Host-guest complexation of phthalimide-derived strigolactone mimics with cyclodextrins. Application in agriculture against parasitic weeds.

Parasitic weeds are noxious plants that damage crops of economic relevance, especially in Mediterranean and African countries. The strategy of suicidal germination was proposed to deal with this plague by using seed germination inducers that work as a pre-emergence herbicide and reduce the parasitic seed load before sowing. N-Substituted phthalimides with a furanone ring were found to be efficient in inducing the germination of Phelipanche ramosa and Orobanche cumana, two of the most problematic parasitic weeds of crops. However, the solubility of these compounds in water is low. A strategy for enhancing their aqueous solubility is the synthesis of host-guest complexes with cyclodextrins. Three bioactive phthalimide-lactones (PL01, PL04, and PL07) were selected and studied to form complexes of increased water solubility with α-, ß-, HP-ß-, and γ-cyclodextrin. The complexes obtained by the coprecipitation method, with increased aqueous solubility (up to 3.8 times), were studied for their bioactivity and they showed similar or slightly higher bioactivity than free phthalimide-lactones, even without the addition of organic solvents. A theoretical study using semiempirical calculations of molecular models including a solvation system confirmed the physicochemical empirical results. These results demonstrated that cyclodextrins can be used to improve the physicochemical and biological properties of parasitic seed germination inducers.

On the formulation of disulfide herbicides based on aminophenoxazinones: polymeric nanoparticle formulation and cyclodextrin complexation to combat crop yield losses.

BACKGROUND: The resistance of weeds to herbicides is a significant issue in ensuring future food supply. Specific examples are Plantago lanceolata, Portulaca oleracea and Lolium rigidum, which mainly infect rice, wheat, barley and pastures, and cause high yield losses every year. In this regard, natural products and their mimics have provided new hope as a result of their different modes-of-action, activity at low concentrations and reduced pollution effects relative to conventional herbicides. However, the poor water solubility and physicochemical properties of these compounds limit their broad application. These problems can be addressed by formulation techniques, and encapsulation appears to be of great interest. RESULTS: Disulfide herbicides inspired by aminophenoxazinones have been formulated with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), γ-CD and polymeric nanoparticles (NPs). In silico studies were employed to identify which complexes would be generated and complex formation was confirmed by nuclear magnetic resonance spectroscopy. Solubility diagrams were generated to assess any improvement in water solubility, which was enhanced 2-13-fold. Scanning electron microscopy and energy-dispersive X-ray spectra confirmed the success of the formulation process for the nanoparticles. Formulated compounds were evaluated in an in vitro wheat coleoptile bioassay, with almost 100% elongation inhibition achieved using only water for the bioassay. Specific in vitro testing on weed phytotoxicity showed that the application of core/shell NPs is highly effective in the fight against P. lanceolata seed germination. CONCLUSIONS: The formulation of disulfide herbicides with CD complexes and NPs led to an enhancement in water solubility and bioactivity. These systems can be applied in pre-emergent mode against P. lanceolata, using only water to prepare the sample, and they showed better activity than the positive controls. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Stability and pKa Modulation of Aminophenoxazinones and Their Disulfide Mimics by Host-Guest Interaction with Cucurbit[7]uril. Direct Applications in Agrochemical Wheat Models.

Aqueous solubility and stability often limit the application of aminophenoxazinones and their sulfur mimics as promising agrochemicals in a sustainable agriculture inspired by allelopathy. This paper presents a solution to the problem using host-guest complexation with cucurbiturils (CBn). Computational studies show that CB7 is the most suitably sized homologue due to its strong affinity for guest molecules and its high water solubility. Complex formation has been studied by direct titrations monitored using UV-vis spectroscopy, finding a preferential interaction with protonated aminophenoxazinone species with high binding affinities (CB7·APOH+, Ka = (1.85 ± 0.37) × 106 M-1; CB7·DiS-NH3+, Ka = (3.91 ± 0.53) × 104 M-1; and DiS-(NH3+)2, Ka= (1.27 ± 0.42) × 105 M-1). NMR characterization and stability analysis were also performed and revealed an interesting pKa modulation and stabilization by cucurbiturils (2-amino-3H-phenoxazin-3-one (APO), pKa = 2.94 ± 0.30, and CB7·APO, pKa = 4.12 ± 0.15; 2,2'-disulfanediyldianiline (DiS-NH2), pKa = 2.14 ± 0.09, and CB7·DiS-NH2, pKa = 3.26 ± 0.09), thus favoring applications in different kinds of crop soils. Kinetic studies have demonstrated the stability of the CB7·APO complex at different pH media for more than 90 min. An in vitro bioassay with etiolated wheat coleoptiles showed that the bioactivity of APO and DiS-NH2 is enhanced upon complexation.

