Novel Lactone-Based Insecticides and Drosophila suzukii Management: Synthesis, Potential Action Mechanisms and Selectivity for Non-Target Parasitoids.

Drosophila suzukii, an invasive insect pest, poses a significant threat to various fruit crops. The use of broad-spectrum insecticides to control this pest can reduce the effectiveness of biological control agents, such as the parasitoid Trichopria anastrephae. Here, we evaluated the toxicity of newly synthesized lactone derivatives on D. suzukii and their selectivity towards T. anastrephae. We used in silico approaches to identify potential targets from the most promising molecules in the D. suzukii nervous system and to understand potential differences in susceptibilities between D. suzukii and its parasitoid. Of the nine molecules tested, (rac)-8 and compound 4 demonstrated efficacy against the fly. Exposure to the estimated LC90 of (rac)-8 and compound 4 resulted in a mortality rate of less than 20% for T. anastrephae without impairing the parasitoid's functional parasitism. The in silico predictions suggest that (rac)-8 and compound 4 target gamma amino butyric acid (GABA) receptors and transient receptor potential (TRP) channels of D. suzukii. However, only the reduced interaction with TRP channels in T. anastrephae demonstrated a potential reason for the selectivity of these compounds on the parasitoid. Our findings suggest the potential for integrating (rac)-8 and compound 4 into D. suzukii management practices.

Synthesis and structural elucidation of a phthalide analog using NMR analysis and DFT calculations.

Phtalides are secondary metabolites found in several fungi with a wide range of biological activities. A novel phthalide analog was synthesized by Diels-Alder reaction between cyclopentadiene and 3,4-dichlorofuran-2(5H)-one. Quantum mechanical calculations were used in conjunction with the spectrometric methods to determine the structure of the title compound. The calculated NMR chemical shifts for eight candidate pairs of enantiomers were compared with the experimental NMR chemical shifts applying the DP4 probability and mean absolute errors methodology. DP4 analysis using 1 H and 13 C NMR chemical shifts without assignment of the signals presented 100% probability for the correct candidate structure 3d, proving the consistency of the method even without spectra interpretation. Results from theoretical calculation and NMR spectra interpretation were in agreement to the structure of rac-(3aR,4S,4aS,5R,8S,8aR,9R,9aS)-3a,9a-dichloro-3a,4,4a,5,8,8a,9,9a-octahydro-4,9:5,8-dimethanonaphtho[2,3-c]furan-1(3H)-one.

Herbicidal activity of isobenzofuranones and in silico identification of their enzyme target.

BACKGROUND: Given the weed resistance to various herbicides with different mechanisms of action, the search for new compounds that are more effective and exhibit low levels of impact to other species in nature has been imperative in the field of the agriculture. For this purpose, 16 phthalides, and furan-2(5H)-one were synthetized and evaluated for their effectiveness as herbicides in seeds of Sorghum bicolor (sorghum), Cucumis sativus (cucumber), and Allium cepa (onion). Furthermore, a preliminary in silico study was carried out to identify the enzyme target of the most active compounds. RESULTS: In the assays with S. bicolor, the mixture rac-(3aR,4R,5S,6S,7S,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one + rac-(3aR,4R,5R,6R,7S,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (15a + 15b) showed comparable inhibitory activity to (S)-metolachlor, which was used as control herbicide at concentrations ranging from 50 µm to 1000 µm. The developments of the seeds evaluated were altered by all 17 compounds, either stimulating or inhibiting. The best results were presented by compounds 15a, and 15b, either in their pure form or as a mixture. CONCLUSION: The results presented by 15a, and 15b were superior to the activity of the commercial herbicide (S)-metolachlor in the assays with C. sativus, and A. cepa. The in silico study provides strong evidence that the most active compounds bind to strigolactones esterases D14 through the same binding site of (5R)-5-hydroxy-3-methylfuran-2(5H)-one (H3M), which is one of the strigolactones (SLs) cleavage products. © 2019 Society of Chemical Industry.

Computation and structural elucidation of compounds formed via epoxide alcoholysis.

Isobenzofuranones are known for their wide range of biological activities such as fungicide, insecticide, and anticancer. The search for novel bioactive compounds was performed by reaction of epoxide 2 with methanol, ethanol, propan-1-ol, propan-2-ol, and butan-1-ol. The mechanism for the stereoselective and stereospecific epoxide opening with methanol was reasoned by calculating the transition states for the two putative structures (rac)-3a and (rac)-3b. The compound (rac)-3a is the kinetic product as inferred from the lower energies of its transition state (TS1). The 1 H and 13 C nuclear magnetic resonance (NMR) chemical shifts for these two candidate structures were calculated and compared with the experimental data using mean absolute error (MAE) and DP4 analyses. Therefore, the relative stereochemistry of (rac)-3a was established by the mechanism, MAE, and DP4 approaches. The hydroxyl group was acetylated to surpass the problem of signal overlapping of H5 and H6 in the 1 H NMR. The relative stereochemistry of the corresponding ester determined by NMR interpretation was in agreement with the structure of (rac)-3a.

