Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity |
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Authors: | Evanoel Crizanto de Lima Frederico S. Castelo-Branco Claudia C. Maquiaveli André B. Farias Magdalena N. Rennó Nubia Boechat Edson R. Silva |
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Affiliation: | 1. Laboratório de Catálise e Síntese de Substâncias Bioativas, Universidade Federal do Rio de Janeiro Campus Macaé Professor Aloísio Teixeira, Estrada do Imburo s/n – Ajuda de Baixo, Macaé, RJ CEP 27979-000, Brazil;2. Departamento de Sintese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos – FIOCRUZ, Rio de Janeiro, RJ 21041-250, Brazil;3. Universidade de São Paulo Faculdade de Zootecnia e Engenharia de Alimentos, Departamento de Medicina Veterinária, Laboratório de Farmacologia e Bioquímica (LFBq), Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil;4. Instituto de Biodiversidade e Sustentabilidade NUPEM/UFRJ, Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Av. São José do Barreto, 764, Macaé, RJ 27965-045, Brazil |
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Abstract: | Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with Ki in the range of 1.3–26 μM. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound 4 (EC50 of 12.7 ± 0.3 μM). In addition, in order to obtain further insight into the binding mode of such compounds, molecular docking studies were performed to obtain additional validation of experimental results. Considering these results, it is possible to conclude that α,α-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg. |
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Keywords: | Corresponding authors. Polyamines Arginase Difluorohydrazide |
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