In Silico Evaluation of Sesquiterpenes and Benzoxazinoids Phytotoxins against Mpro, RNA Replicase and Spike Protein of SARS-CoV-2 by Molecular Dynamics. Inspired by Nature.

In the work described here, a number of sesquiterpenes and benzoxazinoids from natural sources, along with their easily accessible derivatives, were evaluated against the main protease, RNA replicase and spike glycoprotein of SARS-CoV-2 by molecular docking. These natural products and their derivatives have previously shown remarkable antiviral activities. The most relevant compounds were the 4-fluoro derivatives of santamarine, reynosin and 2-amino-3H-phenoxazin-3-one in terms of the docking score. Those compounds fulfill the Lipinski's rule, so they were selected for the analysis by molecular dynamics, and the kinetic stabilities of the complexes were assessed. The addition of the 4-fluorobenzoate fragment to the natural products enhances their potential against all of the proteins tested, and the complex stability after 50 ns validates the inhibition calculated. The derivatives prepared from reynosin and 2-amino-3H-phenoxazin-3-one are able to generate more hydrogen bonds with the Mpro, thus enhancing the stability of the protein-ligand and generating a long-term complex for inhibition. The 4-fluoro derivate of santamarine and reynosin shows to be really active against the spike protein, with the RMSD site fluctuation lower than 1.5 Å. Stabilization is mainly achieved by the hydrogen-bond interactions, and the stabilization is improved by the 4-fluorobenzoate fragment being added. Those compounds tested in silico reach as candidates from natural sources to fight this virus, and the results concluded that the addition of the 4-fluorobenzoate fragment to the natural products enhances their inhibition potential against the main protease, RNA replicase and spike protein of SARS-CoV-2.

Encapsulation of Cynara Cardunculus Guaiane-type Lactones in Fully Organic Nanotubes Enhances Their Phytotoxic Properties.

The encapsulation of bioactive natural products has emerged as a relevant tool for modifying the poor physicochemical properties often exhibited by agrochemicals. In this regard, natural guaiane-type sesquiterpene lactones isolated from Cynara cardunculus L. have been encapsulated in a core/shell nanotube@agrochemical system. Monitoring of the F and O signals in marked sesquiterpenes confirmed that the compound is present in the nanotube cavity. These structures were characterized using scanning transmission electron microscopy-X-ray energy-dispersive spectrometry techniques, which revealed the spatial layout relationship and confirmed encapsulation of the sesquiterpene lactone derivative. In addition, biological studies were performed with aguerin B (1), cynaropicrin (2), and grosheimin (3) on the inhibition of germination, roots, and shoots in weeds (Phalaris arundinacea L., Lolium perenne L., and Portulaca oleracea L.). Encapsulation of lactones in nanotubes gives better results than those for the nonencapsulated compounds, thereby reinforcing the application of fully organic nanotubes for the sustainable use of agrochemicals in the future.

An Overview of the Chemical Characteristics, Bioactivity and Achievements Regarding the Therapeutic Usage of Acetogenins from Annona cherimola Mill.

Annona cherimola Mill., or the custard apple, is one of the species belonging to the Annonaceae family, is widely used in traditional medicine, and has been reported to be a valuable source of bioactive compounds. A unique class of secondary metabolites derived from this family are Annonaceous acetogenins, lipophilic polyketides considered to be amongst the most potent antitumor compounds. This review provides an overview of the chemical diversity, isolation procedures, bioactivity, modes of application and synthetic derivatives of acetogenins from A. cherimola Mill.

