title: Novel dialkylphosphorylhydrazones: Synthesis, leishmanicidal evaluation and theoretical investigation of the proposed mechanism of action.
abstract: As part of a program to develop new drugs for the treatment of neglected diseases, new dialkylphosphorylhydrazones were synthesized and evaluated against the trypanosomatid parasites Leishmania braziliensis and Leishmania amazonensis. The synthesis of these compounds proved satisfactory with yields ranging from moderate to good. The most active compounds against L. braziliensis presented IC50 values in the 10(-2) μM range, similar to that of the reference drug pentamidine. Two compounds, 4m and 4n, showed a significant dose dependent decrease in the infection index of L. amazonensis infected macrophages and caused a complete healing of nodules and ulcers when tested in vivo against L. amazonensis-infected mice, but the control of parasite burden at the inoculation site was statistically significant only in the case of treatment with 4n. A target fishing (reverse docking) approach using molecular docking with 15 enzymes of L. braziliensis indicated that the probable target of the active compounds was hexokinase, the first enzyme of the glycolytic pathway.
authors.affiliation: LaFI - Laboratório de Farmacologia e Imunidade, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, AL, Brazil.
authors.forename: Carolina Barbosa Brito
authors.initials: CB
authors.lastname: da Matta
authors.affiliation: LaFI - Laboratório de Farmacologia e Imunidade, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, AL, Brazil.
authors.forename: Aline Cavalcanti
authors.initials: AC
authors.lastname: de Queiroz
authors.affiliation: LaFI - Laboratório de Farmacologia e Imunidade, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, AL, Brazil.
authors.forename: Mariana Silva
authors.initials: MS
authors.lastname: Santos
authors.affiliation: LaFI - Laboratório de Farmacologia e Imunidade, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, AL, Brazil.
authors.forename: Magna Suzana
authors.initials: MS
authors.lastname: Alexandre-Moreira
authors.affiliation: Universidade Federal Rural do Rio de Janeiro, Departamento de Química, Rio de Janeiro, Seropédica, Brazil; CEFET/RJ - Centro Federal de Educação Tecnológica Celso Suckow da Fonseca, Itaguaí, RJ, Brazil.
authors.forename: Vinicius Tomaz
authors.initials: VT
authors.lastname: Gonçalves
authors.affiliation: Universidade Federal Rural do Rio de Janeiro, Departamento de Matemática, Rio de Janeiro, Seropédica, Brazil.
authors.forename: Catarina de Nigris
authors.initials: Cde N
authors.lastname: Del Cistia
authors.affiliation: Universidade Federal Rural do Rio de Janeiro, Departamento de Química, Rio de Janeiro, Seropédica, Brazil.
authors.forename: Carlos Mauricio R
authors.initials: CM
authors.lastname: Sant'Anna
authors.affiliation: Universidade Federal Rural do Rio de Janeiro, Departamento de Química, Rio de Janeiro, Seropédica, Brazil. Electronic address: dacosta@ufrrj.br.
authors.forename: João Batista N
authors.initials: JB
authors.lastname: DaCosta
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006593:Hexokinase / Q000378:metabolism; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006835:Hydrazones; D014344:Trypanocidal Agents; D006593:Hexokinase
keywords: Dialkylphosphorylhydrazones; Glycolytic pathway; Leishmanicidal activity; Molecular docking