The current worldwide context promoting agroecology and green agriculture require the discovery of new ecofriendly and sustainable plant protection tools. Plant resistance inducers, called also elicitors, are one of the most promising alternatives fitting with such requirements. We produced here a set of 30 molecules from pyroglutamic acid, bio-sourced from sugar beet byproducts, and examined for their biological activity on the major agro-economically pathosystem wheat- Zymoseptoria tritici . Foliar application of the molecules provided significant protection rates (up to 63% disease severity reduction) for 16 among them. Structure–activity relationship analysis highlighted the importance of all chemical groups of the pharmacophore in the bioactivity of the molecules. Further investigations using in vitro and in planta antifungal bioassays as well as plant molecular biomarkers revealed that the activity of the molecules did not rely on direct biocide activity towards the pathogen, but rather on the activation of plant defense mechanisms dependent on lipoxygenase, phenylalanine ammonia-lyase, peroxidase, and pathogenesis-related protein pathways. This study reports a new family of bio-sourced resistance inducers and provides new insights into the valorization of agro-resources to develop the sustainable agriculture of tomorrow.

A clean, safe, and efficient method for the N-carboxyalkylation of lactams was designed and studied in the current report. This three-component coupling of the substrate, carbon dioxide and an alkyl halide, has been developed as a green alternative to phosgene and chloroformates, and takes place at ambient temperature and low pressure of CO2. This provided an improved protocol for the protection of cyclic amides and other functional groups and allowed the obtention of non-classical N-carboxyalkyl derivatives for which the corresponding chloroformates are not accessible or commercially available. The model reaction was successfully performed with car diesel engine emissions and opens the way for new perspectives of carbon capture and use solutions.

Dihydro-1,4-thiazine skeletons bearing olefin fragment at their alpha-position were prepared through a Pd(OAc)(2)-catalysed Fujiwara-Moritani type reaction via C-H alkenylation with olefins. This approach is selective, generalizable to a wide range of olefins and requires only 1 eq. of Ag2CO3 without the need of co-oxidant. The C-H bond activation proved to be strongly dependent on the olefin's substitution while unfused dihydro-1,4-thiazines seemed to be affected by the oxidation state of the sulfur atom. The utility of olefins obtained was demonstrated by their implication in the dipolar cycloaddition reaction with a non-stabilized azomethine ylide.

Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent - hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the -NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate "fungicide-like" properties and were devoted of cytotoxicity.

To gain some insights on the amidoalkylation process, we were interested in studying the product distribution when pterolactam was exposed to acids. The reactivity of pterolactam and its N-aryl derivatives towards TMSOTf or TfOH has been carefully examined in presence and absence of TMS-protected anilines. Under these conditions, the N-acyliminium precursors showed high reactivity at both alpha- and beta-positions of the nitrogen atom. In this context, these salts can induce cascade processes including Povarov type reaction among other transformations. In that way, novel quinolines and tetrahydro-quinolines, among other compounds, were isolated for the first time. [GRAPHICS]

Pterolactam (5-methoxypyrrolidin-2-one) is a heterocycle naturally occurring in plants. In an attempt to identify antifungal agents, a series of novel Mannich bases of amide derivated from Pterolactam have been designed, synthesized and their antifungal activities were evaluated on a panel of nine fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. A third of the target compounds exhibited good to high antifungal activities on at least one strain with EC50 lower than the control antifungal agent. N,N'-aminals derivated from Pterolactam proved to be good candidates for the development of biosourced fungicides, with compound 3o being the most broader-spectrum agent, active against five strains and devoted of any cytotoxicity.

The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones. Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested. Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range. The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules. Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.

gamma-Lactam derivatives are widespread biologically active compounds, covering a large range of activities. Following our interest in both medicinal and green chemistries, we developed an original, cesium salts-mediated, scalable and solvent-free methodology to transform biosourced pyroglutamic acid and its derivatives to their N,N'-aminals, N,O,N,S-acetals and C-5-substituted gamma-lactams in good to excellent yields. This protocol is applicable to a large range of substrates, conducting to C-5-substituted gamma-lactam derivatives as potential new biologically active compounds.

A general five-step synthesis of a short library of benzo[7,8]indolizinoquinolinine analogues of the topoisomerase-1 (topo-1) poison rosettacin and 22-hydroxyacuminatine alkaloids from DMAD and ortho-ketoanilines is reported. This consists on successively, the tandem aza-Michael addition/cyclodehydration, the hydrolysis of the resulting diesters into corresponding o-dicarboxylic acids, and the tandem intermolecular amidation/cyclodehydration into N-substituted imides. The regioselective reduction of one imide carbonyl into corresponding α-hydroxy lactams promoted by a Lewis acid Mg(ClO4)2 was followed ultimately with TFA-promoted π-cationic cyclization via stable N-acyliminiums species as an important key step.

