Larvicidal activity of coumarin derivatives on Toxocara canis larvae, cytotoxicity analysis, and in silico bioavailability studies (original) (raw)

Abstract

Human toxocariasis is a neglected anthropozoonosis with global distribution. Treatment is based on the administration of anthelmintics; however, their effectiveness at the tissue level is low to moderate, necessitating the discovery of new drug candidates. Several groups of synthetic compounds, including coumarin derivatives, have demonstrated bioactivity against fungi, bacteria, and even parasites, such as Dactylogyrus intermedius, Leishmania major, and Plasmodium falciparum. The aim of this study was to evaluate the effect of ten coumarin-derived compounds against Toxocara canis larvae using in vitro, cytotoxicity, and in silico tests for selecting new drug candidates for preclinical tests aimed at evaluating the treatment of visceral toxocariasis. The compounds were tested in vitro in duplicate at a concentration of 1 mg/mL, and compounds with larvicidal activity were serially diluted to obtain concentrations of 0.5 mg/mL; 0.25 mg/mL; 0.125 mg/mL; and 0.05 mg/mL. The tests were performed in a microculture plate containing 100 T_. canis_ larvae in RPMI-1640 medium. One compound (COU 9) was selected for cytotoxicity analysis using J774.A1 murine macrophages and it was found to be non-cytotoxic at any concentration tested. The in silico analysis was performed using computational models; the compound presented adequate results of oral bioavailability. To confirm the non-viability of the larvae, the contents of the microplate wells of COU 9 were inoculated intraperitoneally (IP) into female Swiss mice at 7–8 weeks of age. This confirmed the larvicidal activity of this compound. These results show that COU 9 exhibited larvicidal activity against T. canis larvae, which, after exposure to the compound, were non-viable, and that COU 9 inhibited infection in a murine model. In addition, COU 9 did not exhibit cytotoxicity and presented adequate bioavailability in silico, similar to albendazole, an anthelmintic, which is the first choice for treatment of human toxocariasis, supporting the potential for future investigations and preclinical tests on COU 9.

