Antimalarial evaluation of alkyl-linked bis-thiadiazine derivatives in murine model infected with two Plasmodium strains

Katherine Stefania Loachamin Gualotuña; Lilian M. Spencer; Hortensia Maria Rodriguez Cabrera; Renata Abigail Montero Calderón; Beatriz Pernía; Julieta Coro; Margarita Suarez; Francisco Javier Tingo Jacome; Zully J. Rodriguez Parra; Jose Manuel Lozano; Jesús Cortés Vecino

doi:10.5599/admet.2105

Authors

Katherine Stefania Loachamin Gualotuña School of Biological Sciences and Engineering, University of Investigation and Experimental Technology Yachay, 100650, Ecuador https://orcid.org/0000-0001-5032-4220
Lilian M. Spencer School of Biological Sciences and Engineering, University of Investigation and Experimental Technology Yachay, 100650, Ecuador and Simón Bolívar University, Valle de Sartenejas, Cell Biology Department, Venezuela https://orcid.org/0000-0002-2756-598X
Hortensia Rodriguez School of Chemical Sciences and Engineering, University of Investigation and Experimental Technology Yachay, 100650, Ecuador https://orcid.org/0000-0001-6910-5685
Abigail Montero-Calderon School of Agricultural and Agro-industrial Sciences, University of Investigation and Experimental Technology Yachay, 100650, Ecuador https://orcid.org/0000-0001-8219-8695
Beatriz Pernia University of Guayaquil, Faculty of Natural Sciences, Guayaquil, Ecuador https://orcid.org/0000-0002-2476-7279
Julieta Coro Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400, Cuba https://orcid.org/0000-0002-1687-9756
Margarita Suarez Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400, Cuba https://orcid.org/0000-0002-3138-4364
Francisco Javier Tingo-Jácome Biology Center, Central University of Ecuador, Ecuador https://orcid.org/0000-0002-2286-4374
Zully J. Rodriguez Parra Universidad Nacional de Colombia, Departamento de Farmacia, Mimetismo Molecular de los Agentes Infecciosos , Colombia https://orcid.org/0000-0001-6517-4640
José Manuel Lozano Universidad Nacional de Colombia, Departamento de Farmacia, Mimetismo Molecular de los Agentes Infecciosos , Colombia https://orcid.org/0000-0001-6039-0213
Jesús A. Cortés-Vecino Universidad Nacional de Colombia, Departamento de Salud Animal, Facultad de Medicina Veterinaria y Zootecnia, Colombia https://orcid.org/0000-0003-2641-604X

DOI:

https://doi.org/10.5599/admet.2105

Keywords:

Plasmodium berghei, Plasmodium yoelii, Bis-THTT, drugs, parasitemia, humoral response

Abstract

Background and Purpose: Plasmodium falciparum and P. vivax are responsible for most malaria cases in humans in the African Region and the Americas; these parasites have developed resistance to classic antimalarial drugs. On the other hand, previous investigations of the alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) derivatives compounds show satisfactory results against protozoan parasites such as Trypanosoma cruzi, Trypanosoma vaginalis, Trypanosoma brucei rhodesiense and Leishmania donovani. Therefore, it is possible to see some effect of bis-THTT derivatives on other protozoan parasites, such as Plasmodium. Experimental Approach: This study aimed to perform an in vivo biological evaluation of bis-THTT (JH1 to JH6) derivatives compounds as possible anti-malaria drugs in BALB/c mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL strains. In this work, we evaluated the compounds as potential antimalarial drugs in BALB/c mice infected with Plasmodium strains. Key Results: For each compound, we assess the percentages of parasitemia by smears from tail blood and the humoral response by indirect ELISA test using each compound as an antigen. We also evaluated the B lymphocyte response and the cytotoxicity of the bis-THTT derivatives compounds with MTT cell proliferation assays. Conclusions: Our results show that the bis-THTT derivatives JH2 and JH4 presented effective parasitemia control in mice infected with P. berghei; JH5 and JH6 compounds have similar infection control results as chloroquine in mice infected P. yoelii strain. The evaluation of bis-THTT derivatives compounds in a model of BALB/c mice infected with P. berghei and P. yoelii allowed us to conclude that some of them have an antimalarial effect; however, none of the tested compounds exceeded the efficiency of chloroquine.

Downloads

Download data is not yet available.

References

World Health Organization, https://www.who.int/malaria/media/world-malaria-report-2018/en/ (accessed Jan 21, 2021).

World Health Organization, https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021 (accessed Oct 02, 2022).

R. Killick-Kendrick, Rodent malaria, Elsevier Science, London, England, 2014, p 1-52. ISBN 0124071503

A.G. Craig, G.E. Grau, C. Janse, J.W. Kazura, D. Milner, J.W. Barnwell, G. Turner, and J. Langhorne. The role of animal models for research on severe malaria. PLoS Pathogen 8 (2012) e1002401. https://doi.org/10.1371/journal.ppat.1002401.

K. Plewes, S. J. Leopold, H.W.F. Kingston, A.M. Dondorp. Malaria: What’s new in the management of malaria? Infectious. Disease Clinics of North American 33 (2019) 39-60. https://doi.org/10.1016/j.idc.2018.10.002.

