Abstract
A series of 11 new N,S-acetal juglone derivatives were synthesized and evaluated against T. cruzi epimastigote forms. These compounds were obtained in good to moderate yields using a microwave irradiation protocol. Among all compounds, two N,S-acetal analogs, showed significant trypanocidal activity. Notably, one compound 11g exhibited selectivity index 10-fold higher than the reference drug benznidazole for epimastigote. The compound 11h was more effective for amastigote forms. Both prototypes exhibited S.I. higher than the benznidazole description. Thus, both compounds proving to be useful candidate molecules to further studies in infected animals.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Antinori S, Galimberti L, Bianco R, Grande R, Galli M, Corbellino M (2017) Chagas disease in Europe: A review for the internist in the globalized world. Eur J Intern Med 43:6–15
Arasoglu T, Mansuroglu B, Derman S, Gumus B, Kocyigit B, Acar T, Kocacaliskan I (2016) Enhancement of antifungal activity of juglone (5-hydroxy-1,4-naphthoquinone) using a poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticle system. J Agric Food Chem 64:7087–7094. https://doi.org/10.1021/acs.jafc.6b03309
Bachega JFR, Navarro MVAS, Bleicher L et al (2009) Systematic structural studies of iron superoxide dismutases from human parasites and a statistical coupling analysis of metal binding specificity. Proteins 77:26–37. https://doi.org/10.1002/prot.22412
Bermudez J, Davies C, Simonazzi A, Real JP, Palma S (2016) Current drug therapy and pharmaceutical challenges for Chagas disease. Acta Trop 156:1–16. https://doi.org/10.1016/j.actatropica.2015.12.017
Bern C (2015) Chagas’ disease. N Engl J Med 373:456–466. https://doi.org/10.1056/NEJMc1510996
Bhargava UC, Westfall BA (1968) Antitumor activity of Juglans nigra (black walnut) extractives. J Pharm Sci 57:1674–1677. https://doi.org/10.1002/jps.2600571009
Blankenfeldt W, Montemartini-Kalisz M, Kalisz HM, Hecht H-J, Nowicki C (2008) Crystal structure of trypanosoma cruzi tyrosine aminotransferase: Substrate specificity is influenced by cofactor binding mode. Protein Science 8:2406–2417. https://doi.org/10.1110/ps.8.11.2406
Bonifazi EL, Ríos-Luci C, León LG, Burton G, Padrón JM, Misico RI (2010) Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol. Bioorg Med Chem 18:2621–2630. https://doi.org/10.1016/j.bmc.2010.02.032
Bonjar GS (2004) Anti-yeast activity of some plants used in traditional herbal medicine of Iran. J Biol Sci 4:212–215
Bonney KM, Luthringer DJ, Kim SA, Garg NJ, Engman DM (2019) Pathology and Pathogenesis of Chagas Heart Disease. Annu Rev Pathol 14:421–447. https://doi.org/10.1146/annurev-pathol-020117-043711
Boveris A, Stoppani AO, Docampo R, Cruz FS (1978) Superoxide anion production and trypanocidal action of naphthoquinones on Trypanosoma cruzi. Comp Biochem Physiol C 61:327–379
Buschiazzo A, Amaya MF, Cremona ML, Frasch AC, Alzari PM (2002) The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis. Mol Cell 10(4):757–768
Cardoso MF, Salomão K, Bombaça AC, da Rocha DR, da Silva FC, Cavaleiro JA, de Castro SL, Ferreira VF (2015) Synthesis and anti-Trypanosoma cruzi activity of new 3-phenylthio-nor-β-lapachone derivatives. Bioorg Med Chem 23:4763–4768. https://doi.org/10.1016/j.bmc.2015.05.039
Carneiro PF, do Nascimento SB, Pinto AV, Pinto Mdo C, Lechuga GC, Santos DO, dos Santos Júnior HM, Resende JA, Bourguignon SC, Ferreira VF (2012) New oxirane derivatives of 1,4-naphthoquinones and their evaluation against T. cruzi epimastigote forms. Bioorg Med Chem 20:4995–5000. https://doi.org/10.1016/j.bmc.2012.06.027
Chen YT, Brinen LS, Kerr ID, Hansell E, Doyle PS, McKerrow JH, Roush WR (2010) In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. PLoS Negl Trop Dis 4:pii: e825. https://doi.org/10.1371/journal.pntd.0000825
Clark AM, Jurgens TM, Hufford CD (1990) Antimicrobial activity of juglone. Phytother Res 4:11–14. https://doi.org/10.1002/ptr.2650040104