One-Step Encapsulation of ortho-Disulfides in Functionalized Zinc MOF. Enabling Metal-Organic Frameworks in Agriculture.

Application of natural products as new green agrochemicals with low average lifetime, low concentration doses, and safety is both complex and expensive due to chemical modification required to obtain desirable physicochemical properties. Transport, aqueous solubility, and bioavailability are some of the properties that have been improved using functionalized metal-organic frameworks based on zinc for the encapsulation of bioherbicides (ortho-disulfides). An in situ method has been applied to achieve encapsulation, which, in turn, led to an improvement in water solubility by more than 8 times after 2-hydroxypropyl-ß-cyclodextrin HP-ß-CD surface functionalization. High-resolution high-angle annular dark-field scanning transmission electron microscopy (HR HAADF-STEM) and integrated differential phase contrast (iDPC) imaging techniques were employed to verify the success of the encapsulation procedure and crystallinity of the sample. Inhibition studies on principal weeds that infect rice, corn, and potato crops gave results that exceed those obtained with the commercial herbicide Logran. This finding, along with a short synthesis period, i.e., 2 h at 25 °C, make the product an example of a new generation of natural-product-based herbicides with direct applications in agriculture.

Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach.

Semisynthetic analogs of natural products provide an important approach to obtain safer and more active drugs and they can also have enhanced physicochemical properties such as persistence, cross-membrane processes and bioactivity. Acyl derivatives of different natural product families, from sesquiterpene lactones to benzoxazinoids, have been synthesized and tested in our laboratories. These compounds were evaluated against tumoral and nontumoral cell lines to identify selective derivatives with a reduced negative impact upon application. The mode of action of these compounds was analyzed by anti-caspase-3 assays and molecular dynamics simulations with cell membrane re-creation were also carried out. Aryl derivatives of eudesmanolide stand out from the other compounds and are better than current anticancer drugs such as etoposide in terms of selectivity and activity. Computational studies provide evidence that lipophilicity plays a key role and the 4-fluorobenzoyl derivative can pass easily through the cell membrane.

Bio-Guided Isolation of Acetogenins from Annona cherimola Deciduous Leaves: Production of Nanocarriers to Boost the Bioavailability Properties.

Annonaceous acetogenins (ACGs) are lipophilic polyketides isolated exclusively from Annonaceae. They are considered to be amongst the most potent antitumor compounds. Nevertheless, their applications are limited by their poor solubility. The isolation of ACGs from Annona cherimola leaves, an agricultural waste, has not been reported to date. Molvizarin (1) cherimolin-1 (2), motrilin (3), annonacin (4) and annonisin (5) are isolated for the first time from A. cherimola deciduous leaves. Annonacin was found to be four- and two-times more potent in tumoral cells (HeLa, 23.6% live cells; IGROV-1, 40.8% live cells for 24 h) than in HEK-293 at 50 µM (24 h, 87.2% live cells). Supramolecular polymer micelles (SMPMs) were synthesized to encapsulate the major ACG isolated, annonacin, in order to improve its solubility in aqueous media. The bioavailability of this compound was increased by a factor of 13 in a simulated human digestive system when compared with free annonacin and an encapsulation efficiency of 35% was achieved. In addition, the cytotoxic activity of SMPMs that hosted annonacin (100 µM, 24 h, 5.8% live cells) was increased compared with free annonacin in water (100 µM, 24 h, 92% live cells). These results highlight the use of by-products of A. cherimola, and their pure compounds, as a promising source of anticancer agents. The use of SMPMs as nanocarriers of ACGs could be an alternative for their application in food field as nutraceutical to enhance the administration and efficacy.

Synthesis of Vlasouliolides: A Pathway toward Guaiane-Eudesmane C17/C15 Dimers by Photochemical and Michael Additions.

Vladimiria souliei is a plant found in China used in traditional medicine. Recent isolation studies have led to the discovery of vlasouliolides, which are natural sesquiterpene dimers. However, the yields obtained from isolation have proven to be really low (<0.01%), greatly hindering the study of these molecules. In this work, we propose a simple synthetic route to obtain different vlasouliolides in good yields from dehydrocostuslactone and costunolide, which will lead to further bioactivity studies at a higher scale.

