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Title: Evaluation of the growth-inhibitory effect of trifluralin analogues on in vitro cultured babesia bovis parasites

Author
item Gomes Da Silva, Marta
item DOMINGOS, ANA - Center Of Malaria And Other Tropical Diseases, Institute Of Hygiene And Tropical Medicine
item ESTEVES, MARIA - Fuel Cells And Multi-Lateral Unit, National Laboratory For Energy And Geology
item ANTUNES, SANDRA - Center Of Malaria And Other Tropical Diseases, Institute Of Hygiene And Tropical Medicine
item CRUZ, MARIA E. - University Of Lisbon
item Suarez, Carlos

Submitted to: International Journal for Parasitology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/12/2013
Publication Date: 12/1/2013
Citation: Gomes Da Silva, M., Domingos, A., Esteves, M.A., Antunes, S., Cruz, M.M., Suarez, C.E. 2013. Evaluation of the growth-inhibitory effect of trifluralin analogues on in vitro cultured babesia bovis parasites. International Journal for Parasitology. (3):59-68.

Interpretive Summary: Babesia bovis caused bovine babesiosis is a world tick borne hemoprotozoan disease leading to fever, anemia, weight losses and ultimately death. Several babesicidal drugs that have been in use in cattle for years have proven to be partially ineffective and the development of alternative highly specific and low toxicity chemotherapeutics against babesiosis is needed. In this study we evaluated the potential of a set of Trifluralin derivatives (TFLA) as possible novel babesicidals. A set of previously tested Leishmania inhibitory, TFLA 1-12 minus TFLA-5, in addition to three novel TFLA (termed TFLA 13-15), were tested against in vitro cultured B. bovis parasites. While all of the TFLA tested in the study showed B. bovis in vitro growth inhibition, three of them: TFLA 7, TFLA 10 and TFLA 13, were the most effective inhibitors for both, the biologically cloned B. bovis Mo7 and the virulent B. bovis Texas strains. Importantly, these drugs displayed low levels of toxicity for the host erythrocytes at the doses tested. The demonstrated ability of trifuralin analogues to inhibit in vitro growth of B. bovis parasites combined with their low toxicity for host cells suggests that these compounds may be further developed as novel alternatives for the treatment of bovine babesiosis.

Technical Abstract: Babesia bovis caused bovine babesiosis is a world tick borne hemoprotozoan disease leading to fever, anemia, weight losses and ultimately death. Several babesicidal drugs that have been in use in cattle for years have proven to be partially ineffective and the development of alternative highly specific and low toxicity chemotherapeutics against babesiosis is needed. Trifluralin derivatives specifically bind alpha-tubulin in plants and protozoa parasites causing growth inhibition. A set of twelve trifuralin analogues (TFLA) has previously been shown to be inhibitory for the growth of Leishmania species. Conservation of several key amino acids involved in the trifuralin binding site of alpha-tubulin among Leishmania sp. and B. bovis provides rationale for testing these compounds also as babesiacides. The previously tested Leishmania inhibitory, TFLA 1-12 minus TFLA-5, in addition to three novel TFLA (termed TFLA 13-15), were tested against in vitro cultured B. bovis parasites. While all of the TFLA tested in the study showed B. bovis in vitro growth inhibition, the TFLA 7, TFLA 10 and TFLA 13, were the most effective inhibitors with estimated IC50 (µM) at 72h of 8.5 ± 0.3; 9.2 ± 0.2; 8.9 ± 0.7, respectively for the biologically cloned B. bovis Mo7 strain, and 13.6 ± 1.5; 18.7 ± 1.6; 10.6 ± 1.9, respectively for the virulent B. bovis Texas strain. The differences found between the two strains were not statistically significant. Importantly, these drugs displayed low levels of toxicity for the host erythrocytes at the doses tested. The demonstrated ability of trifuralin analogues to inhibit in vitro growth of B. bovis parasites combined with their low toxicity for host cells suggests that these compounds may be further developed as novel alternatives for the treatment of bovine babesiosis.