Moiety In Position Research Articles

Targeting Lewy body dementia with neflamapimod-rasagiline hybrids.

Lewy body dementia (LBD) represents the second most common neurodegenerative dementia but is a quite underexplored therapeutic area. Nepflamapimod (1) is a brain-penetrant selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase (MAPK) p38α, recently repurposed for LBD due to its remarkable antineuroinflammatory properties. Neuroprotective propargylamines are another class of molecules with a therapeutical potential against LBD. Herein, we sought to combine the antineuroinflammatory core of 1 and the neuroprotective propargylamine moiety into a single molecule. Particularly, we inserted a propargylamine moiety in position 4 of the 2,6-dichlorophenyl ring of 1, generating neflamapimod-propargylamine hybrids 3 and 4. These hybrids were evaluated using several cell models, aiming to recapitulate the complexity of LBD pathology through different molecular mechanisms. The N-methyl-N-propargyl derivative 4 showed a nanomolar p38α-MAPK inhibitory activity (IC50 = 98.7 nM), which is only 2.6-fold lower compared to that of the parent compound 1, while displaying no hepato- and neurotoxicity up to 25 μM concentration. It also retained a similar immunomodulatory profile against the N9 microglial cell line. Gratifyingly, at 5 μM concentration, 4 demonstrated a neuroprotective effect against dexamethasone-induced reactive oxygen species production in neuronal cells that was higher than that of 1.

Surface Functionalised Optical Fibre for Detection of Hydrogen Sulphide.

Dysregulated production of hydrogen sulphide in the human body has been associated with various diseases including cancer, underlining the importance of accurate detection of this molecule. Here, we report the detection of hydrogen sulphide using fluorescence-emission enhancement of two 1,8-naphthalimide fluorescent probes with an azide moiety in position 4. One probe, serving as a control, featured a methoxyethyl moiety through the imide to evaluate its effectiveness for hydrogen sulphide detection, while the other probe was modified with (3-aminopropyl)triethoxysilane (APTES) to enable direct covalent attachment to an optical fibre tip. We coated the optical fibre tip relatively homogeneously with the APTES-azide fluorophore, as confirmed via x-ray photoelectron spectroscopy (XPS). The absorption and fluorescence responses of the control fluorophore free in PBS were analysed using UV-Vis and fluorescence spectrophotometry, while the fluorescence emission of the APTES-azide fluorophore-coated optical fibres was examined using a simple, low-cost optical fibre-based setup. Both fluorescent probes exhibited a significant increase (more than double the initial value) in fluorescence emission upon the addition of HS- when excited with 405 nm. However, the fluorescence enhancement of the coated optical fibres demonstrated a much faster response time of 2 min (time for the fluorescence intensity to reach 90% of its maximum value) compared to the control fluorophore in solution (30 min). Additionally, the temporal evolution of fluorescence intensity of the fluorophore coated on the optical fibre was studied at two pH values (7.4 and 6.4), demonstrating a reasonable overlap and confirming the compound pH insensitivity within this range. The promising results from this study indicate the potential for developing an optical fibre-based sensing system for HS- detection using the synthesised fluorophore, which could have significant applications in health monitoring and disease detection.

Rational design and coloration mechanism of soluble intrinsic black polyimide with high comprehensive performance for black flexible copper clad laminates

With the development of flexible printed circuit boards (FPCBs) and photoelectric devices, the demand for black polyimide (BPI) is increasing, but the existing BPIs have some problems, such as poor electrical properties, mechanical performance, masking ability and solubility. To solve these problems, a novel diamine monomer (TPCPOHPDA) containing tetraphenylcyclopentadienone (TPCP) grafted with hydroxyl groups and benzene rings was customized, and then TPCPOHPDA was polymerized with 4,4'-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) to obtain polyimide (TPCPOHPPI). TPCP had a broad UV–visible light absorption range (250–600 nm). Appending benzene rings and auxochrome (hydroxyl groups) on the TPCP skeleton extended the conjugated π-electron system and enhanced the mobility of electrons in the large π bonds, respectively. These structural modifications further extended its light absorption range, and the resulting TPCPOHPPI was dark black with a cutoff wavelength (λcut) of 680 nm and Commission International Eclairage (CIE) lab color parameter L* of 0.7. Simulation calculations indicated that the visible-light absorption that caused the black appearance of TPCPOHPPI was mainly due to the electron transition from HOMO to LUMO occurring within the TPCP-containing diamine moieties, in which the charge mainly transferred from the aryl moieties in positions 2 and 5 to the central cyclopentadienone core. Further investigation showed that TPCPOHPPI had excellent thermal, electrical and mechanical performances and high solubility. The TPCPOHPPI-based two-layer black flexible copper clad laminate (2L-FCCL) possessed good dip soldering resistance and peeling strength. This work provides a new idea for the design and synthesis of soluble intrinsic black polyimide with excellent comprehensive performance.

Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas.

A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N'-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.

Enzymatic synthesis, characterization and molecular docking of a new functionalized polyphenol: Resveratrol-3,4′-⍺-diglucoside

Transglucosylation of resveratrol by the Q345F variant of sucrose phosphorylase from Bifidobacterium adolescentis (BaSP) was extensively studied during the last decade. Indeed, Q345F is able to catalyze the synthesis of resveratrol-3-O-⍺-D-glucoside (RES-3) with yield up to 97% using a cost-effective glucosyl donor, sucrose (Kraus et al., Chemical Communications, 53(90), 12182–12184 (2017)). Despite the fact that two further products were detectable in low amounts after glucoside synthesis, they were never identified. Here, we isolated and fully characterized one of those two minor products: resveratrol-3,4′-O-⍺-D-diglucoside (RES-3,4′). This original compound had never been described before. Using bioinformatics models, we successfully explained the formation of this diglucosylated product. Indeed, with RES-3 as acceptor substrate, Q345F is able to transfer a glucosyl moiety in position 4′-OH, what had been reported as impossible in the literature. The low yield observed is due to the steric hindrance into the catalytic site between RES-3 and residues Tyr132 and Tyr344. Nevertheless, the substrate orientation in the active site is favored by stabilizing interactions. Ring A of RES-3 bearing the diol moiety is stabilized by hydrogen bonds with residues Asp50, Arg135, Asn347 and Arg399. Hydroxyl group OH-4′ shares hydrogen bonds with the catalytic residues Asp192 and Glu232. Multiple hydrophobic contacts complete the stabilization of the substrate to favor the glucosylation at position 4′. Understanding of the mechanisms allowing the glucosylation at position 4′ of resveratrol will help the development of enzymatic tools to target and control the enzymatic synthesis of original ⍺-glucosylated polyphenols with high added value and better biodisponibility.

Benzyl- and dibenzyl tetrahydropyridinylidene ammonium salts with antiplasmodial and antitrypanosomal activity

Several 1-benzyl and 1,3-dibenzyl derivatives of tetrahydropyridinylidene salts with differing electron withdrawing substituents at the aromatic residues have been prepared. In addition, the amine moiety in position 4 was varied. The new compounds were investigated for their antiplasmodial and antitrypanosomal activities as well as for their cytotoxicity. They were characterized using FT-IR, HRMS and NMR spectroscopy. Structure–activity relationships including reported compounds are discussed.Graphical abstract

Synthesis of esters and amides of 2-aryl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acids and study of their antiviral activity against orthopoxviruses

Smallpox was eradicated >40 years ago but it is not a reason to forget forever about orthopoxviruses pathogenic to humans. Though in 1980 the decision of WHO to cease vaccination against smallpox had seemed logical, it led to the decrease of cross immunity against other infections caused by orthopoxviruses. As a result, in 2022 the multi-country monkeypox outbreak becomes a topic of great concern. In spite of existing FDA-approved drugs for the treatment of such diseases, the search for new small-molecule orthopoxvirus inhibitors continues. In the course of this search a series of novel 2-aryl-1-hydroxyimidazole derivatives containing ester or carboxamide moieties in position 5 of heterocycle has been synthesized and tested for activity against Vaccinia virus in Vero cell culture. Some of the compounds under consideration revealed a selectivity index higher than that of the reference drug Cidofovir. The highest selectivity index SI = 919 was exhibited by ethyl 1-hydroxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-5-carboxylate 1f. The most active compound also demonstrated inhibitory activity against the cowpox virus (SI = 20) and the ectromelia virus (SI = 46).

