Cinamatos e tionocinamatos larvicidas: uma contribuição ao controle químico do Aedes aegypti L.

Abstract

Dengue has become a public health problem, not only in Brazil but in the world, in addition to other arboviruses that Aedes aegypti transmits such as Zika, chikungunya and yellow fever. As an alternative in vector control, we have natural products, in particular cinnamic acid derivatives, which are alternative, renewable and biodegradable sources. Therefore, the aim of this study was to evaluate the larvicidal activity of a series of cinnamic acid derivatives on L4 larvae of Aedes aegypti L. and perform in silico analyses from the data obtained. Alkyl and aryl esters cinnamic acid derivatives were prepared through Fischer esterification, reaction with alkyl and aryl halides, and Mitsunobu reaction; while thionoesters were obtained via the thionation reaction. They were characterized by IR, 1H and 13C NMR, and EMAR for the unpublished derivatives. All products were submitted to the larvicidal assay to determine the concentration that kills 50% of the larvae, the LC50. Thirty-two cinnamic acid derivatives were obtained, with yields varying between 10.9–90.0%, being 7 unpublished compounds in the literature: 3,5-dimethyl-benzyl cinnamate (12), 4-thio-methyltrifluor-benzyl cinnamate (13), 3-metiltrifluor-benzyl cinnamate (14), 4-isopropyl-benzyl cinnamate (23), 4-hydroxy-3-methoxy-benzyl cinnamate (28), pentyl thionocinnamate (31) and benzyl thionocinnamate (32). The larvicidal assay showed that 26 esters and 4 thionoesters showed larvicidal activity. Cinnamates with alkyl substituents, isopropyl cinnamate (4), butyl cinnamate (6) and pentyl cinnamate (7) showed the best larvicidal activities (0.52 mM, 0.21 mM and 0.17 mM, respectively); while for aryls, the most pronounced result was for the benzyl cinnamate (21) (0.55 mM). In relation to thionocinnamates, 29 (R = isopropyl), 30 (R = butyl), 31 (R = pentyl) and 32 (R = benzyl), all were bioactive (0.24 mM, 0.54 mM, 0.37 mM and 0.28 mM, respectively). The analysis of the structure-activity relationship showed that the linear chain with a maximum of 5 carbons, benzyl ring without substitution and the presence of thiocarbonyl in the chemical structure influenced the larvicidal activity. The result of molecular docking of the most potent compound, pentyl cinnamate (7), and its respective thionoester, pentyl thionocinnamate (31), suggested the possible biological targets: HDAC2, CCC2, CA and CCC3 for 7; and CAV, SDH3 and TRYP for 31. The QSAR indicated in the ecotoxicological prediction low toxicity for the thionocinnamates in relation to the control.