Abstract
Schistosomiasis is a major public health problem that afflicts more than 240 million individuals globally, particularly in poor communities. Treatment of schistosomiasis relies heavily on a single oral drug, praziquantel, and there is interest in the search for new antischistosomal drugs. This study reports the anthelmintic evaluation of carvacryl acetate, a derivative of the terpene carvacrol, against Schistosoma mansoni ex vivo and in a schistosomiasis animal model harboring either adult (patent infection) or juvenile (prepatent infection) parasites. For comparison, data obtained with gold standard antischistosomal drug praziquantel are also presented. Initially in vitro effective concentrations of 50% (EC50) and 90% (EC90) were determined against larval and adult stages of S. mansoni. In an animal with patent infection, a single oral dose of carvacryl acetate (100, 200, or 400 mg/kg) caused a significant reduction in worm burden (30–40%). S. mansoni egg production, a process responsible for both life cycle and pathogenesis, was also markedly reduced (70–80%). Similar to praziquantel, carvacryl acetate 400 mg/kg had low efficacy in pre-patent infection. In tandem, although carvacryl acetate had interesting in vitro schistosomicidal activity, the compound exhibited low efficacy in terms of reduction of worm load in S. mansoni-infected mice.
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References
Alvarenga EM, Sousa NA, de Araújo S, Júnior JLP, Araújo AR, Iles B, Pacífico DM, Brito GAC, Souza EP, Sousa DP, Medeiros JVR (2017) Carvacryl acetate, a novel semisynthetic monoterpene ester, binds to the TRPA1 receptor and is effective in attenuating irinotecan-induced intestinal mucositis in mice. J Pharm Pharmacol 69:1773–1785. https://doi.org/10.1111/jphp.12818
Amorim CR, Pavani TFA, Lopes AFS, Duque MD, Mengarda ACA, Silva MP, de Moraes J, Rando DGG (2020) Schiff bases of 4-phenyl-2-aminothiazoles as hits to new antischistosomals: synthesis, in vitro, in vivo and in silico studies. Eur J Pharm Sci 150:105371. https://doi.org/10.1016/j.ejps.2020.105371
André WPP, Paiva Junior JR, Cavalcante GS, Ribeiro WLC, Araújo Filho JV, Santos JMLD, Alves APNN, Monteiro JP, Morais SM, Silva INGD, Oliveira LMB, Abreu FOMDS, Bevilaqua CML (2020) Anthelmintic activity of nanoencapsulated carvacryl acetate against gastrointestinal nematodes of sheep and its toxicity in rodents. Rev Bras Parasitol Vet 29:e013119. https://doi.org/10.1590/S1984-29612019098
André WP, Ribeiro WL, Cavalcante GS, dos Santos JM, Macedo IT, de Paula HC, de Freitas RM, de Morais SM, de Melo JV, Bevilaqua CM (2016) Comparative efficacy and toxic effects of carvacryl acetate and carvacrol on sheep gastrointestinal nematodes and mice. Vet Parasitolol 218:52–58. https://doi.org/10.1016/j.vetpar.2016.01.001
Bergquist R, Elmorshedy H (2018) Artemether and praziquantel: origin, mode of action, impact, and suggested application for effective control of human schistosomiasis. Trop Med Infect Dis 3:1–13. https://doi.org/10.3390/tropicalmed3040125
Campelo YDM, Mafud AC, Véras LMC, Guimarães MA, Yamaguchi LF, Lima DF, Arcanjo DDR, Kato MJ, Mendonça RZ, Pinto PLS, Mascarenhas YP, Silva MPN, de Moraes J, Eaton P, de Souza de Almeida Leite JR, (2017) Synergistic effects of in vitro combinations of piplartine, epiisopiloturine and praziquantel against Schistosoma mansoni. Biome Pharmacother 88:488–499. https://doi.org/10.1016/j.biopha.2016.12.057
Cioli D, Pica-Mattoccia L, Basso A, Guidi A (2014) Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol 195:23–29. https://doi.org/10.1016/j.molbiopara.2014.06.002