L.L. Gustafsson, Handbook of drugs for tropical parasitic infections, Taylor & Francis, London, England, 1995. ISBN 0748401687

DrugBank online, https://www.drugbank.ca/drugs/DB00608 (accessed Jan 21, 2021).

P.G Bray, O. Janneh, K.J. Raynes, M. Mungthin, H. Ginsburg, S.A. Ward. Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum. Journal of Cell Biology 145 (1999) 363-376. https://doi.org/10.1083/jcb.145.2.363.

M. Chinappi, A. Via, P. Marcatili, A. Tramontano. On the mechanism of chloroquine resistance in Plasmodium falciparum. PLoS One 5 (2010) e14064. https://doi.org/10.1371/journal.pone.0014064.

G.N.L. Galappaththy, P. Tharyan, R. Kirubakaran. Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine. Cochrane Database of Systematic Reviews 10 (2013) CD004389. https://doi.org/10.1002/14651858.CD004389.pub3.

C.V. Plowe, C. Roper, J.W. Barnwell, C.T. Happi, H.H. Joshi, W. Mbacham, S.R. Meshnick, K. Mugittu, I. Naidoo, R. N. Price, R. W. Shafer, C. H. Sibley, C. J. Sutherland, P. A. Zimmerman, P. J. Rosenthal. World antimalarial resistance network (WARN) III: Molecular markers for drug resistant malaria. Malaria Journal 6 (2007) 121. https://doi.org/10.1186/1475-2875-6-121.

A.N. El-Shorbagi. New tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as potential antimicrobial agents. Archive der Pharmazie 333 (2000) 281-286. https://doi.org/10.1002/1521-4184(20009)333:9<281::aid-ardp281>3.0.co;2-e.

J. Coro, R. Pérez, H. Rodríguez, M. Suárez, C. Vega, M. Rolón, D. Montero, J.J. Nogal, A. Gomez-Barrio. Synthesis and antiprotozoan evaluation of new alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids. Bioorganicand Medicinal Chemistry 13 (2005) 3413-3421. https://doi.org/10.1016/j.bmc.2005.03.009.

J. Coro, R. Pérez, L. Monzote, H. Rodríguez, M. Suárez. Thiadiazine derivatives as antiprotozoal new drugs. The open medicinal chemistry journal 5 (2011) 51-60. https://doi.org/10.2174/1874104501105010051.

J. Coro, R. Atherton, S. Little, H. Wharton, V. Yardley, A. Alvarez A, M. Suárez, R. Pérez, H. Rodriguez. Alkyl-linked bis-thtt derivatives as potent in vitro trypanocidal agents. Bioorganic and Medicinal Chemistry Letters 16 (2006) 1312-1315. https://doi.org/10.1016/j.bmcl.2005.11.060.

J. Coro, S. Little, V. Yardley, M. Suárez, H. Rodríguez, N. Martín, R. Perez-Piñeiro. Synthesis and antiprotozoal evaluation of new n4-(benzyl)spermidyl-linked bis(1,3,5-thiadiazinane-2-thiones). Archive del Pharmazie 341 (2008) 708-713. https://doi.org/10.1002/ardp.200800011.

B.R. Moore, M. Page-Sharp, J.R. Stoney, K.F. Ilett, J.D. Jago, K.T. Batty. Pharmacokinetics, pharmacodynamics, and allometric scaling of chloroquine in a murine malaria model. Antimicrobial Agents and Chemotherapy 55 (2011) 3899-3907. https://doi.org/10.1128/AAC.00067-11.

C.F. Brayton. Dimethyl sulfoxide (DMSO): A review. The Cornell Veterinarian 76 (1986) 61-90. https://pubmed.ncbi.nlm.nih.gov/3510103/

L.M. Spencer-Valero, S.A. Ogun, S.L. Fleck, I.T. Ling, T.J. Scott-Finnigan, M.J. Blackman, A.A. Holder. Passive immunization with antibodies against three distinct epitopes on Plasmodium yoelii merozoite surface protein 1 suppresses parasitemia. Infection and Immunity 66 (1998) 3925-3930. https://doi.org/10.1128/IAI.66.8.3925-3930.1998.

K. Moll, A. Kaneko, A. Scherf, M. Wahlgren. Methods in malaria research; EviMalar, 6th ed. Glasgow, U.K., 2013, 1-499. https://www.beiresources.org/portals/2/MR4/Methods_In_Malaria_Research-6th_edition.pdf (accessed Jan 21, 2021).

A. Voller, D.E. Bidwell, A. Bartlett. Enzyme immunoassays in diagnostic medicine. theory and practice. Bulletin of the World Health Organization 53 (1976) 55-65. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366417/

A. Voller, D. Bidwell. Enzyme-linked immunosorbent assay. Manual of clinical immunology, 3rd edn. American Society for Microbiology, Washington DC, United States of America, 1986, 99-109.

Promega Corporation, https://www.promega.es/products/cell-health-assays/cell-viability-and-cytotoxicity-assays/celltiter-96-aqueous-one-solution-cell-proliferation-assay-_mts_/?catNum=G3582 (accessed Jan 21, 2021).

I. Abrahasem, J.B. Lorens. Evaluating extracellular matrix influence on adherent cell signaling by cold trypsin phosphorylation-specific flow cytometry. BMC Molecular and Cell Biology 19 (2013) 14-36. https://doi.org/10.1186/1471-2121-14-36.