Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis

• Published in: European journal of medicinal chemistry 2015-10, Vol.103, p.409-417
• Main Authors: de Melos, Jorge Luiz R., Torres-Santos, Eduardo Caio, Faiões, Viviane dos S., de Nigris Del Cistia, Catarina, Sant'Anna, Carlos Maurício R., Rodrigues-Santos, Cláudio Eduardo, Echevarria, Aurea
• Format: Article
• Language: English
• Subjects: Amastigotes; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Benzodioxoles - chemical synthesis; Benzodioxoles - chemistry; Benzodioxoles - pharmacology; Dose-Response Relationship, Drug; Leishmania - drug effects; Leishmania amazonensis; Molecular Structure; Parasitic Sensitivity Tests; Promastigotes; Structure-Activity Relationship; Thiosemicarbazones; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.09.009

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. [Display omitted] •New 6-X-piperonal-thiosemicarbazones with antileishmanial activity were synthesized.•Among thiosemicarbazones assayed two had good activity against L. amazonensis.•The thiosemicarbazones showed smaller toxicity compared to pentamidine used as positive control.