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References

• Annunziata F, Pinna C, Dallavalle S, Tamborini L, Pinto A (2020) An overview of coumarin as a versatile and readily accessible scaffold with broad-ranging biological activities. Int J Mol Sci 21(13):4618. https://doi.org/10.3390/ijms21134618
  Article CAS PubMed PubMed Central Google Scholar
• Ansar Ahmed S, Gogal RM, Walsh JE (1994) A new rapid and simple non-radioactive assay to monitor and determine the proliferation of lymphocytes: an alternative to [3H]thymidine incorporation assay. J Immunol Method 170(2):211–224. https://doi.org/10.1016/0022-1759(94)90396-4
  Article CAS Google Scholar
• Arya CG, Gondru R, Li Y, Banothu J (2022) Coumarin–benzimidazole hybrids: A review of developments in medicinal chemistry. Eur J Med Chem 227:113921. https://doi.org/10.1016/j.ejmech.2021.113921
  Article CAS Google Scholar
• Avila LF, Telmo PD, Martins LH et al (2013) Protective effect of the probiotic Saccharomyces boulardii in Toxocara canis infection is not due to direct action on the larvae. Rev Inst Med Trop Sao Paulo 55(5):363–365. https://doi.org/10.1590/s0036-46652013000500012
  Article PubMed PubMed Central Google Scholar
• Bhowmik D, Jagadeesan R, Rai P, Nandi R, Gugan K, Kumar D (2020) Evaluation of potential drugs against leishmaniasis targeting catalytic subunit of Leishmania donovani nuclear DNA primase using ligand based virtual screening, docking and molecular dynamics approaches. J Biomol Struct Dyn 1–15. https://doi.org/10.1080/07391102.2020.1739557
• Brocksom T, Desiderá A, Carvalho Alves L, Oliveira K (2015) The New Directions of Organic Synthesis. Curr Org Synth 12(5):496–522. https://doi.org/10.2174/157017941205150821121222
  Article CAS Google Scholar
• Chen J, Liu Q, Liu GH et al (2018) Toxocariasis: a silent threat with a progressive public health impact. Infect Dis Poverty 7(1):59. https://doi.org/10.1186/s40249-018-0437-0
  Article PubMed PubMed Central Google Scholar
• Chen H, Li M, Liu C, Zhang H, Xian M, Liu H (2020) Correction to: Enhancement of the catalytic activity of Isopentenyl diphosphate isomerase (IDI) from Saccharomyces cerevisiae through random and site-directed mutagenesis. Microb Cell Fact 19(1). https://doi.org/10.1186/s12934-019-1268-9.
• Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7(1). https://doi.org/10.1038/srep42717
• Epe C, Kaminsky R (2013) New advancement in anthelmintic drugs in veterinary medicine. Trends Parasitol 29(3):129–134. https://doi.org/10.1016/j.pt.2013.01.001
  Article CAS PubMed Google Scholar
• Fakhri Y, Gasser RB, Rostami A et al (2018) Toxocara eggs in public places worldwide - A systematic review and meta-analysis. Environ Pollut 242:1467–1475. https://doi.org/10.1016/j.envpol.2018.07.087
  Article CAS PubMed Google Scholar
• Fillaux J, Magnaval JF (2013) Laboratory diagnosis of human toxocariasis. Vet Parasitol 193(4):327–336. https://doi.org/10.1016/j.vetpar.2012.12.028
  Article CAS PubMed Google Scholar
• Halford B (2014) Reflections On ChemDraw. Chem Amp Eng News Arch 92(33):26–27. https://doi.org/10.1021/cen-09233-scitech1
  Article Google Scholar
• Kumar N, Mishra SS, Sharma CS, Singh HP, Singh H (2017) In silico pharmacokinetic, bioactivity and toxicity evaluation of some selected anti-ulcer agents. Int J Pharm Sci Drug Res 9(2). https://doi.org/10.25004/ijpsdr.2017.090205
• Lacroix D, Prado S, Kamoga D, Kasenene J, Bodo B (2011) Structure and in vitro antiparasitic activity of constituents of Citropsis articulata Root Bark. J Nat Prod 74(10):2286–2289. https://doi.org/10.1021/np2004825
  Article CAS PubMed Google Scholar
• Lescano SZ, Chieffi PP, Amato Neto V, Ikai DK, Ribeiro MC (2005) Anthelmintics in experimental toxocariasis: effect on the recovery of Toxocara canis larvae and on the humoral response. J Bras Patol Med Lab 41(1). https://doi.org/10.1590/s1676-24442005000100006
• Li JW, Vederas JC (2009) Drug discovery and natural products: end of an era or an endless frontier? Science 325(5937):161–165. https://doi.org/10.1126/science.1168243
  Article CAS PubMed Google Scholar
• Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today 1(4):337–341. https://doi.org/10.1016/j.ddtec.2004.11.007
  Article CAS Google Scholar
• Liu GL, Hu Y, Chen XH, Wang GX, Ling F (2016) Synthesis and anthelmintic activity of coumarin–imidazole hybrid derivatives against Dactylogyrus intermedius in goldfish. Bioorganic Amp Med Chem Lett 26(20):5039–5043. https://doi.org/10.1016/j.bmcl.2016.08.090
  Article CAS Google Scholar
• Magnaval JF, Glickman LT, Dorchies P, Morassin B (2001) Highlights of human toxocariasis. Korean J Parasitol 39(1):1. https://doi.org/10.3347/kjp.2001.39.1.1
  Article CAS PubMed PubMed Central Google Scholar
• Magnaval JF, Bouhsira E, Fillaux J (2022) Therapy and prevention for human toxocariasis. Microorganisms 10(2):241. https://doi.org/10.3390/microorganisms10020241
  Article CAS PubMed PubMed Central Google Scholar
• Man-Son-Hing M, Laupacis A, O’Rourke K et al (2002) Determination of the clinical importance of study results. J Gen Intern Med 17(6):469–476. https://doi.org/10.1046/j.1525-1497.2002.11111.x
  Article PubMed PubMed Central Google Scholar