In Situ Eco Encapsulation of Bioactive Agrochemicals within Fully Organic Nanotubes.

Agrochemical encapsulation agents used up to now are commonly based on polymeric compounds or metal particles, but the employment of other natural products such as host structures has not been tackled in detail. In the work reported here, fully organic nanotubes composed of human bile acid (lithocholic acid) have been synthesized. These nanotubes were employed to encapsulate potential disulfide herbicide mimics that have previously shown relevant inhibitory activity against weeds. The three-dimensional chemical information from scanning transmission electron microscope analytical tomography with subnanometer scale resolution convincingly demonstrates for the first time the occurrence of efficient encapsulation within a fully organic nanotube of different organic molecules with activity as herbicides. The encapsulation was achieved in a one-pot synthesis, in an aqueous environment and under in situ conditions without using any marker or coating with contrast materials, which renders the process greener than those routinely used. The nanotubes allow complete water solubilization, with an encapsulation percentage of up to 78% in all of the herbicide compounds. Furthermore, nanotubes showed a flattened arrangement due to the host-guest interaction. The synthetic approach represents a step forward in solving the key problem of the quite limited solubility of natural agrochemicals in aqueous environments. In addition, the process presents a breakthrough in the use of natural products produced by the human body as encapsulating agents, which expands possible future applications. The preliminary docking approach clarifies that the 2o01 transmembrane transport protein seems to be the prior channel of the organic nanotube in the delivery process to vegetable cells. The etiolated wheat coleoptile bioassay demonstrated that the encapsulated herbicides have improved the bioactivity of free compounds, keeping 60% of inhibition of the weed at least for every disulfide, a requisite for their fruitful application as agrochemicals.

Provitamin supramolecular polymer micelle with pH responsiveness to control release, bioavailability enhancement and potentiation of cytotoxic efficacy.

Encapsulation techniques to generate core/shell systems provide a method that improves physicochemical properties, which are very important in biological applications. ß-carotene is a common carotenoid that has shown preventive effects in skin diseases and vitamin A deficiency but this compound has limited water solubility and bioavailability, which hinder its broad application. The use of polyrotaxane compounds formed from cyclodextrins has allowed supramolecular polymer micelles (SMPMs) to be synthesized to encapsulate ß-carotene. The polymeric compound Pluronic F127® was also used to create core/shell nanoparticles (NPs) that contain ß-carotene. Bioactive compound encapsulation was fully confirmed by nuclear magnetic resonance spectroscopy and by scanning and transmission electron microscopy. The method based on cyclodextrin and lecithin allow to release slowly when the systems were exposed to an aqueous medium by pH control, with an increase of 16 times of bioavailability comparing with free carotenoid. This allowed to potentiate the cytotoxic activity on a melanoma cell line by enhancing the water solubility to more than 28 mg/L, and present promising applications of SMPMs to provitamins.

A Novel Electron Microscopic Characterization of Core/Shell Nanobiostimulator Against Parasitic Plants.

Nanoencapsulation has proven to be an efficient route to increase significantly the solubility and bioavailability of organic compounds. This aspect of nanotechnology is illustrated for the case of phthalimide-lactone (PL), a recently synthesized strigolactone mimic whose very limited solubility in water, as a free chemical, precludes its practical use as an agrochemical in the fight against parasitic plants. Pluronic F-127 (P127) nanoparticles functionalized with PL have been synthesized and embedded in a polymeric matrix of poly(vinyl alcohol) (PVA). Low-voltage and medium voltage imaging and spectroscopic scanning electron microscopy (S(T)EM) techniques were combined to confirm the synthesis of multicore nanoparticles that were rich in nitrogen, a finding that is due to the successful encapsulation of PL. This PL@P127/PVA nanobiostimulator formulation has an impressive solubility in water, that is, 27 times higher than that of pure phthalimide-lactone. Also critical from the functional point of view, comparative bioassays clearly showed that the intrinsic stimulatory activity of this agrochemical is fully maintained in the nanoencapsulated formulation.