Synthesis of vanillin derivatives with 1,2,3-triazole fragments and evaluation of their fungicide and fungistatic activities.

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well-known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3-triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty-two vanillin derivatives were obtained, with yields in the range of 60%-91%, from copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL-1 . Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four-dimensional structure-activity relationship (4D-SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α-demethylase enzyme active site with binding energies ranging from -9.1 to -12.2 kcal/mol.

Leishmanicidal and cytotoxic activities and 4D-QSAR of 2-arylidene indan-1,3-diones.

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.

Synthesis, insecticidal activity, and phytotoxicity of novel chiral amides.

BACKGROUND: The lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae), is an important pest of stored grains worldwide. Chemical control is the main method used to manage this pest, but the continuous use of insecticides can lead to the selection of resistant R. dominica strains. Thus, there is a constant demand for the development of new insecticide molecules. This study describes the synthesis of 14 chiral amides and evaluation of their insecticidal activity against R. dominica. Their phytotoxicity to wheat (Triticum sativum) seeds is also evaluated. RESULTS: In the screening assay, compounds 8i and 8j caused 100% and 87% mortality of R. dominica. These values did not differ from the mortality caused by Bifenthrin® (75%). Amide 8i presented similar toxicity (LD50  = 27.98 µmol g-1 , CI95  = 25.14-30.71) and speed of action (LT50  = 22 h, CI95  = 19.34-24.66) to amide 8j (LD50  = 29.37 µmol g-1 , CI95  = 27.43-31.09, and LT50  = 19 h, CI95  = 17.05-20.95) against the pest. Both amides inhibited less than 44% of wheat growth. CONCLUSION: Among the tested amides, only 8i and 8j were effective in R. dominica control and presented no considerable phytotoxicity towards wheat seeds. Therefore, these amides are promising as insecticides for the management of R. dominica. © 2018 Society of Chemical Industry.

Active insecticides for Diaphania hyalinata selective for the natural enemy Solenopsis saevissima.

The objective of this study was to determine the toxicity of the nine synthetic dienamides against the insect pest Diaphania hyalinata (melonworm) and the selectivity of these substances for the predator Solenopsis saevissima (fire ant). Four bioassays were conducted. To begin with, the dienamides that caused high mortality of D. hyalinata have been selected. In the second bioassay the dose-mortality curves of the selected dienamides have been constructed. In the third bioassay, the survival curves for D. hyalinata and the elapsed time to kill 50% of their population have been determined. In the fourth biological test, the selectivity of the substances to the predator S. saevissima has been evaluated. The most active (2E,4E)-N-butylhexa-2,4-dienamide 3d has killed 95% of the melonworm, D. hyalinata, and less than 10% of the natural enemy S. saevissima. The results presented by this compound are superior to the outcome displayed by the commercial insecticide Malathion®. Three of the dienamides prepared in this manuscript have proven to be selective in killing the pest, but not the beneficial insect.