Colley DG, Bustinduy AL, Secor WE, King CH (2014) Human schistosomiasis. Lancet 383:2253–2264. https://doi.org/10.1016/S0140-6736(13)61949-2
Colley DG, Secor WE (2014) Immunology of human schistosomiasis. Parasite Immunol 36:347–357. https://doi.org/10.1111/pim.12087
Damasceno SR, Oliveira FR, Carvalho NS, Brito CF, Silva IS, Sousa FB, Silva RO, Sousa DP, Barbosa AL, Freitas RM, Medeiros JV (2014) Carvacryl acetate, a derivative of carvacrol, reduces nociceptive and inflammatory response in mice. Life Sci 94:58–66. https://doi.org/10.1016/j.lfs.2013.11.001
de Almeida LM, de Carvalho LS, Gazolla MC, Silva Pinto PL, da Silva MP, de Moraes J, Da Silva Filho AA (2016) Flavonoids and sesquiterpene lactones from Artemisia absinthium and Tanacetum parthenium against Schistosoma mansoni worms. Evid Based Complement Alternat Med 2016:9521349. https://doi.org/10.1155/2016/9521349
de Brito MG, Mengarda AC, Oliveira GL, Cirino ME, Silva TC, de Oliveira RN, Allegretti SM, de Moraes J (2020) Therapeutic effect of diminazene aceturate on parasitic blood fluke Schistosoma mansoni infection. Antimicrob Agents Chemother 64:e01372-e1420. https://doi.org/10.1128/AAC.01372-20
de Moraes J (2015) Natural products with antischistosomal activity. Future Med Chem 7:801–820. https://doi.org/10.4155/fmc.15.23
de Moraes J, Carvalho AA, Nakano E, de Almeida AA, Marques TH, Andrade LN, de Freitas RM, de Sousa DP (2013a) Anthelmintic activity of carvacryl acetate against Schistosoma mansoni. Parasitol Res 112:603–610. https://doi.org/10.1007/s00436-012-3172-7
de Moraes J, Dario BS, Couto RA, Pinto PL, da Costa Ferreira AM (2015) Antischistosomal activity of oxindolimine-metal complexes. Antimicrob Agents Chemother 59:6648–6652. https://doi.org/10.1128/AAC.01371-15
de Moraes J, Keiser J, Ingram K, Nascimento C, Yamaguchi LF, Bittencourt CR, Bemquerer MP, Leite JR, Kato MJ, Nakano E (2013b) In vitro synergistic interaction between amide piplartine and antimicrobial peptide dermaseptin against Schistosoma mansoni schistosomula and adult worms. Curr Med Chem 20:301–309. https://doi.org/10.2174/092986713804806694
de Moraes J, Nascimento C, Yamaguchi LF, Kato MJ, Nakano E (2012) Schistosoma mansoni: in vitro schistosomicidal activity and tegumental alterations induced by piplartine on schistosomula. Exp Parasitol 132:222–227. https://doi.org/10.1016/j.exppara.2012.07.004
Dias MM, Zuza O, Riani LR, de Faria PP, Pinto PLS, Silva MP, de Moraes J, Ataíde ACZ, de Oliveira SF, Cecílio AB, Da Silva Filho AA (2017) In vitro schistosomicidal and antiviral activities of Arctium lappa L. (Asteraceae) against Schistosoma mansoni and herpes simplex virus-1. Biomed Pharmacother 94:489–498. https://doi.org/10.1016/j.biopha.2017.07.116
Guerra RA, Silva MP, Silva TC, Salvadori MC, Teixeira FS, de Oliveira RN, Rocha JA, Pinto PLS, de Moraes J (2019) In vitro and in vivo studies of spironolactone as an antischistosomal drug capable of clinical repurposing. Antimicrob Agents Chemother 63:e01722-e1818. https://doi.org/10.1128/AAC.01722-18
Guimarães MA, de Oliveira RN, de Almeida RL, Mafud AC, Sarkis ALV, Ganassin R, da Silva MP, Roquini DB, Veras LM, Sawada TCH, Ropke CD, Muehlmann LA, Joanitti GA, Kuckelhaus SAS, Allegretti SM, Mascarenhas YP, de Moraes J, Leite JRSA (2018) Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity. PLoS ONE 13:e0196667. https://doi.org/10.1371/journal.pone.0196667
Keiser J, Koch V, Deckers A, Cheung HTA, Jung N, Bräse S (2020) Naturally occurring cardenolides affecting Schistosoma mansoni. ACS Infec Dis 6:1922–1927. https://doi.org/10.1021/acsinfecdis.0c00175
Lago EM, Silva MP, Queiroz TG, Mazloum SF, Rodrigues VC, Carnaúba PU, Pinto PL, Rocha JA, Ferreira LLG, Andricopulo AD, de Moraes J (2019) Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis. EBioMedicine 43:370–379. https://doi.org/10.1016/j.ebiom.2019.04.029
