Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 103, Issue -, Pages 409-417Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.09.009
Keywords
Leishmania amazonensis; Promastigotes; Amastigotes; Thiosemicarbazones
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Funding
- CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [3808181/2011-5]
- CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) [E-26/110.590/2012]
- FAPERJ (Fundacao de Apoio a Pesquisa do Estado do Rio de Janeiro)
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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 mu M and 16.40 mu M, respectively. The intracellular amastigotes assays showed IC50 = 22.00 mu M (22) and 17.00 mu M (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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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