Silver-Catalyzed Cascade Radical Bicyclization Reaction: An Atom- and Step-Economical Strategy Accessing γ-Lactam Containing Isoquinolinediones.

An efficient and convenient method for the cascade radical bicyclization of N-phenyl-4-pentenamides with N-methyl-N-methacryloylbenzamides under silver-catalyzed conditions is described. Based on this newly developed strategy, a variety of valuable γ-lactam containing isoquinolinediones can be effectively synthesized in one step within 0.5 h, during which two C-C bonds, one C-N bond, and two new N-heterocycles were formed concurrently. With N-aryl allyl carbamates, similar 2-oxazolidinone substituted isoquinolinedione compounds can likewise be produced. The approach demonstrates wide functional group compatibility, high step- and atom-economy, and the ability to be scaled up to gram quantities in a satisfactory yield. It marks the first instance of introducing γ-lactams into isoquinoline-1,3(2H,4H)-diones to construct linked hybrid drug-like molecules, thereby making this strategy highly attractive to drug discovery.

Electrophysiological Assessment of Newly Synthesized 2,3-Benzodiazepine Derivatives for Inhibiting the AMPA Receptor Channel.

Three major subtypes of ionotropic receptors regulate glutamatergic synaptic transmission, one of which is α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). They are tetrameric, cation-permeable ionotropic glutamate receptors found across the brain. Abnormalities in AMPA receptor trafficking and synaptic assembly are linked to cognitive decline and neurological diseases such as Alzheimer's, Parkinson's, and Huntington's. The present study will investigate the effects of four novel 2,3-benzodiazepine derivatives on AMPA receptor subunits by comparing their effects on synaptic responses, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits using whole-cell patch-clamp electrophysiology. All four 2,3-BDZ compounds showed inhibitory activity against all the homomeric and heteromeric subunits tested. While the desensitization and deactivation rates in 2,3-BDZ-1 and 2,3-BDZ-2 decreased and increased, respectively, in the other two compounds (i.e., 2,3-BDZ-3 and 2,3-BDZ-4), there was no change in the desensitization or deactivation rates. These results contribute to a better understanding of AMPARs by identifying potential 2,3-BDZ drugs that demonstrate inhibitory effects on the AMPAR subunits.

Constituents, Antibacterial Adhesion, Cytotoxic and in Vitro Metastasis Blocking Properties of Salvia fruticosa Essential Oils from Three Palestinian Localities.

Essential oils (EOs) of Salvia fruticosa Mill. gathered from three Palestinian localities were studied to determine their constituents, antibacterial adhesion impact against Klebsiella pneumonia, cytotoxicity, and their function in cancer cell migration. Gas chromatography-mass spectrometry identified the chemical components, while the MTT technique was used to measure the EOs' cytotoxicity against HeLa (cervical) and Caco-2 (colorectal) cancer cells. Antibacterial adhesion was assessed by examining Klebsiella pneumoniae's ability to adhere to Caco-2 cells. Our study found that eucalyptol was present as the main constituent in all S. fruticosa EOs. In addition, K. pneumoniae adhesion and metastasis were reduced after 48 h of application. Salfit's and Hebron's EOs had the most potent cytotoxic effects on Caco-2 and HeLa, with IC50 values in the range of 0.7-1.3 µg/mL. Taking into account the obtained results, it may be concluded that S. fruticosa EOs can serve as potential disinfectant agents for the treatment and prevention of K. pneumoniae-associated illness and cancer.

Isolation, Identification and Pharmacological Effects of Mandragora autumnalis Fruit Flavonoids Fraction.