• Mata-Santos T, Pinto NF, Mata-Santos HA et al (2015) Anthelmintic activity of lapachol, β-lapachone and its derivatives against Toxocara canis larvae. Rev Inst Med Trop Sao Paulo 57(3):197–204. https://doi.org/10.1590/s0036-46652015000300003
  Article PubMed PubMed Central Google Scholar
• Mata-Santos T, Mata-Santos HA, Carneiro PF et al (2016a) Toxocara canis: anthelmintic activity of quinone derivatives in murine toxocarosis. Parasitology 143(4):507–517. https://doi.org/10.1017/s0031182016000068
  Article CAS PubMed Google Scholar
• Mata-Santos T, D’Oca CD, Mata-Santos HA et al (2016b) Toxocara canis : Larvicidal activity of fatty acid amides. Bioorg Med Chem Lett 26(3):739–741. https://doi.org/10.1016/j.bmcl.2016.01.002
  Article CAS PubMed Google Scholar
• Muthipeedika NJ, Yadav DB, Sandeep T, Vasily AB (2019) Synthesis of coumarins linked with 1,2,3-triazoles under microwave irradiation and evaluation of their antimicrobial and antioxidant activity. J Mex Chem Soc 64(1). https://doi.org/10.29356/jmcs.v64i1.1116
• Napolitano HB, Silva M, Ellena J et al (2004) Aurapten, a coumarin with growth inhibition against Leishmania major promastigotes. Braz J Med Biol Res 37(12):1847–1852. https://doi.org/10.1590/s0100-879x2004001200010
  Article CAS PubMed Google Scholar
• 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(3):770–803. https://doi.org/10.1021/acs.jnatprod.9b01285
  Article CAS PubMed Google Scholar
• Patil SA, Kandathil V, Sobha A et al (2022) Comprehensive review on medicinal applications of coumarin-derived imine–metal complexes. Molecules 27(16):5220. https://doi.org/10.3390/molecules27165220
  Article CAS PubMed PubMed Central Google Scholar
• Pawlowski Z (2001) Toxocariasis in humans: clinical expression and treatment dilemma. J Helminthol 75(4):299–305. https://doi.org/10.1017/s0022149x01000464
  Article CAS PubMed Google Scholar
• Pereira TM, Franco DP, Vitorio F, Kummerle AE (2018) Coumarin compounds in medicinal chemistry: some important examples from the last years. Curr Top Med Chem 18(2):124–148. https://doi.org/10.2174/1568026618666180329115523
  Article CAS PubMed Google Scholar
• Pinto LS, de Souza M (2017) Sonochemistry as a general procedure for the synthesis of coumarins­, including multigram synthesis. Synthesis 49(12):2677–2682. https://doi.org/10.1055/s-0036-1590201
  Article CAS Google Scholar
• Ramírez-Prada J, Robledo SM, Vélez ID et al (2017) Synthesis of novel quinoline–based 4,5–dihydro–1 H –pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents. Eur J Med Chem 131:237–254. https://doi.org/10.1016/j.ejmech.2017.03.016
  Article CAS PubMed Google Scholar
• Reis M, Trinca A, Ferreira MJ, Monsalve-Puello AR, Grácio MA (2010) Toxocara canis: Potential activity of natural products against second-stage larvae in vitro and in vivo. Exp Parasitol 126(2):191–197. https://doi.org/10.1016/j.exppara.2010.04.023
  Article PubMed Google Scholar
• Rodrigues G, Avelino J, Siqueira A, Ramos L, Santos G (2021) The use of free software in a practical lesson on molecular filters for the oral bioavailability of drugs. Quimica Nova. https://doi.org/10.21577/0100-4042.20170739.
• Sangi DP (2016) Synthetic strategies in drug discovery: employng diversity-oriented synthesis. Quim Nova. https://doi.org/10.5935/0100-4042.20160089
  Article Google Scholar
• Santos JCB, de Melo JA, Maheshwari S et al (2020) Bisphosphonate-based molecules as potential new antiparasitic drugs. Molecules 25(11):2602. https://doi.org/10.3390/molecules25112602
  Article CAS Google Scholar
• Savigny DH (1975) In vitro maintenance of Toxocara canis larvae and a simple method for the production of Toxocara ES antigen for use in serodiagnostic tests for visceral Larva Migrans. J Parasitol 61(4):781. https://doi.org/10.2307/3279492
  Article CAS PubMed Google Scholar
• Stefanachi A, Leonetti F, Pisani L, Catto M, Carotti A (2018) Coumarin: a natural, privileged and versatile scaffold for bioactive compounds. Molecules 23(2):250. https://doi.org/10.3390/molecules23020250
  Article CAS PubMed PubMed Central Google Scholar
• Strube C, Heuer L, Janecek E (2013) Toxocara spp. infections in paratenic hosts. Vet Parasitol 193(4):375–389. https://doi.org/10.1016/j.vetpar.2012.12.033
  Article PubMed Google Scholar
• Walcher DL, Cruz LA, de Lima Telmo P et al (2017) Lactobacillus rhamnosus reduces parasite load on Toxocara canis experimental infection in mice, but has no effect on the parasite in vitro. Parasitol Res 117(2):597–602. https://doi.org/10.1007/s00436-017-5712-7
  Article PubMed Google Scholar
• Woods DJ, Vaillancourt VA, Wendt JA, Meeus PF (2011) Discovery and development of veterinary antiparasitic drugs: past, present and future. Future Med Chem 3(7):887–896. https://doi.org/10.4155/fmc.11.39
  Article CAS PubMed Google Scholar
• Xi WG, Jin LZ (1998) A novel method for the recovery of Toxocara canis in mice. J Helminthol 72(2):183–184. https://doi.org/10.1017/s0022149x00016382
  Article CAS PubMed Google Scholar
• Zhu JJ, Jiang JG (2018) Pharmacological and nutritional effects of natural coumarins and their structure-activity relationships. Mol Nutr Food Res 62(14):1701073. https://doi.org/10.1002/mnfr.201701073
  Article CAS Google Scholar

