Efficacy of the 7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline derivative against infection caused by <i>Leishmania amazonensis</i>

In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed.

RESULTS:

Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties.

CONCLUSIONS:

Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.

Keywords:
Leishmania amazonensis; Quinoline; Chemotherapy; Cutaneous leishmaniasis; Toxicity

Authorship

Luciana Maria Ribeiro Antinarelli

Universidade Federal de Juiz de Fora, Campus Universitário, Departamento de Parasitologia, Microbiologia e Imunologia, Juiz de Fora, MG, Brasil.Universidade Federal de Juiz de ForaBrasilJuiz de Fora, MG, BrasilUniversidade Federal de Juiz de Fora, Campus Universitário, Departamento de Parasitologia, Microbiologia e Imunologia, Juiz de Fora, MG, Brasil.

Universidade Federal de Minas Gerais, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Belo Horizonte, MG, Brasil.Universidade Federal de Minas GeraisBrasilBelo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais, Faculdade de Medicina, Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Belo Horizonte, MG, Brasil.

Marcus Vinicius Nora de Souza

Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-FarManguinhos, Rio de Janeiro, RJ, Brasil.Fundação Oswaldo CruzBrasilRio de Janeiro, RJ, BrasilFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-FarManguinhos, Rio de Janeiro, RJ, Brasil.

Eduardo Antonio Ferraz Coelho

Universidade Federal de Minas Gerais, Colégio Técnico, Departamento de Patologia Clínica, Belo Horizonte, MG, Brasil.Universidade Federal de Minas GeraisBrasilBelo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais, Colégio Técnico, Departamento de Patologia Clínica, Belo Horizonte, MG, Brasil.

Wallace Pacienza Lima

Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Imunofarmacologia, Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de JaneiroBrasilRio de Janeiro, RJ, BrasilUniversidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Imunofarmacologia, Rio de Janeiro, RJ, Brasil.

Universidade do Grande Rio, Escola de Ciências da Saúde, Duque de Caxias, RJ, Brasil.Universidade do Grande RioBrasilDuque de Caxias, RJ, BrasilUniversidade do Grande Rio, Escola de Ciências da Saúde, Duque de Caxias, RJ, Brasil.

Elaine Soares Coimbra

http://orcid.org/0000-0003-1005-278X

Corresponding author: Dra. Elaine Soares Coimbra. e-mail:elaine.coimbra@ufjf.edu.br

Authors’ contribution:LMRA: Conception and design of the study, Acquisition of data, Analysis and interpretation of data, Drafting the article, Final approval of the version to be submitted; MVNS: Conception and design of the study, Synthesis of the compound, Drafting the article; EAFC: Conception and design of the study, Interpretation of data, Drafting the article; WPL: Conception and design of the study, Analysis and interpretation of data; ESC: Conception and design of the study, Interpretation of data, Drafting the article, Final approval of the version to be submitted.

Conflicts of interest: The authors declare no conflicts of interest.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (3)

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FIGURE 1:
Effect of Hydraqui in the treatment of L. amazonensis-infected macrophages. Murine macrophages were infected with L. amazonensis and treated with the indicated concentrations of Hydraqui for 72 h at 33 ºC/5% CO₂. After the cells were stained with Giemsa, the percentage of infection (A) and the number of recovered amastigotes (B) were calculated by counting 200 cells, in duplicate. Data were expressed as the means of three independent experiments, which were performed in duplicate. ***P<0.001; **P<0.01, and *P<0.1 (compared with control group).

Thumbnail

FIGURE 2:
Efficacy of Hydraqui in the treatment of L. amazonensis-infected mice. The effect of Hydraqui treatment on lesion size was evaluated by measuring the lesion with a dial caliper twice a week until the end of the treatment (A). Lesion size at the end of the treatment (35 days post-infection) (B). Evaluation of the parasite load in the infected tissues 35 days post-infection using limiting dilution analysis (LDA) (C), and by fluorometric assay (D). Fluorometric values are expressed as specific fluorescence units (FU) and are corrected for background uninfected ear values. ***P<0.001, **P<0.01, and *P<0.1 (compared with control group).

Thumbnail

FIGURE 3:
Evaluation of systemic toxicity in the treated mice. After 72 h of the end of the treatment period, serum samples were collected for the determination of the levels of (A) alanine aminotransferase (ALT), (B) aspartate transaminase (AST), (C) gamma-glutamyl transpeptidase (GGT) and (D) creatinine, using colorimetric diagnostic kits. Results are expressed as mean ± standard deviation, and ***P<0.001 and **P<0.01 represent significant difference compared to the control group.

FIGURE 1: **Effect of Hydraqui in the treatment of L. amazonensis-infected macrophages.** Murine macrophages were infected with L. amazonensis and treated with the indicated concentrations of Hydraqui for 72 h at 33 ºC/5% CO₂. After the cells were stained with Giemsa, the percentage of infection (A) and the number of recovered amastigotes (B) were calculated by counting 200 cells, in duplicate. Data were expressed as the means of three independent experiments, which were performed in duplicate. P<0.001; P<0.01, and P<0.1 (compared with control group).

FIGURE 2: **Efficacy of Hydraqui in the treatment of L. amazonensis-infected mice. The effect of Hydraqui treatment on lesion size was evaluated by measuring the lesion with a dial caliper twice a week until the end of the treatment (A). Lesion size at the end of the treatment (35 days post-infection) (B). Evaluation of the parasite load in the infected tissues 35 days post-infection using limiting dilution analysis (LDA) (C), and by fluorometric assay (D). Fluorometric values are expressed as specific fluorescence units (FU) and are corrected for background uninfected ear values. *P<0.001, **P<0.01, and *P<0.1 (compared with control group).

FIGURE 3: Evaluation of systemic toxicity in the treated mice. After 72 h of the end of the treatment period, serum samples were collected for the determination of the levels of (A) alanine aminotransferase (ALT), (B) aspartate transaminase (AST), (C) gamma-glutamyl transpeptidase (GGT) and (D) creatinine, using colorimetric diagnostic kits. Results are expressed as mean ± standard deviation, and *P<0.001 and P<0.01 represent significant difference compared to the control group.

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Efficacy of the 7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline derivative against infection caused by <i>Leishmania amazonensis</i>

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[1] Corresponding author: Dra. Elaine Soares Coimbra. e-mail:elaine.coimbra@ufjf.edu.br