Couladouros EA, Plyta ZF, Haroutounian SA, Papageorgiou VP (1997) Efficient synthesis of aminonaphthoquinones and azidobenzohydroquinones: mechanistic Considerations of the Reaction of Hydrazoic Acid with Quinones. An overview. J Org Chem 62:6–10
da Rocha DR, de Souza AC, Resende JA, Santos WC, dos Santos EA, Pessoa C, de Moraes MO, Costa-Lotufo LV, Montenegro RC, Ferreira VF (2011) Synthesis of new 9-hydroxy-α- and 7-hydroxy-β-pyran naphthoquinones and cytotoxicity against cancer cell lines. Org Biomol Chem 9:4315–4322. https://doi.org/10.1039/c1ob05209h
da Rocha DR, de Souza AM, de Souza AC, Castro HC, Rodrigues CR, Menna-Barreto RF, de Castro SL, Ferreira VF (2014) Effect of 9-hydroxy-α- and 7-hydroxy-β-pyran naphthoquinones on Trypanosoma cruzi and structure-activity relationship studies. Med Chem 10:564–570
Dama L, Poul B, Jadhav B (1998) Antimicrobial activity of naphthoquinonic compounds. J Ecotoxicol Environ Monit 8:213–215
Dos Santos PF, Moreira DS, Baba EH, Volpe CMO, Ruiz JC, Romanha AJ, Murta SMF (2016) Molecular characterization of lipoamide dehydrogenase gene in Trypanosoma cruzi populations susceptible and resistant to benznidazole. Exp Parasitol 170:1–9. https://doi.org/10.1016/j.exppara.2016.08.006
Fernandez P, Haouz A, Pereira CA, Aguilar C, Alzari PM (2007) The crystal structure of Trypanosoma cruzi arginine kinase. Proteins 69:209–212. https://doi.org/10.1002/prot.21557
Ferreira SB, Salomão K, de Carvalho da Silva F, Pinto AV, Kaiser CR, Pinto AC, Ferreira VF, de Castro SL (2011) Synthesis and anti-Trypanosoma cruzi activity of β-lapachone analogs. Eur J Med Chem 46:3071–3077. https://doi.org/10.1016/j.ejmech.2011.03.012
Focia PJ, Craig SP, Nieves-Alicea R, Fletterick RJ, Eakin AE (1998) A 1.4 Å Crystal Structure for the Hypoxanthine Phosphoribosyltransferase ofTrypanosomacruzi. Biochemistry 37:15066–15075. https://doi.org/10.1021/bi981052s
Gabelli SB, McLellan JS, Montalvetti A, Oldfield E, Docampo R, Amzel LM (2005) Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: Implications for drug design. Proteins 62(1):80–88. https://doi.org/10.1002/prot.20754
Gilbert S, La Clair JJ, Spargo P, Nargund RP, Totah N (1996) Stereocontrolled Synthesis of (±)-12a-Deoxytetracycline. J Am Chem Soc 118:5304–5305. https://doi.org/10.1021/cr040630+
Hai Y, Dugery RJ, Healy D, Christianson DW (2013) Formiminoglutamase from Trypanosoma cruzi is an arginase-like manganese metalloenzyme. Biochemistry 5:9294–9309. https://doi.org/10.1021/bi401352h
Halgren TA (1996) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 17:490–519. https://doi.org/10.1002/(SICI)1096-987X(199604)17:5/6<490::AID-JCC1>3.0.CO;2-P
Harkiolaki M, Dodson EJ, Bernier-villamor V, Turkenburg JP, González-pacanowska D, Wilson KS (2004) The crystal structure of Trypanosoma cruzi dUTPase reveals a novel dUTP/dUDP binding fold. Structure 12(1):41–53
Izumi E, Ueda-Nakamura T, Dias Filho BP, Veiga Júnior VF, Nakamura CV (2011) Natural products and Chagas disease: a review of plant compounds studied for activity against Trypanosoma cruzi. Nat Prod Rep 28:809–823. https://doi.org/10.1039/c0np00069h
Klotz LO, Hou X, Jacob C (2014) 1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling. Molecules 19:14902–14918. https://doi.org/10.3390/molecules190914902
Kumagai Y, Shinkai Y, Miura T, Cho AK (2012) The chemical biology of naphthoquinones and its environmental implications. Annu Rev Pharmacol Toxicol 52:221–247. https://doi.org/10.1146/annurev-pharmtox-010611-134517
Lantwin CB, Schlichting I, Kabsch W, Pai EF, Krauth-Siegel RL (1994) The structure ofTrypanosoma cruzitrypanothione reductase in the oxidized and NADPH reduced state. Proteins 18:161–173. https://doi.org/10.1002/prot.340180208
Lepesheva GI, Hargrove TY, Anderson S et al (2010) Structural Insights into Inhibition of Sterol 14α-Demethylase in the Human PathogenTrypanosoma cruzi. J Biol Chem 285:25582–22590. https://doi.org/10.1074/jbc.M110.133215
