Conservation Biological Control of Codling Moth (Cydia pomonella): Effects of Two Aromatic Plants, Basil (Ocimum basilicum) and French Marigolds (Tagetes patula).

The addition of flowering companion plants within or around crop fields is a promising strategy to strengthen pest regulation by their natural enemies. Aromatic plants are frequently used as companion plants, but their effects on natural enemies remain unclear under field conditions. Here, we evaluated the effects of two aromatic plant species on the parasitism of the codling moth (Cydia pomonella) and the recruitment of predatory arthropods (spiders, earwigs) in a factorial field experiment. Apple trees were intercropped with basil (Ocimum basilicum), French marigolds (Tagetes patula), or ryegrass (Lolium perenne). The association between apple trees and O. basilicum increases codling moth parasitism, but does not affect arthropod predator abundances. Furthermore, we find a general negative effect of T. patula on arthropod diversities and abundances, including the pest and its natural enemies. Finally, changes in the parasitism rate and arthropod community structure due to the aromatic plants do not reduce codling moth density or associated apple damage. Further experiments are needed to determine the mechanisms involved in aromatic plant effects on pest repellence and on natural enemy recruitment (volatile organic compound composition, floral resource supply, or pest density dependence).

Non-host volatiles disturb the feeding behavior and reduce the fecundity of the green peach aphid, Myzus persicae.

BACKGROUND: The association of crops of value with companion plants could be one of the strategies to reduce the harmful effects of pests. We hypothesize that volatile organic compounds (VOCs) emitted by some aromatic plants may negatively impact M. persicae, disturbing its feeding behavior and consequently its reproduction. RESULTS: VOCs emitted from six potential companion plant species affected the reproduction of M. persicae feeding on pepper plants, Capsicum annuum. Reproduction of M. persicae was reduced when exposed to VOCs from leaves of Ocimum basilicum and flowers of Tagetes patula. Thus, species and phenology of the companion plant can influence the effect. The VOCs from O. basilicum and T. patula also reduced phloem feeding by the aphids based on electropenetrography (EPG). CONCLUSION: The reduced fecundity of M. persicae could be linked to aphid feeding disruption provoked by the VOCs emitted by O. basilicum in the vegetative stage or T. patula cv. Nana in the flowering stage. © 2020 Society of Chemical Industry.

Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat.

Inhibition of phosphodiesterase 2A (PDE2A) has been proposed as a potential approach to enhance cognitive functioning and memory through boosting intracellular cGMP/cAMP and enhancing neuroplasticity in memory-related neural circuitry. Previous preclinical studies demonstrated that PDE2A inhibitors could reverse N-methyl-D-aspartate receptor antagonist (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]-imidazo[5,1-f][1,2,4]triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg. Target engagement at this efficacious dose was explored using in vivo autoradiography. Converse to the results of a decrease of PDE2A binding (target occupancy) by the PDE2A inhibitor, a paradoxical increase (up to 40%) in PDE2A binding was detected. However, a typical target occupancy curve could be generated by PF-05180999 at much higher doses. In vitro experiments using recombinant PDE2A protein or rat brain homogenate that contains native PDE2A protein demonstrated that increased cGMP after initial PDE2A inhibition could be responsible for the activation of PDE2A enzyme via allosteric binding to the GAF-B domain, leading to positive cooperativity of the dormant PDE2A enzymes. Our results suggest that when evaluating target engagement of PDE2A inhibitors for memory disorder in clinical setting with occupancy assays, the efficacious dose may not fall on the typical receptor/target curve. On the contrary, an increase in PDE2A tracer binding is likely seen. Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered.

Repellence of Myzus persicae (Sulzer): evidence of two modes of action of volatiles from selected living aromatic plants.