Front Cover: Selective Monovalent Galectin‐8 Ligands Based on 3‐Lactoylgalactoside (ChemMedChem 3/2022)

The Front Cover shows the development of a potent ligand for galectin-8 (in light blue), a protein produced by endothelial cells and involved in many processes, such as promoting angiogenesis. Starting from a 3-lactoylgalactoside (in pink), the best fit to complete the “puzzle of the binding” consisted of a molecule with a cyclohexyl moiety in position 3 of the galactose and a dichlorothiophenyl group in position 1. The new ligand showed an improved affinity of almost 200-fold, representing an optimal starting point for the development of high-affinity ligands for galectin-8, a promising target for cancer and diseases associated with bone loss and inflammation. Cover graphics by Benedetta Girardi, Department of Pharmaceutical Sciences, University of Basel. More information can be found in the Communication by Benedetta Girardi, Oliver Schwardt, Marko Anderluh et al.

On the protonation of a polysubstituted 1,2,4-triazole: A structural study of a hexabromotellurate salt

Previous findings in the chemistry of 5-amino-1,2,4-triazol-3-thioles show the possibility of protonation of such systems on the nitrogen atom in position 1 of the triazole ring. To expand the molecular design synthetic strategies for triazole systems, it was suggested that the weakening of the basicity of the guanidine fragment via the introduction of a phenyl ring from one side and addition of a flexible 3-(carboxymethyl)sulfanyl moiety in position 3 of the cycle can lead to the formation of a triazole compound that would attach a proton on the nitrogen atom in the second position of the ring. Synthesis of the model 3-[(carboxymethyl)sulfanyl]-4-phenyl-5-phenylamino-4H-1,2,4-triazole via the selective S-alkylation of known 4-phenyl-5-phenylamino-1,2,4-triazole-3-thione has been performed. The synthesized triazole amino acid was converted into a corresponding hexabromotellurate salt which has been further explored and characterized via DFT, NMR and XRD methods.

Glycosamine Derivatives through Metal‐Catalyzed C−N Bond Formation on Protected and Unprotected 2‐Iodoglycals

AbstractGlycosamines are important building blocks of natural biopolymers. The development of synthetic routes to such glycoside family is of big interest in terms of biological application. Herein, access to glycosamine derivatives through dual nickel/copper‐catalyzed C−N bond formation via a cross‐coupling reaction is presented. Diverse benzyl‐ and cyclic amide‐containing glycals were successfully synthesized in moderate to excellent yields starting from perbenzylated and protecting group‐free 2‐iodoglycals. 16 examples presenting d‐glucal or d‐galactal configuration and an electron‐rich or electron‐poor amide moiety in position 2 of the carbohydrate are obtained by this methodology. Post‐functionalization by hydrogenolysis conditions of three synthesized compounds allows access to d‐mannosamine and d‐talosamine mimics.

Design and synthesis of 3, 5- hetero diesters of 4-deoxy quinic acid and their aphicidal activity against Acyrthosiphon pisum

Four analogs of 3,5-dicaffeoylquinic acid, including a new heterodiester of 4-deoxyquinic acid, were found toxic against the pea aphid. Several 4-deoxy quinic analogs featuring two different hydroxyl cinnamoyl moieties in position 3 and 5 were prepared for the first time and carefully analysed. Through an assay on pea aphid nymphs, interesting indications on the structure-aphicidal activity relationships and higher levels of toxicity were observed for four compounds related to the reference natural compound. • Analogs of chlorogenic acids featuring different and various hydroxyl cinnamoyl groups in 3 and 5 positions. • Four compounds were found to exhibit higher aphicidal activities than natural 3,5-di- O -caffeoylquinic acid. • Both acetylated 3- O -feruloyl-5- O -caffeoyl and 3- O -caffeoyl-5- O -coumaroyl compounds were active. • Observation of an interesting structure-activity difference for two regioisomers.

Triarylborane-Appended Anils and Boranils: Solid-State Emission, Mechanofluorochromism, and Phosphorescence.