Lopes JN, Cruz FS, Docampo R, Vasconcellos ME, Sampaio MC, Pinto AV, Gilbert B (1978) In vitro and in vivo evaluation of the toxicity of 1,4-naphthoquinone and 1,2-naphthoquinone derivatives against Trypanosoma cruzi. Ann Trop Med Parasitol 72:523–531
Lountos GT, Tropea JE, Waugh DS (2013) Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease. Mol Biochem Parasitol 187:1–8. https://doi.org/10.1016/j.molbiopara.2012.10.006
Maldonado E, Soriano-garcía M, Moreno A et al (1998) Differences in the intersubunit contacts in triosephosphate isomerase from two closely related pathogenic trypanosomes. J Mol Biol 283:193–203
Menna-Barreto RF, Goncalves RL, Costa EM, Silva RS, Pinto AV, Oliveira MF, de Castro SL (2009a) The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction. Free Radic Biol Med 47:644–653. https://doi.org/10.1016/j.freeradbiomed.2009.06.004
Menna-Barreto RF, Salomão K, Dantas AP, Santa-Rita RM, Soares MJ, Barbosa HS, de Castro SL (2009b) Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron 40:157–168. https://doi.org/10.1016/j.micron.2008.08.003
Merritt EA, Arakaki TL, Gillespie JR et al (2010) Crystal Structures of Trypanosomal Histidyl-tRNA Synthetase Illuminate Differences between Eukaryotic and Prokaryotic Homologs. J Mol Biol 397:481–494. https://doi.org/10.1016/j.jmb.2010.01.051
Moen SO, Fairman JW, Barnes SR et al (2015) Structures of prostaglandin F synthase from the protozoaLeishmania majorandTrypanosoma cruziwith NADP. Acta Crystallogr F Struct Biol Commun 71:609–614. https://doi.org/10.1107/S2053230X15006883
Morello A, Pavani M, Garbarino JA, Chamy MC, Frey C, Mancilla J, Guerrero A, Repetto Y, Ferreira J (1995) Effects and mode of action of 1,4-naphthoquinones isolated from Calceolaria sessilis on tumoral cells and Trypanosoma parasites. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 112:119–128
Morgan HP, Zhong W, McNae IW, Michels PAM, Fothergill-Gilmore LA, Walkinshaw MD (2014) Structures of pyruvate kinases display evolutionarily divergent allosteric strategies. R Soc Open Sci 1:140120. https://doi.org/10.1098/rsos.140120
Niemirowicz G, Fernández D, Solà M, Cazzulo JJ, Avilés FX, Gomis-Rüth FX (2008) The molecular analysis ofTrypanosoma cruzimetallocarboxypeptidase 1 provides insight into fold and substrate specificity. Mol Microbiol 70:853–866. https://doi.org/10.1111/j.1365-2958.2008.06444.x
Olmo F, Clares MP, Marín C, Gonzalez J, Inclan M, Soriano C, Urbanova K, Tejero R, Rosales MJ, Krauth-Siegel RL, Sanchez-Moreno M, García-Espana E (2014) Synthetic single and double aza-scorpiand macrocycles acting as inhibitors of the antioxidant enzymes iron superoxide dismutase and trypanothione reductase in Trypanosoma cruzi with promising results in a murine model. RSC Adv 4:65108
Paucar R, Moreno-Viguri E, Pérez-Silanes S (2016) Challenges in chagas disease drug discovery: a review. Curr Med Chem 23:3154–3170
Paulsen MT, Ljungman M (2005) The natural toxin juglone causes degradation of p53 and induces rapid H2AX phosphorylation and cell death in human fibroblasts. Toxicol Appl Pharmacol 209:1–9
Pérez-Molina JA, Molina I (2018) Chagas disease. Lancet 391:82–94. https://doi.org/10.1016/S0140-6736(17)31612-4
Piñeyro MD, Pizarro JC, Lema F, Pritsch O, Cayota A, Bentley GA, Robello C (2005) Crystal structure of the tryparedoxin peroxidase from the human parasite. J Struct Biol 150:11–22. https://doi.org/10.1016/j.jsb.2004.12.005
Pinto AV, de Castro SL (2009) The trypanocidal activity of naphthoquinones: a review. Molecules 14:4570–4590. https://doi.org/10.3390/molecules14114570
Pinto Dias JC (2013) Human chagas disease and migration in the context of globalization: some particular aspects. J Trop Med 2013:789758. https://doi.org/10.1155/2013/789758
Ramos-Junior AN, Sousa AS. The continuous challenge of Chagas disease treatment: bridging evidence-based guidelines, access to healthcare, and human rights. Rev Soc Bras Med Trop. 2017;50:745-747.doi: 10.1590/0037-8682-0495-2017.