BACKGROUND: Intercropping companion plants (CPs) with horticultural crops could be an eco-friendly strategy to optimize pest management. In this research, volatile organic compounds (VOCs) emitted by some CPs were investigated for their repellent properties towards the green peach aphid (Myzus persicae Sulzer). The aim of this study was to understand the modes of action involved: direct effects on the aphid and/or indirect effects via the host plant (pepper, Capsicum annuum L.). RESULTS: We identified two promising repellent CP species: the volatile blend from basil (Ocimum basilicum, direct repellent effect) and the mixture of (or previously intercropped) C. annuum plants with Tagetes patula cv. Nana (indirect effect). This effect was cultivar-dependent and linked to the volatile bouquet. For the 16 compounds present in the O. basilicum or T. patula bouquets tested individually, (E)-ß-farnesene, and eugenol reported good repellent properties against M. persicae. Other compounds were repellent at medium and/or highest concentrations. Thus, the presence of repellent VOCs in a mixture does not mean that it has a repellent propriety. CONCLUSION: We identified two promising repellent CP species towards M. persicae, with a likely effect of one CP's VOCs on the host plant repellency and highlighted the specific effectiveness of VOC blends. © 2018 Society of Chemical Industry.

Decision Making in Medicinal Chemistry: The Power of Our Intuition.

Medicinal chemists rely on their intuition to make decisions regarding the course of a medicinal chemistry program. Our ability to accurately and efficiently process large data sets routinely requires that we reduce the volume of information to manageable proportions. This prioritization process, however, can be affected by intuitive biases. One such situation is structure-activity relationship (SAR) analysis in nonadditive data sets in which attempts to intuitively predict the activity of compounds based on preliminary data can lead to erroneous conclusions. Matrix analysis can be a useful tool to accurately determine the nature of the SAR and to improve our decision-making process during an analoging campaign.

Mathematical and Structural Characterization of Strong Nonadditive Structure-Activity Relationship Caused by Protein Conformational Changes.

In medicinal chemistry, accurate prediction of additivity-based structure-activity relationship (SAR) analysis rests on three assumptions: (1) a consistent binding pose of the central scaffold, (2) no interaction between the R group substituents, and (3) a relatively rigid binding pocket in which the R group substituents act independently. Previously, examples of nonadditive SAR have been documented in systems that deviate from the first two assumptions. Local protein structural change upon ligand binding, through induced fit or conformational selection, although a well-known phenomenon that invalidates the third assumption, has not been linked to nonadditive SAR conclusively. Here, for the first time, we present clear structural evidence that the formation of a hydrophobic pocket upon ligand binding in PDE2 catalytic site reduces the size of another distinct subpocket and contributes to strong nonadditive SAR between two otherwise distant R groups.

Companion Plants for Aphid Pest Management.

A potential strategy for controlling pests is through the use of "companion plants" within a crop system. This strategy has been used in several trials to fight against a major crop insect pest: the aphid. We reviewed the literature to highlight the major mechanisms by which a companion plant may act. Trials carried out under laboratory or field conditions revealed that companion plants operate through several mechanisms. A companion plant may be associated with a target crop for various reasons. Firstly, it can attract aphids and draw them away from their host plants. Secondly, it can alter the recognition of the host plant. This effect is mostly attributed to companion plant volatiles since they disturb the aphid host plant location, and additionally they may react chemically and physiologically with the host plant, making it an unsuitable host for aphids. Thirdly, it can attract natural enemies by providing shelter and food resources. In this review, the feasibility of using companion plants is discussed. We conclude that many factors need to be taken into account for a successful companion plant strategy. For the best long-term results, companion plant strategies have to be combined with other alternative approaches against aphids.

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.

A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.

The early spring N uptake of young peach trees (Prunus persica) is affected by past and current fertilizations and levels of C and N stores.