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Funding

D. F. Ramos is productivity research fellows from National Council for Scientific and Technological Development (CNPq) (process number PQ 306806/2022–3). The authors acknowledge the financial support from the Brazilian Agency Coordenação de Aperfeiçoamento de Pessoal de Nível Superior and the scholarship granted.

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Authors and Affiliations

1. Parasitology Laboratory, Faculty of Medicine, Federal University of Rio Grande, Rio Grande, Brazil
   Débora Carvalho Rodrigues, Carolina Netto de Oliveira da Cunha, Gabriela Torres Mattos, Lourdes Helena Rodrigues Martins, Luciana Farias da Costa de Avila & Carlos James Scaini
2. Synthesi Department, Institute of Drug Technology, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
   Thais Cristina Mendonça Nogueira & Marcus Vinícius Nora de Souza
3. New Drug Development Laboratory, Faculty of Medicine, Federal University of Rio Grande, Rio Grande, Brazil
   Daniela Fernandes Ramos

Authors

1. Débora Carvalho Rodrigues
2. Carolina Netto de Oliveira da Cunha
3. Gabriela Torres Mattos
4. Lourdes Helena Rodrigues Martins
5. Thais Cristina Mendonça Nogueira
6. Marcus Vinícius Nora de Souza
7. Luciana Farias da Costa de Avila
8. Daniela Fernandes Ramos
9. Carlos James Scaini

Contributions

Débora Carvalho Rodrigues - Writing – review & editing, Methodology, Formal analysis, Conceptualization. Carolina Netto de Oliveira da Cunha - Methodology. Gabriela Torres Mattos - Methodology. Lourdes Helena Rodrigues Martins - Methodology. Thais Cristina Mendonça Nogueira - Methodology. Marcus Vinícius Nora de Souza - Methodology. Luciana Farias da Costa de Avila - Formal analysis, Conceptualization. Daniela Fernandes Ramos - Project supervisor, Writing – review & editing, Methodology, Formal analysis, Conceptualization. Carlos James Scaini - Project administration, Writing – review & editing, Formal analysis, Conceptualization.

Corresponding author

Correspondence toDébora Carvalho Rodrigues.

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According to Brazilian law no 11.794/2008 (Arouca law), article 2◦ applies to animals of species classified as phylum Chordata, subphylum Vertebrata, subject to environmental legislation. The Federal University of Rio Grande is accredited by the Commission for Ethics in the Use of Animals (CEUA) in accordance with the provisions of article 8◦ of the Arouca law. This study was approved by the Ethics Committee in Research of the Federal University of Rio Grande (P034/2020).

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Rodrigues, D.C., de Oliveira da Cunha, C.N., Mattos, G.T. et al. Larvicidal activity of coumarin derivatives on Toxocara canis larvae, cytotoxicity analysis, and in silico bioavailability studies.Parasitol Res 123, 246 (2024). https://doi.org/10.1007/s00436-024-08272-4

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• Received: 06 April 2024
• Accepted: 13 June 2024
• Published: 19 June 2024
• Version of record: 19 June 2024
• DOI: https://doi.org/10.1007/s00436-024-08272-4

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