Lago EM, Xavier RP, Teixeira TR, Silva LM, da Silva Filho AA, de Moraes J (2018) Antischistosomal agents: state of art and perspectives. Future Med Chem 10:89–120. https://doi.org/10.4155/fmc-2017-0112
Mafud AC, Ferreira LG, Mascarenhas YP, Andricopulo AD, de Moraes J (2016) Discovery of novel antischistosomal agents by molecular modeling approaches. Trends Parasitol 32:874–886. https://doi.org/10.1016/j.pt.2016.08.002
Mafud AC, Silva MPN, Nunes GBL, de Oliveira MAR, Batista LF, Rubio TI, Mengarda AC, Lago EM, Xavier RP, Gutierrez SJC, Pinto PLS, da Silva Filho AA, Mascarenhas YP, de Moraes J (2018) Antiparasitic, structural, pharmacokinetic, and toxicological properties of riparin derivatives. Toxicol in Vitro 50:1–10. https://doi.org/10.1016/j.tiv
McManus DP, Dunne DW, Sacko M, Utzinger J, Vennervald BJ, Zhou XN (2018) Schistosomiasis Nat Ver Dis Primers 4:13. https://doi.org/10.1038/s41572-018-0013-8
Mengarda AC, Mendonça PS, Morais CS, Cogo RM, Mazloum SF, Salvadori MC, Teixeira FS, Morais TR, Antar GM, Lago JHG, Moraes J (2020) Antiparasitic activity of piplartine (piperlongumine) in a mouse model of schistosomiasis. Acta Trop 205:105350. https://doi.org/10.1016/j.actatropica.2020.105350
Newman DJ, Cragg GM (2020) Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 83:770–803. https://doi.org/10.1021/acs.jnatprod.9b01285
Peng L, Xiong Y, Wang M, Han M, Cai W, Li Z (2018) Chemical composition of essential oil in Mosla chinensis Maxim Cv. Jiangxiangru and its inhibitory effect on Staphylococcus aureus biofilm formation. Open Life Sci 13:1–10. https://doi.org/10.1515/biol-2018-0001
Pereira VRD, da Silveira LS, Mengarda AC, Alves Júnior IJ, da Silva OOZ, Miguel FB, Silva MP, Almeida ADC, Torres DDS, Pinto PF, Coimbra ES, de Moraes J, Couri MRC, da Silva Filho AA (2021) Antischistosomal properties of aurone derivatives against juvenile and adult worms of Schistosoma mansoni. Acta Trop 213:105741. https://doi.org/10.1016/j.actatropica.2020.105741
Porto R, Mengarda AC, Cajas RA, Salvadori MC, Teixeira FS, Arcanjo DDR, Siyadatpanah A, Pereira ML, Wilairatana P, Moraes J (2021) Antiparasitic properties of cardiovascular agents against human intravascular parasite Schistosoma mansoni. Pharmaceuticals (basel) 14(7):686. https://doi.org/10.3390/ph14070686
Rando DGG, da Costa MOL, Pavani TFA, Oliveira T, Dos Santos PF, Amorim CR, Pinto PLS, de Brito MG, Silva MPN, Roquini DB, de Moraes J (2019) Vanillin-related N-acylhydrazones: synthesis, antischistosomal properties and target fishing studies. Curr Top Med Chem 19:1241–1251. https://doi.org/10.2174/1568026619666190620163237
Roquini DB, Cogo RM, Mengarda AC, Mazloum SF, Morais CS, Xavier RP, Salvadori MC, Teixeira FS, Ferreira LE, Pinto PL, Morais TR, de Moraes J (2019) Promethazine exhibits antiparasitic properties in vitro and reduces worm burden, egg production, hepato-, and splenomegaly in a schistosomiasis animal model. Antimicrob Agents Chemother 63:e01208-e1219. https://doi.org/10.1128/AAC.01208-19
Sessa DP, Mengarda AC, Simplicio PE, Antar GM, Lago JHG, de Moraes J (2020) 15β-Senecioyl-oxy-ent-kaur-16-en-19-oic acid, a diterpene isolated from Baccharis lateralis, as promising oral compound for the treatment of schistosomiasis. J Nat Prod 83:3744–3750. https://doi.org/10.1021/acs.jnatprod.0c01050
Silva MP, de Oliveira RN, Mengarda AC, Roquini DB, Allegretti SM, Salvadori MC, Teixeira FS, de Sousa DP, Pinto PLS, da Silva Filho AA, de Moraes J (2017) Antiparasitic activity of nerolidol in a mouse model of schistosomiasis. Int J Antimicrob Agents 50:467–472. https://doi.org/10.1016/j.ijantimicag.2017.06.005