In deciduous trees, shoot development in early spring is assumed to be achieved mainly at the expense of nitrogen (N) stores. Indeed, the possible compensation for poor autumn N storage by early spring N uptake has been little studied. We therefore determined the dynamics of spring N uptake in relation to spring N supply, carbon and N storage and shoot development. Young peach trees (Prunus persica L. Batsch, cv. 'GF305') were raised outdoors in a hydroponic set-up during the spring and summer, with an excessive N supply. During the autumn, half of the trees were then N limited. The following spring, the N supply remained either high or low, or changed from high to low or low to high. Between 6 March and 13 May, N uptake was measured automatically on an hourly basis, while shoot growth was monitored once a week. These in situ measurements were completed by three destructive harvests to assess organ composition in N and total non-structural carbohydrates (TNC). Until the end of April, N uptake was dependent on the autumn N treatment, being higher in trees that had been N limited in the autumn. Total non-structural carbohydrate mobilization was also higher in those trees that had lost at least 17 g TNC by 24 April, while TNC levels in non-limited trees remained stable or even rose. Shoot development, estimated by the number of elongated axes and leaves per axis, was also slightly delayed by an N limitation in autumn. After 24 April, N uptake rates increased notably under all treatments and was determined by the spring N supply. In trees receiving a high N supply in the spring, the uptake rates also displayed marked short-term variations. That reduced the differences between treatments and by 13 May no differences could be evidenced between the trees in terms of organ biomass and TNC and N contents, whatever the treatment. We concluded that in the early spring, N uptake may compensate for a deficit of N storage insofar as large quantities of TNC can be mobilized for that purpose.

PDE2 inhibition: potential for the treatment of cognitive disorders.

Phosphodiesterase inhibition has received much attention in the past 20 years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic.

Azabenzthiazole inhibitors of leukotriene A4 hydrolase.

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.

Tricyclic aminopyrimidine histamine H4 receptor antagonists.

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.

Practical and scalable synthesis of a selective CCK1 receptor antagonist.

We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.

HPLC assay of tomato carotenoids: validation of a rapid microextraction technique.

Carotenoids are studied for their role as pigments and as precursors of aromas, vitamin A, abscisic acid, and antioxidant compounds in different plant tissues. A novel, rapid, and inexpensive analytical protocol is proposed to enable the simultaneous analysis of four major tomato carotenoids: lutein, lycopene, beta-carotene, and phytoene. Microextraction is performed in the presence of sodium chloride, n-hexane, dichloromethane, and ethyl acetate on fresh tomato powder that has been finely ground in liquid nitrogen. The carotenoids are extracted by agitation and centrifugation and then analyzed by HPLC using a diode array detector. The principal advantage of this extraction resides in the absence of an evaporation step, often necessary to assay tomato carotenoids other than lycopene. Whatever the carotenoid, tests for accuracy, reproducibility, and linearity were satisfactory and indicative of the method's reliability. The stability of extracts over time (several days at -20 degrees C) as the satisfactory sensitivity of the assay whatever the fruit ripeness had a part in the robustness of the method. Reliable, rapid, simple, and inexpensive, this extraction technique is appropriate for the routine analysis of carotenoids in small samples.

SAR studies of 1,5-diarylpyrazole-based CCK1 receptor antagonists.

A high throughput screening campaign revealed compound 1 as a potent antagonist of the human CCK(1) receptor. Here, we report the syntheses and SAR studies of 1,5-diarylpyrazole analogs with various structural modifications of the alkane side chain of the molecule. The difference in affinity between the two enantiomers for the CCK(1) receptor and the flexible nature of the linker led to the design of constrained analogs with increased potency.

Tetrahydroindazole inhibitors of bacterial type II topoisomerases. Part 2: SAR development and potency against multidrug-resistant strains.

We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.

Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis.

In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.

Pyrazole CCK(1) receptor antagonists. Part 2: SAR studies by solid-phase library synthesis and determination of Free-Wilson additivity.

High-throughput screening revealed compound 1 as a potent antagonist of the CCK(1) receptor. Here, we disclose the synthesis of combinatorial libraries by solid-phase synthesis on Kenner 'safety catch' resin. Additive QSAR models were used to determine a lack of consistent additive SAR within the matrix.

Tandem double intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes. The fused/bridged mode.

A new class of tandem [4+2]/[3+2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4+2]/intra [3+2] cycloadditions have been explored in which the dipolarophile is tethered at either C(5) or C(6) of the nitronate. For both families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and stereoselective. This method converts linear polyenes to functionalized polycyclic systems bearing up to six stereogenic centers.