Phthalides as promising insecticides against Tuta absoluta (Lepidoptera: Gelechiidae).

In this study, the insecticide potential of eight phthalides derived from furan-2(5H)-one was evaluated against Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) larvae. The potency of the most active phthalides and the susceptibility of six different T. absoluta populations to these compounds were determined. The toxicity of these molecules to two non-target species (Solenopsis saevissima Smith and Tetragonisca angustula Latreille) was also evaluated. Two phthalides (3 and 4) presented insecticide potential against T. absoluta. Phthalide 4 was as toxic as piperine (positive control) and both phthalides exhibited rapid action (LT50 < 2 hours). The variation in the susceptibility of T. absoluta populations to the phthalides 3 and 4 was low. Neither phthalide presented physiological selectivity for non-target species. Therefore, the phthalides 3 and 4 are promising molecules, or at least, a starting point for a chemical optimization program leading to formulations for the management of the tomato leafminer. The application of such products should be conducted according to the principles of ecological selectivity.

Characterization of novel isobenzofuranones by DFT calculations and 2D NMR analysis.

Phthalides are frequently found in naturally occurring substances and exhibit a broad spectrum of biological activities. In the search for compounds with insecticidal activity, phthalides have been used as versatile building blocks for the syntheses of novel potential agrochemicals. In our work, the Diels-Alder reaction between furan-2(5H)-one and cyclopentadiene was used successfully to obtain (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (2) and (3aS,4S,7R,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3). The endo adduct (2) was brominated to afford (3aR,4R,5R,7R,7aS,8R)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4S,5S,7S,7aR,8S)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (4) and (3aS,4R,5R,6S,7S,7aR)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4S,5S,6R,7R,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (5). Following the initial analysis of the NMR spectra and the proposed two novel unforeseen products, we have decided to fully analyze the classical and non-classical assay structures with the aid of computational calculations. Computation to predict the (13) C and (1) H chemical shifts for mean absolute error analyses have been carried out by gauge-including atomic orbital method at M06-2X/6-31+G(d,p) and B3LYP/6-311+G(2d,p) levels of theory for all viable conformers. Characterization of the novel unforeseen compounds (4) and (5) were not possible by employing only the experimental NMR data; however, a more conclusive structural identification was performed by comparing the experimental and theoretical (1) H and (13) C chemical shifts by mean absolute error and DP4 probability analyses. Copyright © 2016 John Wiley & Sons, Ltd.

Theoretical and experimental study of inclusion complexes formed by isoniazid and modified ß-cyclodextrins: 1H NMR structural determination and antibacterial activity evaluation.

Me-ß-cyclodextrin (Me-ßCD) and HP-ß-cyclodextrin (HP-ßCD) inclusion complexes with isoniazid (INH) were prepared with the aim of modulating the physicochemical and biopharmaceutical properties of the guest molecule, a well-known antibuberculosis drug. The architectures of the complexes were initially proposed according to NMR data Job plot and ROESY followed by density functional theory (DFT) calculations of (1)H NMR spectra using the PBE1PBE functional and 6-31G(d,p) basis set, including the water solvent effect with the polarizable continuum model (PCM), for various inclusion modes, providing support for the experimental proposal. An analysis of the (1)H NMR chemical shift values for the isoniazid (H6',8' and H5',9') and cyclodextrins (H3,5) C(1)H hydrogens, which are known to be very adequately described by the DFT methodology, revealed them to be extremely useful, promptly confirming the inclusion complex formation. An included mode which describes Me-ßCD partially enclosing the hydrazide group of the INH is predicted as the most favorable supramolecular structure that can be used to explain the physicochemical properties of the encapsulated drug. Antibacterial activity was also evaluated, and the results indicated the inclusion complexes are a potential strategy for tuberculosis treatment.

Experimental and theoretical NMR determination of isoniazid and sodium p-sulfonatocalix[n]arenes inclusion complexes.

In this work the inclusion complex formation of isoniazid with sodium p-sulfonatocalix[n]arenes is reported aiming to improve the physicochemical and biopharmaceutical properties of isoniazid a first line antibuberculosis drug. The architectures of the complexes were proposed according to NMR data Job plot indicating details on the insertion of the isoniazid in the calix[n]arenes cavities. DFT theoretical NMR calculations were also performed for sodium p-sulfonatocalix[4]arene complex with isoniazid, with various modes of complexation being considered, to provide support for the experimental proposal. A comparison between experimental and theoretical ¹H NMR chemical shifts profiles allowed for the inclusion complex characterization confirming the isoniazid inclusion mode which is preferentially through the hydrazide moiety. The remarkable agreement between experimental and theoretical NMR profiles adds support to their use in the structural characterization of inclusion compounds. Antibacterial activity was evaluated and the results indicated the inclusion complexes as a potential strategy for tuberculosis treatment.