Since ancient times, Mandragora autumnalis has been used as a traditional medicinal plant for the treatment of numerous ailments. In light of this, the current study was designed to isolate and identify the chemical constituents of the flavonoids fraction from M. autumnalis ripe fruit (FFM), and evaluate its DPPH scavenging, anti-lipase, cytotoxicity, antimicrobial and antidiabetic effects. An ethyl acetate extract of M. autumnalis was subjected to a sequence of silica gel column chromatography using different eluents with various polarities. The chemical structures of the isolated compounds were identified using different spectral techniques, including 1H NMR and 13C NMR. FFM's anti-diabetic activity was assessed using a glucose transporter-4 (GLUT4) translocation assay, as well as an inhibition against α-amylase and α-glucosidase using standard biochemical assays. The FFM anti-lipase effect against porcine pancreatic lipase was also evaluated. Moreover, FFM free radical scavenging activity using the DPPH test and antimicrobial properties against eight microbial strains using the micro-dilution method were also assessed. Four flavonoid aglycones were separated from FFM and their chemical structures were identified. The structures of the isolated compounds were established as kaempferol 1, luteolin 2, myricetin 3 and (+)-taxifolin 4, based on NMR spectroscopic analyses. The cytotoxicity test results showed high cell viability (at least 90%) for up to 1 mg/mL concentration of FFM, which is considered to be safe. A dose-dependent increase in GLUT4 translocation was significantly shown (p < 0.05) when the muscle cells were treated with FFM up to 0.5 mg/mL. Moreover, FFM revealed potent α-amylase, α-glucosidase, DPPH scavenging and porcine pancreatic lipase inhibitory activities compared with the positive controls, with IC50 values of 72.44 ± 0.89, 39.81 ± 0.74, 5.37 ± 0.41 and 39.81 ± 1.23 µg/mL, respectively. In addition, FFM inhibited the growth of all of the tested bacterial and fungal strains and showed the greatest antibacterial activity against the K. pneumoniae strain with a MIC value of 0.135 µg/mL. The four flavonoid molecules that constitute the FFM have been shown to have medicinal promise. Further in vivo testing and formulation design are needed to corroborate these findings, which are integral to the pharmaceutical and food supplement industries.

Chemical Markers and Pharmacological Characters of Pelargonium graveolens Essential Oil from Palestine.

Pelargonium graveolens leaves are widely used in traditional medicine for relieving some cardiovascular, dental, gastrointestinal, and respiratory disorders. They are also used as food and tea additives in Palestine and many other countries. Consequently, this investigation aimed to describe the chemical markers, cytotoxic, antioxidant, antimicrobial, metabolic, and cyclooxygenase (COX) enzymes inhibitory characteristics of P. graveolens essential oil (PGEO) from Palestine utilizing reference methods. There were 70 chemicals found in the GCMS analysis, and oxygenated terpenoids were the most abundant group of the total PGEO. Citronellol (24.44%), citronellyl formate (15.63%), γ-eudesmol (7.60%), and iso-menthone (7.66%) were the dominant chemical markers. The EO displayed strong antioxidant activity (IC50 = 3.88 ± 0.45 µg/mL) and weak lipase and α-amylase suppressant effects. Notably, the PGEO displayed high α-glucosidase inhibitory efficacy compared with Acarbose, with IC50 doses of 52.44 ± 0.29 and 37.15 ± 0.33 µg/mL, respectively. PGEO remarkably repressed the growth of methicillin-resistant Staphylococcus aureus (MRSA), even more than Ampicillin and Ciprofloxacin, and strongly inhibited Candida albicans compared with Fluconazole. The highest cytotoxic effect of the PGEO was noticed against MCF-7, followed by Hep3B and HeLa cancer cells, with IC50 doses of 32.71 ± 1.25, 40.71 ± 1.89, and 315.19 ± 20.5 µg/mL, respectively, compared with doxorubicin. Moreover, the screened EO demonstrated selective inhibitory activity against COX-1 (IC50 = 14.03 µg/mL). Additionally, PGEO showed a weak suppressant effect on COX-2 (IC50 = 275.97 µg/mL). The current research can be considered the most comprehensive investigation of the chemical and pharmacological characterization of the PGEO. The results obtained in this study demonstrate, without doubt, that this plant represents a rich source of bioactive substances that can be further investigated and authenticated for their medicinal potential.

Phytochemical Profile, Antimicrobial, Cytotoxic, and Antioxidant Activities of Fresh and Air-Dried Satureja nabateorum Essential Oils.