This report deals with the design, the synthesis, and the pharmacological evaluation of pyroglutamide-based P2X7 antagonists. A dozen were shown to possess improved properties, among which inhibition of YO-PRO-1/TO-PRO-3 uptake and IL1β release upon BzATP activation of the receptor and dampening signs of DSS-induced colitis on mice, in comparison with reference antagonist GSK1370319A. Docking study and biological evaluation of synthesized compounds has highlighted new SAR, and low toxicity profiles of pyroglutamides herein described are clues for the finding of a usable h-P2X7 antagonist drug. Such a drug would raise the hope for a cure to many P2X7-dependent pathologies, including inflammatory, neurological, and immune diseases.

Unprecedented triazinyl-isoxazoles were afforded via an effective cycloaddition reaction between nitrile oxides and the scarcely described 2-ethynyl-4,6-dimethoxy-1,3,5-triazine as dipolarophile. The biological evaluation of the newly synthesized compounds showed that the inhibition of human farnesyltransferase by zinc complexation could be improved with triazine-isoxazole moieties. The replacement of the isoxazole unit by a pyrrolidin-2-one was detrimental to the inhibitory activity while the pyrrolidin-2-thione derivatives conserved the biological potential. The potential of selected compounds to disrupt protein farnesylation in Chinese hamster ovary (CHO) cells transfected with pEGFP-CAAX was also evaluated.

Imidazo[1,2-a]pyridines (azaindolizines) 1a-k have been designed and easily synthesized by the [3 + 2] cycloaddition reaction between cycloimmonium salts and ethyl cyanoformate used as dipolarophile. The behavior of the latter in cycloaddition reactions has been studied using different pyridinium, (iso)quinolinium or benzimidazolium salts and demonstrated the substrate-dependent reactivity, and the observation in many cases of its reaction as a cyano or an ethoxycarbonyl donor reagent. New chemical platforms have been identified thanks to the different reactivity of ethyl cyanoformate. Final molecules were subjected to a biological evaluation on ESKAPE pathogens (five bacteria: Escherichia coli, Klebsiella pneumoniae (MDR), Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus (MRSA) and two fungi: Cryptococcus neoformans (H99) and Candida albicans). Azaindolizines 1b and 1e displayed antifungal activity on Candida albicans and ylide 11 inhibited both fungi Candida albicans and Cryptococcus neoformans. These results open the way for the development of analogues with improved antifungal activity.

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.

Enantiopure N ‐benzyl 6‐oxopipecolic acid, obtained from ( S )‐2‐aminoadipic acid, was evaluated under π‐cationic cyclization conditions. If the combination of SOCl 2 /AlCl 3 seems to be superior in terms of the reaction yields, use of PPA, (CF 3 CO) 2 O/BF 3 · Et 2 O, and Eaton's reagent is also very interesting since in addition to the expected keto‐lactam, reduced‐ and oxidized keto‐lactam, enamides and enamidones containing CF 3 CO– residue are isolated. Mechanisms leading to these products as well as the ones resulting from their acidic treatment were proposed and discussed with the help, in some cases, of univocal transformations and X‐ray analysis.

The concept of green chemistry began in the USA in the 1990s. Since the publication of the 12 principles of this concept, many reactions in organic chemistry have been developed, and chemical products have been synthesized under environmentally friendly conditions. Lewis acid mediated synthetic transformations are by far the most numerous and best studied. However, the use of certain Lewis acids may cause risks to environmental and human health. This Review discusses the evolution of Lewis acid catalyzed reactions from a homogeneous liquid phase to the solid phase to yield the expected organic molecules under green, safe conditions. In particular, recent developments and applications of biosourced catalysts from plants are highlighted.

Here we report an efficient solvent-free pinacolic-pinacolone rearrangement using supported acids. Given a standard procedure (5 minutes microwave heating at 180 degrees C), changing the acid catalyst allow to reverse the selectivity of the reaction. The optimized conditions represent an efficient means by which pinacol-pinacolone rearrangement can be carried out while avoiding the use of strong homogeneous Bronsted acids and extended reaction times. This neat reaction gave the products in high yield, purity and ease of recovery. Moreover, the catalyst can be reused on 10 runs without any loss of activity nor selectivity. As a consequence, that protocol can be referred as a green and efficient process for pinacol-pinacolone rearrangement.

BACKGROUND:To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of γ-aminobutyric acid, has never been studied in the context of plant protection.RESULTS:The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance.CONCLUSION:Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture. © 2018 Society of Chemical Industry.