Rassi A Jr, Rassi A (2012) Marcondes de Rezende J. American trypanosomiasis (Chagas disease). Infect Dis Clin North Am 26:275–291. https://doi.org/10.1016/j.idc.2012.03.002
Salas CO, Faúndez M, Morello A, Maya JD, Tapia RA (2011a) Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease. Curr Med Chem 18:144–161
Salas CO, Faúndez M, Morello A, Maya JD, Tapia RA (2011b) Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease. Curr Med Chem 18:144–161
Salmon-Chemin L, Buisine E, Yardley V, Kohler S, Debreu MA, Landry V, Sergheraert C, Croft SL, Krauth-Siegel RL (2001) Davioud-Charvet E.2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J Med Chem 44:548–565
Salomão K, De Santana NA, Molina MT, De Castro SL, Menna-Barreto RF (2013) Trypanosoma cruzi mitochondrial swelling and membrane potential collapse as primary evidence of the mode of action of naphthoquinone analogs. BMC Microbiol 13:196. https://doi.org/10.1186/1471-2180-13-196
Schormann N, Senkovich O, Walker K et al (2008) Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function. Proteins 73:889–901. https://doi.org/10.1002/prot.22115
Souza TACB, Trindade DM, Tonoli CCC et al (2011) Molecular adaptability of nucleoside diphosphate kinase b from trypanosomatid parasites: stability, oligomerization and structural determinants of nucleotide binding. Mol Biosyst 7:2189–2195. https://doi.org/10.1039/c0mb00307g
Stern AL, Naworyta A, Cazzulo JJ, Mowbray SL (2011) Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family. FEBS Journal 278:793–808. https://doi.org/10.1111/j.1742-4658.2010.07999.x
Stewart JJ (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13:1173–1213
Sugie S, Okamoto K, Rahman KM, Tanaka T, Kawai K, Yamahara J, Mori H (1998) Inhibitory effects of plumbagin and juglone on azoxymethane- induced intestinal carcinogenesis in rats. Cancer Lett 127:177–183
Tessarolo LD, Menezes RRPPB, Mello CP, Lima DB, Magalhães EP, Bezerra EM, Sales FAM, Neto ILB, Oliveira MF, Santos RP, Albuquerque EL, Freire VN, Martins AM (2018) Nanoencapsulation of benznidazole in calcium carbonate increases its selectivity to Trypanosoma cruzi. Nanoencapsulation of benznidazole in calcium carbonate increases its selectivity to Trypanosoma cruzi. Parasitology 145:1191–1198
Thakur A (2011) Juglone: A therapeutic phytochemical from Juglans regia L. J Med Plants Res 5:5324–5330
Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315–3321. https://doi.org/10.1021/jm051197e
Trapani S, Linss J, Goldenberg S, Fischer H, Craievich AF, Oliva G (2001) Crystal structure of the dimeric phosphoenolpyruvate carboxykinase (PEPCK) from Trypanosoma cruzi at 2 Å resolution. J Mol Biol 313:1059–1072. https://doi.org/10.1006/jmbi.2001.5093
Wang J, Cheng Y, Wu R, Jiang D, Bai B, Tan D, Yan T, Sun X, Zhang Q, Wu Z (2016) Antibacterial activity of Juglone against Staphylococcus aureus: From apparent to proteomic. Int J Mol Sci 17:pii: E965. https://doi.org/10.3390/ijms17060965
Wang J, Liu K, Wang XF, Sun DJ (2017) Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis. Oncol Rep 38:1959–1966. https://doi.org/10.3892/or.2017.5878
Author information
Authors and Affiliations
Corresponding authors
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 16518 kb)
Rights and permissions
About this article
Cite this article
Pacheco, P.A.F., de Menezes Ribeiro, T., dos Santos Galvão, R.M. et al. Synthesis of new N,S-acetal analogs derived from juglone with cytotoxic activity against Trypanossoma cruzi. J Bioenerg Biomembr 52, 199–213 (2020). https://doi.org/10.1007/s10863-020-09834-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-020-09834-8