Satureja nabateorum (Danin and Hedge) Bräuchler is a perennial herb in the Lamiaceae family that was discovered and classified in 1998. This green herb is restricted to the mountains overlooking the Dead Sea, specifically in Jordan's southwest, the Edom mountains, and the Tubas mountains in Palestine. Gas chromatography-mass spectrometry (GC-MS) analysis of essential oil (EO) of air-dried and fresh S. nabateorum resulted in the identification of 30 and 42 phytochemicals accounting for 99.56 and 98.64% of the EO, respectively. Thymol (46.07 ± 1.1 and 40.64 ± 1.21%) was the major compound, followed by its biosynthetic precursors γ-terpinene (21.15 ± 1.05% and 20.65 ± 1.12%), and p-cymene (15.02 ± 1.02% and 11.51 ± 0.97%), respectively. Microdilution assay was used to evaluate the antimicrobial property of EOs against Staphylococcus aureus (ATCC 25923), clinical isolate Methicillin-Resistant Staphylococcus aureus (MRSA), Enterococcus faecium (ATCC 700221) Klebsiella pneumoniae (ATCC 13883), Proteus vulgaris (ATCC 700221), Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 27853) and Candida albicans (ATCC-90028). With a MIC of 0.135 µg/mL, the EOs has the most potent antibacterial action against K. pneumonia. Both EOs display good antifungal efficacy against C. albicans, with a MIC value of 0.75 µg/mL, which was better than that of Fluconazole's (positive control, MIC = 1.56 µg/mL). The antioxidant capacity of EOs extracted from air-dried and fresh S. nabateorum was determined using the DPPH assay, with IC50 values of 4.78 ± 0.41 and 5.37 ± 0.40 µg/mL, respectively. The tested EOs showed significant cytotoxicity against Hela, HepG2, and COLO-205 cells, with IC50 values ranging from 82 ± 0.98 to 256 ± 1.95 µg/mL. The current work shows there is a possibility to use the S. nabateorum EOs for various applications.

Isolation, identification, and antimycotic activity of plumbagin from Plumbago europaea L. roots, leaves and stems.

Plumbago europaea L. is a plant utilized in Palestinian ethnomedicine for the treatment of various dermatological diseases. The current investigation was designed to isolate plumbagin from P. europaea leaves, roots and for the first time from the stems. Moreover, it aimed to evaluate the antimycotic activity against three human fungal pathogens causing dermatophytosis, also against an animal fungal pathogen. The qualitative analysis of plumbagin from the leaves, stems, and roots was conducted using HPLC and spectrophotometer techniques, while the structure of plumbagin was established utilizing Proton and Carbon-13 Nuclear Magnetic Resonance (NMR) and Infrared (IR) techniques. The entire plant constituents were determined by GC-MS. Moreover, the antimycotic activity against Ascosphaera apis, Microsporum canis, Trichophyton rubrum, and Trichophyton mentagrophytes was assessed utilizing the poison food technique method. The percentage of plumbagin recorded in the leaves, stems, and roots was found to be 0.51±0.001%, 0.16±0.001%, and 1.65±0.015%, respectively. The GC-MS examination declared the presence of 59 molecules in the plant extract. The plant extract and pure plumbagin exhibited complete inhibition against all tested dermatophytes at 6.0mg/mL for the extracts and 0.2mg/mL for plumbagin. P. europaea root is the best source of plumbagin and the plant extract could represent a potential drug candidate for the treatment of dermatophytosis infections. Further studies required to design suitable dosage forms from the natural P. europaea root extracts or plumbagin alone, to be utilized for the treatment of dermatological and veterinary ailments.

Fluorine-Induced Pseudo-Anomeric Effects in Methoxycyclohexanes through Electrostatic 1,3-Diaxial Interactions.

We report counter-intuitive axial preferences in non-stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo-anomeric effects are apparent when electronegative CF2 groups are placed at the C-2, C-4 and C-6 positions of the cyclohexane ring to render the C-3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the -OMe oxygen is stabilising. The effect is explored using high-level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally (19 F{1 H}-NMR at -80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry.

Probing the helical integrity of multivicinal all-syn-fluoro alkanes.

This study extends our interest in the synthesis and conformational behaviour of all-syn multivicinal fluoro alkane motifs. Specifically an all-syn 1,2,3,6,7,8-hexafluorooctane chain was assembled with a run of three fluorines, of the same stereochemical sense (syn) to the direction of the chain, on each side of an ethylene (-CH2CH2-) spacer to explore if the helical sense of the chain crosses the ethylene bridge. The solid state (X-ray) structure indicated a continuous helix however in solution (NMR) and by DFT computation, although the individual all-syn 1,2,3-trifluoro motifs maintain good helical integrity, the molecule is much more dynamic across the ethylene bridge. It was notable however that a low energy, non-helical conformer has a high molecular dipole (µ = 7.15 D) indicating a role for this skipped motif in soft materials such as liquid crystals or polar polymers.

Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes.

This paper describes the synthesis of a series of organic liquid crystals (LCs) containing selectively fluorinated cyclopropanes at their termini. The syntheses used difluorocarbene additions to olefin precursors, an approach which proved straightforward such that these liquid crystal candidates could be efficiently prepared. Their physical and thermodynamic properties were evaluated and depending on individual structures, they either displayed positive or negative dielectric anisotropy. The study gives some guidance into effective structure-property relationships for the design of LCs containing selectively fluorinated cyclopropane motifs.

Isolation of naturally occurring novel isoflavonoids: an update.

Covering: Jan. 2012 to Dec. 2017 This review describes the 391 new isoflavonoids isolated and identified from natural sources between January 2012 and December 2017, commenting on their sources, identification and biological activities. Due to the length of this review, the synthesis of isoflavonoids is not included. Furthermore, new applications of analytical techniques for the isolation and identification of isoflavonoids are also reviewed.

Fingerprinting, Antimicrobial, Antioxidant, Anticancer, Cyclooxygenase and Metabolic Enzymes Inhibitory Characteristic Evaluations of Stachys viticina Boiss. Essential Oil.

The present study aimed to identify the chemical constituents and to assess the in-vitro, antimicrobial, anticancer, antioxidant, metabolic enzymes and cyclooxygenase (COX) inhibitory properties of essential oil (EO) of Stachys viticina Boiss. leaves. The S. viticina EO was isolated and identified using microwave-ultrasonic and GC-MS techniques, respectively. Fifty-two compounds were identified, of which endo-borneol was the major component, followed by eucalyptol and epizonarene. The EO was evaluated against a panel of in-vitro bioassays. The EO displayed antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Epidermophyton floccosum, with MIC values of 0.039, 0.078 and 0.78 mg/mL, respectively. The EO exhibited cytotoxicity against HeLa (cervical adenocarcinoma) and Colo-205 (colon) cancer cell lines with percentages of inhibition of 95% and 90%, for EO concentrations of 1.25 and 0.5 mg/mL, respectively. Furthermore, it showed metabolic enzyme (α-amylase, α-glucosidase, and lipase) inhibitory (IC50 = 45.22 ± 1.1, 63.09 ± 0.26, 501.18 ± 0.38 µg/mL, respectively) and antioxidant activity, with an IC50 value of 19.95 ± 2.08 µg/mL. Moreover, the S. viticina EO showed high cyclooxygenase inhibitory activity against COX-1 and COX-2 with IC50 values of 0.25 and 0.5 µg/mL, respectively, similar to those of the positive control (the NSAID etodolac). Outcomes amassed from this investigation illustrate that S. viticina EO represents a rich source of pharmacologically active molecules which can be further validated and explored clinically for its therapeutic potential and for the development and design of new natural therapeutic preparations.

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif.

We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl-SCF2CH3 ethers with the model yeast organism Cunninghamella elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (p-OMe)PhSCF2CH3, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the ß-substituted-SCF2CH3 naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (p-OMe)PhOCF2CH3, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude that the aryl-S-CF2CH3 motif is metabolised in a similar manner to aryl-SCF3, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF3 which may offer a practical advantage in tuning overall pharmacokinetic profiles of molecules in development.

Benzylic Functionalisation of Phenyl all-cis-2,3,5,6-Tetrafluorocyclohexane Provides Access to New Organofluorine Building Blocks.

Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all-cis-2,3,5,6-tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all-cis-2,3,5,6-tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn-amino-alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans-halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23-26 and the preferred conformations of these α-fluoroamides were explored by DFT, X-ray structure and 1 H-19 F HOESY NMR analysis.

Synthesis of aryl α,α-difluoroethyl thioethers a novel structure motif in organic chemistry, and extending to aryl α,α-difluoro oxyethers.