Silva TC, Mengarda AC, Silva BC, Relvas-Lima TS, Rodrigues VC, Salvadori MC, Teixeira FS, Lopes AF, Rando DG, Moraes J (2021a) New evidence for tamoxifen as an antischistosomal agent: in vitro, in vivo and target fishing studies. Future Med Chem 13:945–957. https://doi.org/10.4155/fmc-2020-0311
Silva MP, Silva TM, Mengarda AC, Salvadori MC, Teixeira FS, Alencar SM, Luz Filho GC, Bueno-Silva B, de Moraes J (2021b) Brazilian red propolis exhibits antiparasitic properties in vitro and reduces worm burden and egg production in an mouse model harboring either prepatent or patent Schistosoma mansoni infection. J Ethnopharmacol 264:113387. https://doi.org/10.1016/j.jep.2020.113387
Skelly PJ, Wilson RA (2006) Making sense of the schistosome surface. Adv Parasito 63:185–284. https://doi.org/10.1016/S0065-308X(06)63003-0
Spangenberg T (2021) Alternatives to praziquantel for the prevention and control of schistosomiasis. ACS Infect Dis 7:939–942. https://doi.org/10.1021/acsinfecdis.0c00542
Van Nassauw L, Toovey S, Van Op den bosch J, Timmermans JP, Vercruysse J (2008) Schistosomicidal activity of the antimalarial drug, mefloquine, in Schistosoma mansoni-infected mice. Travel Med Infect Dis 6:253–258. https://doi.org/10.1016/j.tmaid.2008.06.006
Whiteland H, Crusco A, Bloemberg LW, Tibble-Howlings J, Forde-Thomas J, Coghlan A, Murphy PJ, Hoffmann KF (2020) Quorum sensing N-Acyl homoserine lactones are a new class of anti-schistosomal. PLoS Negl Trop Dis 14:e0008630. https://doi.org/10.1371/journal.pntd.0008630
World Health Organization (2020). Factsheet 2020. Available online: www.who.int/news-room/factsheets/detail/schistosomiasis (Accessed on 14 May 2021)
Acknowledgements
We are grateful to Dr. Daniel B. Roquini and Marcos P. Silva (Núcleo de Pesquisa em Doenças Negligenciadas, Universidade Guarulhos, Brazil) for support during in vitro and in vivo studies and Dr. Aparecida R dos Santos (Ecovet Industria Veterinaria Ltda, São Paulo, SP, Brazil) for donation of praziquantel. We also thank to Dra Suzana A. Z. Lescano (Instituto de Medicina Tropical, Universidade de São Paulo, Brazil) for her support during in vivo experiments.
Funding
This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), grant number 2016/22488–3. ACM and VCR were supported by a fellowship from the FAPESP (grant 2019/25905–2 and grant 2019/25289–0). BCS received a scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (PROSUP/CAPES). The funding institutions had not any role in study design, data collection, data analysis, interpretation, or writing of the report in this study.
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BCS and JM: Conceptualization. BCS, ACM, VCR, RAC, PUC, and CSMBF: Methodology. ACM and JM: Software. ACM, VCR, and RAC: Validation. BCS and ACM: Formal analysis. BCS, ACM, VCR, and RAC: Investigation. MCCES, DPS, and JM: Resources. ACM and VCR: Data curation. BCS and ACM: Writing—original draft preparation. JM: Writing—review and editing. BCS, ACM, VCR, RAC, PUC, MCCES, CSMBF, DPS, and JM: Visualization. ACM: Supervision. JM: Project administration. JM: Funding acquisition. All authors have read and agreed to the published version of the manuscript.
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Silva, B.C., Mengarda, A.C., Rodrigues, V.C. et al. Efficacy of carvacryl acetate in vitro and following oral administration to mice harboring either prepatent or patent Schistosoma mansoni infections. Parasitol Res 120, 3837–3844 (2021). https://doi.org/10.1007/s00436-021-07333-2
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DOI: https://doi.org/10.1007/s00436-021-07333-2