Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity

Autor(es)

de Lima, Evanoel Crizanto ^[1] ; Castelo-Branco, Frederico S. ^[2] ; Maquiaveli, Claudia C. ^[3] ; Farias, Andre B. ^[4] ; Renno, Magdalena N. ^[4] ; Boechat, Nubia ^[2] ; Silva, Edson R. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Fed Rio de Janeiro, Lab Catalise & Sintese Subst Bioat, Campus Macae Prof Aloisio Teixeira, BR-27979000 Macae, RJ - Brazil

^[2] Farmanguinhos FIOCRUZ, Dept Sintese Farmacos, Inst Tecnol Farmacos, BR-21041250 Rio De Janeiro, RJ - Brazil

^[3] Univ Sao Paulo, Fac Zootecnia & Engn Alimentos, Dept Med Vet, Lab Farmacol & Bioquim LFBq, Av Duque de Caxias Norte 225, BR-13635900 Pirassununga, SP - Brazil

^[4] UFRJ, Inst Biodiversidade & Sustentabilidade NUPEM, Campus Macae Prof Aloisio Teixeira, BR-27965045 Macae, RJ - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 27, n. 17, p. 3853-3859, SEP 1 2019.
• Citações Web of Science: 0

Resumo

Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of alpha,alpha-difluorohydrazide and alpha,alpha-difluoramides against Leishmania amazonensis arginase (LaArg). Four alpha,alpha-difluorohydrazide derivatives showed activity against LaArg with K-i in the range of 1.3-26 mu M. 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 mu M). 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 alpha,alpha-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg. (AU)

• Processo FAPESP: 17/06917-4 - Estudo da via de síntese de poliaminas e síntese de tripanotiona para desenvolvimento de novos fármacos para tratamento da leishmaniose
• Beneficiário: Edson Roberto da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular