A synthesis of novel hydroxyethyl‐substituted tri‐ and penta‐hydroxylated spiro[cyclopentane‐indolizidines] has been reported, featuring an interesting lithium diisopropylamide “LDA”‐mediated α‐diallylation and tetrahydrofuran “THF” ring opening in one‐pot procedure as the key transformation. The synthetic sequence explored herein uses an enantiopure tricyclic lactam as a common chiral precursor, prepared on a gram scale from cost‐effective basic reagents. The key steps in this synthetic way included diastereoselective dihydroxylation reaction, ring‐closing ene–ene metathesis, enamine reduction, and finally lactam reduction. These transformations enabled the efficient and stereoselective construction of the ultimate polyhydroxy‐indolizidine scaffolds. As an application, the biological activity of the synthesized spiro‐indolizidines was evaluated against a panel of α‐glucosidases.

1,4-Thiazine frameworks bearing a halide X (X = I, Br or Cl) at the α-position of their sulfur atom were prepared in one or two steps. This approach involves Morin-rearrangement of N,S-acetal using user-friendly N-halogenating reagents (NIS, NBS, NCS, DBH, DIH) or ICl to yield 1,4-thiazines. The latter successfully afforded the corresponding halogenated derivatives through interesting domino Morin-rearrangement/halogenation when an excess of halogenating agents, which act as catalysts and halogenating reagents in the same operation, was used. The brominated 1,4-thiazines, obtained in good to excellent yields, were then arylated through Pd(0)-catalyzed Suzuki-Miyaura coupling with organoboronic acids or esters. Ultimately, these conditions were applied to one example of an amidation reaction.

A series of novel optically pure aminoindolizidines featuring fused tetrahydro-furan, thiophene, or pyrrole ring were synthesized from the proteinogenic L-glutamic acid as a chiral precursor and a nitrogen atom source. The synthetic sequence employed tricyclic indolizidinols as advanced building blocks, which were prepared on a gram-scale from bioavailable reagents. Key transformations within the used synthetic sequence included diastereoselective Thompson azidation, Staudinger reduction, Jurjew reaction, and highly diastereoselective catalytic hydrogenation. These steps facilitated the efficient and stereoselective synthesis of the ultimate amino- and N-acetylamino-indolizidines.

A novel sequential one-pot bimetallic catalytic system combining Fe(III)-catalyzed alkynylation and a Rh(I)-catalyzed [2+2+2] reaction was successfully developed. The σ-Lewis acid properties of iron (III) and the π-Lewis acid properties of rhodium (I) catalysts were unified in an unprecedented intermolecular alkynylation/cyclotrimerization one-pot process. Using this unique Fe/Rh bimetallic relay catalytic system, a variety of benzo and pyrridinoisoindolinone derivatives were obtained under mild conditions from easily available N-(propargyl) hydroxy aminals, as the simplest N-acyliminium ion precursors, and several alkynes.

P2 × 7R is crucial in the pathogenesis of chronic inflammatory diseases, and its activation leads to the release of pro-inflammatory cytokines, exacerbating the inflammatory response. Two new series of scarce cyclic N, O-acetals (ATF 61–74) and corresponding opened N, N-aminals (CS 1–14) have been designed as novel potential P2RX7 antagonists, then synthesized and evaluated for their anti-inflammatory properties through investigating the pro-inflammatory markers and also for their antifungal activity against Candida albicans. Three compounds (ATF 64, CS 8, and CS 9) exhibited dual antifungal and anti-inflammatory properties. ATF 64, CS 8, and CS 9 reduced ROS production and IL-1β expression in macrophages and intestinal cells in a manner correlated with NF-KB expression. These compounds showed excellent antifungal activity against clinical isolates of C. albicans resistant to fluconazole and caspofungin, and reduced C. albicans biofilm formation. Treatment with CS 8 or CS 9 protected the nematode Caenorhabditis elegans against infection with C. albicans and enhanced antimicrobial gene expression. This duality of action offers a promising new pharmacological strategy to counteract inflammatory diseases and propels N, N-aminals as promising candidates for future optimization and investigation.

We report in this contribution the synthesis and in vitro biological evaluation of a novel class of chiral thiazoloisoindolinone scaffolds as potent inhibitors against human farnesyltransferase (FTase-h). The targeted products, sulfides (4), sulfoxides (5,6), and sulfones (7), containing up to three points of diversification, were obtained in a short-step sequence starting from the available and cost-effective L-cysteine hydrochloride (1), which is the source of N and S atoms and the chiral pool, and α-carbonyl benzoic acids (2), which are isoindolinone precursors. Concisely, the key ester intermediates (1) provide (a) sulfide-amides (4) by solvent-free amidation, (b) sulfoxides (5,6) by selective S-oxidation using NaIO4, and (c) sulfones (7) by oxidation using MMPP. Finally, the obtained N,S-acetal systems have shown promising inhibitory activities on FTase-h in the nanomolar range with excellent half maximal inhibitory concentration (IC50) values up to 4.0 nanomolar (for example, 25.1 nM for sulfide 4bI, 67.3 nM for sulfone 7bG, and more interesting of 4.03 nM for sulfoxide 5bG).

A new series of N-benzyl-2,5-dihydro-1H-pyrrole-linked benzopyrimidines 5 and 6 were synthesized via the 1,3-dipolar cycloaddition reaction of acetylenic dipolarophiles 3 and 4 with azomethine ylide generated in situ from N-(methoxymethyl)-N-(trimethylsilyl)benzylamine and evaluated for their in vitro antimicrobial activity. The structures of the prepared products were characterized using H-1/C-13 NMR, IR, and ESI-HRMS techniques. Further, the synthesized compounds were assessed for their antibacterial activity against five types of pathogenic bacteria and three fungal strains. The results show that the degree of antimicrobial effect displayed by the synthesized compounds was variable. Notably, compounds 2a, 2d, 2f, 3e, 3h, 4a, 4d, 4f, 5a, 5b, 5d, 5f, 6b, and 6c showed high activity against the bacterial strains, with MIC values ranging from 15.12 to 15.62 mu g mL(-1). Moreover, compounds 2a, 2f, 5a, 5b, 5d, 5g, and 5h exhibited promising antifungal activity against three Candida strains, with MIC values ranging from 62.5 to 125 mu g mL(-1). In addition, molecular docking studies performed to identify the most effective antibacterial compounds against B. subtilis highlighted the high binding affinity of the synthesized compounds toward Bacillus subtilis YdiB (pdb: 5MVR).

In the context of designing innovative anticancer agents, the synthesis of a series of chalcones bearing a 3,4,5-trimethoxylated A ring and a variety of B rings, including phenols and original heterocycles such as chromones, was conducted. For this end, Claisen–Schmidt condensation was performed in basic or acidic conditions between the common starting material 3,4,5-trimethoxyacetophenone and appropriate aldehydes; this allowed the recovery of fifteen chalcones in moderate–good yields. The synthesized compounds were screened for their antiproliferative activity against colorectal and prostatic cancer cells, using a colorimetric MTT assay. Among the new chromonyl series, chalcone 13 demonstrates an interesting antiproliferative effect, with IC50 values in the range of 2.6–5.1 µM at 48 h. Then, our study evidenced that indolyl chalcone 10 exhibits excellent activity towards the selected cell lines (with IC50 less than 50 nM). This compound has already been described and has been shown to be a potent anticancer agent against other cancer cell lines. Our investigations highlighted apoptosis induction, through several pro-apoptotic markers, of these two heterocyclic chalcones. Considering phenolic chalcones, compounds 2 and 8 were found to be the most active against cell proliferation, exerting their effect by inducing the depolymerization of cell microtubules. The most promising compounds in this series will be selected for application in a strategy of vectorization by either active or passive targeting.

The current study highlights the synthesis of Zn-enriched biosourced catalysts (BIOCATs) obtained from ryegrass (Lolium perenne L.) cultivated on contaminated soils located in the North of France (Noyelles-Godault and Auby, Hauts-de-France). These cultures were located on brownfield land, next to two former industrial sites where the zinc and lead metallurgists Metaleurop and Nyrstar were installed. Physical and morphological properties of BIOCATs were compared to heterogeneous catalysts (CATs) prepared from commercial zinc chloride and montmorillonite K10. The catalysts were thermally activated (120(degrees ) C, 280(degrees )C or 500(degrees ) C). BIOCATs have been further compared to CATs and different commercial metal chlorides in terms of efficiency in the synthesis of antiinflammatory agents, Piroxicam and Meloxicam, both of them being involved in the inhibition of cyclooxygenases (COX) and being the main ingredients of the Feldene (R) and Mobic (R) drugs, respectively. BIOCATassisted synthesis resulted in the best reaction yields (84% and 78%, respectively) among all the tested catalysts. The results indicated that ryegrass provides appropriate quantity of biomass and can be considered as a bioore resource to improve green metrics in an environmental context involving clean and green technologies. Furthermore, the Zn/Cd and Zn/Pb ratios obtained in the ashes of ryegrass shoots were in general comprised between 153 and 202. This result demonstrated the excellent selectivity of ryegrass for zinc at the expense of the more problematic Cd and Pb, which are carcinogenic, mutagenic and reprotoxic. Future efforts are now needed to use BIOCATs in the synthesis of other high value-added molecules.

Scarce dihydro-1,4-diazinoisoindole framework bearing two points of diversity was prepared through a cascade process based on concomitant C-sp(3)-N and C-sp(2)-N bond formation. This approach consists of an amidation in basic medium of a tosyl group by nucleophilic substitution followed by Cu-mediated Goldberg reaction in the same operation. The required beta-bromoenamide bearing a tosyl group was obtained by tosylation of fused brominated N,O-acetals for the first time in acidic medium using submolar amounts of PTSA. The obtained piperazines are useful building blocks as illustrated by the formation of a pentacyclic product via the intramolecular interception of the enamide function.

C-H activation is a powerful strategy for forming C-C bonds without the need for prefunctionalization. In this paper, we present a general, direct, and regioselective palladium-catalyzed functionalization of a phosphorus heterocycle, 2-phenyl-1H-isophosphinoline 2-oxide. The mild reaction conditions enabled the introduction of various functionalized alkenes. Moreover, the flame-retardant properties of selected products clearly highlighted the synergy between the phosphine oxide and another heteroatom-based group, even in the condensed phase.

Electron-poor arenesulfonyloxypyridines are selectively dearomatized whether on the pyridine or on the phenyl group through 1,3-dipolar cycloaddition (1,3-DC) involving non-stabilized azomethine ylides (AMY). Electronic effects of substituents on the aromatic rings allow to induce the regioselectivity of the transformation. Novel pyrrolidinic polycyclic heterocycles are thereby produced under mild acidic conditions at room temperature.

As part of the valorization of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a–u bearing 1,2,3-triazole moieties were designed and synthesized by treating an azide 4 previously prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues, 18a–u, were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes, and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained, notably against L. monocytogenes. Compounds 18d, 18g, and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. A molecular docking study was performed to explore the binding mode of the most active derivatives into the active site of the ABC substrate-binding protein Lmo0181 from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor of the experimental data.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Maslinic acid- and oleanolic acid-based hyrids with potent antibacterial and antibiofilm activities were designed and semi-synthesized from pentacyclic triterpene acids isolated from olive oil manufacturing solid waste.

The modification of drug delivery routes can be used as a promising strategy to improve the therapeutic profile of various drug agents. Herein, the synthesis and molecular modeling of a series of 6,7,8,9-tetrahydrobenzo [b] [1,8] naphthyridines derivatives were reported to explore potent and less toxic scaffolds. The tacrine analogs 6–10 were obtained by an efficient strategy using Friedlander's condensation between 2-aminopyridine-3-carbonitriles 1–5 and cyclohexanone under microwave irradiations without catalysts and solvents. The synthesized compounds were identified through 1H NMR, 13C NMR, IR. Their inhibition activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were focused as probable drug targets for Alzheimer’s disease (AD). The pharmaco-kinetic properties, the risk of probable hepato-toxic metabolites, and the toxicological properties were predicted using computational methods. The prediction of the toxicity risks via the GUSAR software allowed us to resolve the best approach for drug delivery, namely the subcutaneous, intravenous, or oral route., Also, the GUSAR software was used to reveal all possible adverse effects. All these techniques were tested for the L1-6 compounds by choosing tacrine as a template compound. Among these compounds, the optimal compound L1 was the most potent inhibitor and had the best score binding affinity compared to the reference drug (Tacrine) -7.926 and -7.007 kcal/mol for AChE and BuChE, respectively. Moreover, this same compound presented a satisfying pharmaceutical profile. In the present study, subcutaneous delivery is considered a promising administration of reference drug and their derivatives against AD.

Pyroglutamide derivatives have emerged as promising inhibitors of human farnesyltransferase (FTIs), an important target in oncology and also in rare diseases such as Hutchinson-Gilford progeria syndrome (HGPS). This report describes the chemical efforts to enrich the pyroglutamide series using greener and recyclable catalysts. The central reaction studied was an amidation between methyl pyroglutamates or vinylogues and amines. Ten catalysts have been tested in this amidation reaction: two classical Lewis acids (ZnCl2, ZrCl4), four impregnated montmorillonite K10 with ZnCl2 namely Cat1, Cat2, Cat3 and Cat4 (not activated, activated at 120 degrees C, 280 degrees C and 500 degrees C, respectively) and four montmorillonites K10 (commercial montmorillonite K10 not activated, activated at 120 degrees C, 280 degrees C and 500 degrees C). The most efficient catalyst was Cat4. The recyclability of Cat4 over five synthesis runs has been successfully tested. Twenty-six amides were synthesized and screened for their potential to inhibit human farnesyltrans-ferase. Four points of chemical modulation around the pyrrolidine-2-one ring have been realized allowing to complete structure-activity relation-ships in these series. The study revealed several potent inhibitors targeting human farnesyltransferase in vitro with IC50 values in the submicromolar range and down to 30 nM. The docking of compounds in the active site of FTase highlighted that the S-isomers of pyroglutamides had good affinity. This study propels pyroglutamide derivatives as promising candidates for future functionality assays and in vivo evaluation.

The cycle between the preparation of sulfonated polyvinylidene fluoride (PVDF) membranes and the study of their properties allows several groups to make critical observations that lead to a hypothesis-driven process for sulfonation optimization. To facilitate this previously poorly understood process, we studied an example of PVDF sulfonation by chlorosulfonic acid (ClSO3H). We prepared sulfonated polyvinylidene fluoride (S-PVDF_X) samples with different sulfonation reaction times (X = 3, 5, and 16 h) and confirmed the sulfonation by means of Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and NMR spectroscopy. The microstructure of the sulfonated sample S-PVDF_5 h was determined using a multinuclear {1H, 13C, 19F} NMR study. The results obtained allowed, for the first time, highlighting the dehydrofluorination of the PVDF chain in a super acidic medium and the formation of a sequence due to the esterification reaction between the alcoholic and acidic chain ends. In addition, we identified the two primary grafting sites of the sulfonic acid groups in the S-PVDF chain and demonstrated the importance of the head-to-head and tail-to-tail defects in the dehydrofluorination and sulfonation mechanisms.

We report an efficient 1,3-dipolar cycloaddition involving non-stabilized electron-rich azomethine ylides and diversely substituted 2-pyridones bearing two potential C=C dipolarophilic sites. The 1,3-dipoles were prepared in situ under TFA catalysis and cycloadditions were studied according to the nature of the pyridones and position of the various substituents. These reactions occur under mild conditions, and lead to the expected cycloadducts in good yields and full control of the regioselectivity. Furthermore, mono- or biscycloadditions were performed, leading to the formation of polycyclic scaffolds bearing biologically relevant pyrrolidine rings, prevalent in natural products. The diastereoselectivity of the second cycloaddition was fully controlled by the first addition, leading to heterocycles with a trans relative stereochemistry of the two generated rings in the final tricyclo-adduct.