title: Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis.
abstract: A series of eleven 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones (16-27) was synthesised as part of a study to search for potential new drugs with a leishmanicidal effect. The thiosemicarbazones, ten of which are new compounds, were prepared in good yields (85-98%) by the reaction of 3,4-methylenedioxyde-6-benzaldehydes (6-X-piperonal), previously synthesised for this work by several methodologies, and thiosemicarbazide in ethanol with a few drops of H2SO4. These compounds were evaluated against Leishmania amazonensis promastigotes, and derivatives where X = I (22) and X = CN (23) moieties showed impressive results, having IC₅₀ = 20.74 μM and 16.40 μM, respectively. The intracellular amastigotes assays showed IC₅₀ = 22.00 μM (22) and 17.00 μM (23), and selectivity index >5.7 and >7.4, respectively, with a lower toxicity compared to pentamidine (positive control, SI = 4.5). The results obtained from the preliminary QSAR study indicated the hydrophobicity (log P) as a fundamental parameter for the 2D-QSAR linear model. A molecular docking study demonstrated that both compounds interact with flavin mononucleotide (FMN), important binding site of NO synthase.
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23.890-000 Seropédica, RJ, Brazil.
authors.forename: Jorge Luiz R
authors.initials: JL
authors.lastname: de Melos
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Eduardo Caio
authors.initials: EC
authors.lastname: Torres-Santos
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Viviane dos S
authors.initials: Vdos S
authors.lastname: Faiões
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23.890-000 Seropédica, RJ, Brazil.
authors.forename: Catarina de Nigris
authors.initials: Cde N
authors.lastname: Del Cistia
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23.890-000 Seropédica, RJ, Brazil.
authors.forename: Carlos Maurício R
authors.initials: CM
authors.lastname: Sant'Anna
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23.890-000 Seropédica, RJ, Brazil.
authors.forename: Cláudio Eduardo
authors.initials: CE
authors.lastname: Rodrigues-Santos
authors.affiliation: Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23.890-000 Seropédica, RJ, Brazil. Electronic address: echevarr@ufrrj.br.
authors.forename: Aurea
authors.initials: A
authors.lastname: Echevarria
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007891:Leishmania / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D052117:Benzodioxoles; D013882:Thiosemicarbazones
keywords: Amastigotes; Leishmania amazonensis; Promastigotes; Thiosemicarbazones