A method for the preparation of aryl α,α-difluoroethyl thioethers (ArSCF2CH3) is reported and the synthesis approach is extended to aryl α,α-difluoroethyl oxygen ethers. Selected building blocks are further elaborated in cross-coupling reactions and are incorporated into analogues of established trifluoromethyl ether drugs. Conformations are explored and log P studies of these motifs indicate that they are significantly more polar than their trifluoromethyl ether analogues rendering them attractive for bioactives discovery.

Incorporation of [2H1]-(1R,2R)- and [2H1]-(1S,2R)-glycerols into the antibiotic nucleocidin in Streptomyces calvus.

Deuterium incorporations from [2H1]-(1R,2R) and [2H1]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5' site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5' of nucleocidin after a feeding experiment with [2H5]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic.

Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif.

This paper reports the synthesis of three amine stereoisomers 5a-c of the tetrafluorocyclohexyl ring system, as building blocks for discovery chemistry programmes. The synthesis starts from a Birch reduction of benzonitrile, followed by an in situ methyl iodide quench. The resultant 2,5-cyclohexadiene was progressed via double epoxidations and then hydrofluorination ring opening reactions. The resultant fluorohydrin moieties were then converted to different stereoisomers of the tetrafluorocyclohexyl ring system, and then reductive hydrogenation of the nitrile delivered three amine stereoisomers. It proved necessary to place a methyl group on the cyclohexane ring in order to stabilise the compound against subsequent HF elimination. The two all-cis tetrafluorocyclohexyl isomers 5a and 5b constitute facially polarized cyclohexane rings, with fluorines on the electronegative face and hydrogens on the electropositive face.

Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes.

This paper reports the preparation of methyl substituted all-cis tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was reduced to the alcohol, protected as an ether and then a sequence of functional group manipulations carried out to introduce four fluorines. The cyclohexadienyl ring was then epoxidised and the C-O bonds sequentially converted through deoxyfluorination reactions to two sets of isomers of all-cis tetrafluorocyclohexane isomers. The blocking methyl group renders the ring safe to hydrogen fluoride elimination. Deprotection of the benzylic ether and then oxidation gave aldehydes which were then used in Ugi and Passerini multicomponent reactions, allowing this facially polarised cyclohexane to be incorporated into peptidic structural motifs.

Fluorinated liquid crystals: evaluation of selectively fluorinated facially polarised cyclohexyl motifs for liquid crystal applications.

This paper explores the synthesis of a series of prototype negative dielectric liquid crystalline (LC) compounds which contain fluorinated cyclohexane motifs. The series are analogues and differ only in that they contain between one to four fluorine atoms. The stereochemistry is such that all of the fluorines/C-F bonds are on one face of the cyclohexane ring. This follows from the recent recognition that cyclohexanes with fluorines orientated in one direction, perpendicular to the ring have a strong molecular dipole, a characteristic that might be an advantage in the design of negative dielectric materials. However it is found that the increased polarity, particularly with two or more oriented C-F bonds, leads to higher melting points and poorer solubility in test matrix formulations, relative to hydrocarbon liquid crystals. This arises due to electrostatic intermolecular interactions between the polarised cyclohexyl and aryl rings. The study highlights that in order to take advantage of these polar cyclohexane motifs for liquid crystal design, appropriate scaffolds are required which are free of aromatic rings and contain peripheral solubilising motifs.

Stepwise preparation of all-cis 1,3,4-trifluoro-2-phenylcyclohexane, avoiding a phenonium intermediate.

The original synthesis of all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane resulted in a trifluorocyclohexene as a significant co-product of the final fluorination step. This product was notable in that an elimination reaction was accompanied by C-F bond formation that had occurred with a retention of configuration. In order to deconvolute this reaction, the two isomers of the ditriflate diol precursor were separated, and they were each treated independently with Et3N·3HF. One gave the original all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane and the other the trifluorocyclohexene. A deuterium labeling experiment was carried out, resulting in a distribution of the isotope in the trifluorocyclohexene consistent with an intermediate (symmetrical) phenonium intermediate. Cognisant of this, a controlled elimination reaction of one of the diastereoisomers with DBU, followed by hydrogenation, gave a cyclohexane triflate, which, on fluorination, gave the all-cis 1,2,3-trifluoro-2-phenylcyclohexane now with an inversion of configuration.