kaiser, M, Weber, M, Derbani, H and Brun, R (2014) Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase. ChemMedChem 9, 1880–1891.Google Scholar
Pollo, LA, de Moraes, MH, Cisilotto, J, Creczynski-Pasa, TB, Biavatti, MW, Steindel, M and Sandjo, LP (2017) Synthesis and in vitro evaluation of Ca2+ channel blockers 1,4-dihydropyridines analogues against Trypanosoma cruzi and Leishmania amazonensis: SAR analysis. Parasitology International 66, 789–797.Google Scholar
Robledo, SM, Cardona, W, Ligardo, K, Henao, J, Arbeláez, N, Montoya, A, Alzate, F, Pérez, JM, Arango, V and Vélez, ID (2015) Antileishmanial effect of 5,3′-hydroxy-7,4′-dimethoxyflavanone of Picramnia gracilis Tul. (Picramniaceae) fruit: in vitro and in vivo studies. Advances in pharmacological sciences 2015, Article ID 978379, 1–8.Google Scholar
Sandjo, LP, Fru, CG, Kuete, V, Nana, F, Yeboah, SO, Mapitse, R, Abegaz, BM, Efferth, T, Opatz, T and Ngadjui, BT (2014 a) Elatumic acid: a new ursolic acid congener from Omphalocarpum elatum Miers (Sapotaceae). Zeitschrift für Naturforschung 69c, 276–282.Google Scholar
Sandjo, LP, Kuete, V, Tchangna, RS, Efferth, T and Ngadjui, BT (2014 b) Cytotoxic benzophenanthridine and furoquinoline alkaloids from Zanthoxylum buesgenii (Rutaceae). Chemistry Central Journal 8, 1–5.Google Scholar
Sandjo, LP, de Moraes, MH, Kuete, V, Kamdoum, BC, Ngadjui, BT and Steindel, M (2016 a) Individual and combined antiparasitic effect of six plant metabolites against Leishmania amazonensis and Trypanosoma cruzi. Bioorganic & Medicinal Chemistry Letters 26, 1772–1775.Google Scholar
Sandjo, LP, Kuete, V, Siwe, XN, Poumale, HMP and Efferth, T (2016 b) Cytotoxicity of an unprecedented brominated oleanolide and a new furoceramide from the Cameroonian spice, Echinops giganteus. Natural Product Research 30, 2529–2537.Google Scholar
Sousa, PL, da Silva Souza, RO, Tessarolo, LD, Sampaio, TL, Canuto, JA and Martins, AMC (2017) Betulinic acid induces cell death by necrosis in Trypanosoma cruzi. Acta Tropica 174, 72–75.Google Scholar
Tasdemir, D, Kaiser, M, Brun, R, Yardley, V, Schmidt, TJ, Tosun, F and Rüedi, P (2006) Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies. Antimicrobial Agents and Chemotherapy 50, 1352–1364.Google Scholar
Thomsen, R and Christensen, MH (2006) Moldock: a new technique for high-accuracy molecular docking. Journal of Medicinal Chemistry 49, 3315–3321.Google Scholar
Uchiyama, N (2009) Antichagasic activities of natural products against Trypanosoma cruzi. Journal of Health Science 55, 31–39.Google Scholar
WHO (2018 a) Chagas disease (American trypanosomiasis). Retrieved from World Health Organization. Available at http://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis) (Accessed 24 October 2018).Google Scholar
WHO (2018 b) Global Health Observatory (GHO) data, Leishmaniasis – Situation and trends. Retrieved from World Health Organization. Available at http://www.who.int/gho/neglected_diseases/leishmaniasis/en/ (Accessed 24 October 2018).Google Scholar
WHO (2018 c) Leishmaniasis, Epidemiological situation. Retrieved from World Health Organization. Available at http://www.who.int/leishmaniasis/burden/en/ (Accessed 24 October 2018).Google Scholar
Yenesew, A, Induli, M, Derese, S, Midiwo, JO, Heydenreich, M, Peter, MG, Akala, H, Wangui, J, Liyala, P and Waters, NC (2004) Anti-plasmodial flavonoids from the stem bark of Erythrina abyssinica. Phytochemistry 65, 3029–3032.Google Scholar
Zulfiqar, B, Jones, AJ, Sykes, ML, Shelper, TB, Davis, RA and Avery, VM (2017) Screening a natural product-based library against kinetoplastid parasites. Molecules 22, 1715–1733.Google Scholar