Herein, the design, synthesis, optical properties, and mechanofluorochromism characteristics of a series of conjugates having covalently linked triarylborane (TAB) and anil/boranil units (TAB-anil: 1 a-3 a and TAB-boranil: 1-3) are reported. The electronic interactions between TAB and anil/boranil in 1 a-3 a and 1-3 were fine-tuned by changing the boryl moiety's position on the phenyl spacer connecting the BMes2 (Mes=mesityl) and anil/boranil units. A boryl moiety at the meta position (1 a) of the phenyl spacer stabilizes the enolic form (E-OH), whereas a boryl moiety at the para position (2 a and 3 a) stabilizes the keto form (Z-NH) in the solid state. However, in solution 1 a, 2 a, and 3 a exhibit keto-enol tautomerism in both ground and excited states. Compounds 1 a-3 a and 1-3 show red-shifted absorption compared with 4 a and 4, which are devoid of TAB moieties, which indicate effective participation of an empty p orbital on the boron center in 1 a-3 a and 1-3. Compounds 1 and 2 showed fluorescence variations in response to external stimuli such as mechanical grinding. Long phosphorescence lifetimes of 18-46 ms were observed for compounds 1-3. The observed optical properties of 1 a-3 a and 1-3 are rationalized in the context of quantum mechanical calculations.

Synthesis and biological evaluation of 3-amino-1,2,4-triazole derivatives as potential anticancer compounds

Two series of compounds carrying 3-amino-1,2,4-triazole scaffold were synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using XTT assay. The 1,2,4-triazole synthesis was revisited for the first series of pyridyl derivatives. The biological results revealed the efficiency of the 3-amino-1,2,4-triazole core that could not be replaced and a clear beneficial effect of a 3-bromophenylamino moiety in position 3 of the triazole for both series (compounds 2.6 and 4.6) on several cell lines tested. Moreover, our results point out an antiangiogenic activity of these compounds. Overall, the 5-aryl-3-phenylamino-1,2,4-triazole structure has promising dual anticancer activity.

Structural Features Defining NF-κB Inhibition by Lignan-Inspired Benzofurans and Benzothiophenes.

A series of 2-arylbenzofurans and 2-arylbenzothiophenes was synthesized carrying three different side chains in position five. The synthesized compounds were tested for NF-κB inhibition to establish a structure activity relationship. It was found that both, the side chain in position five and the substitution pattern of the aryl moiety in position two have a significant influence on the inhibitory activity.

SYNTHESIS OF 4-HETARYL-2-(DICHLOROMETHYL)PYRAZOLO[1,5-a][1,3,5]-TRIAZINES

New pyrazolo[1,5-a][1,3,5]triazines with a heteroaromatic substituent in position 4 and dichloromethyl moiety in position 2 were obtained via a heterocyclization reaction of readily available reagents - N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 3(5)-aminopyrazoles. The high efficiency of the proposed method for the synthesis of 2-(dichloromethyl)-pyrazolo[1,5-a][1,3,5]triazines with furan-2-yl, thien-2-yl, and pyridine-3-yl substituents was demonstrated.

Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds.

Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D2.

Blue fluorescent zinc(II) complexes based on tunable imidazo[1,5-a]pyridines

Herein, we investigate the photophysical features of new zinc(II) chlorido complexes containing fluorescent 1,3-substituted imidazo[1,5-a]pyridines as ligands. The derivatives introduce electron-donating or electron-withdrawing moieties in position 3 on the ligand skeleton. The obtained compounds have been characterized with different spectroscopic techniques, their structure has been defined by single-crystal X-ray diffraction and mass spectrometry and their optical properties have been discussed in relation to the chemical structure. The comparison between the emission spectra of the free ligands and of the corresponding zinc(II) chlorido complexes shows an intense hypsochromic shift, due to the modification of the ligands conformation upon metal coordination, and a significant increase of the quantum yield after complexation.

Chemical transformations of new mono- and bis-derivatives of spiroindol-3,3’-pyrrolo[3,4-c]pyrrole based on bis-maleiminides and the study of the microbiological activity of the compounds synthesized

Aim. To synthesize new derivatives based on hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo-[3,4-c]pyrrole-2a,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trions) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H- spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2,2’,6’(1H,1’H,5’H)-trions by modifying the NH-group of the pyrrole moiety in position 4’ (alkylation, acylation, nitrosation) and study their microbiological activity.Results and discussion. The possibility of further chemical modification of the derivatives of hexamethylene(ethylene)-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) has been developed on the example of ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrol-5’-methyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion), ethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-isopropyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trione), hexamethylene-N,N’-bis(spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-benzyl-2a’,5a’-dihydro-2,2’,6’(1H,1’H,5’H)-trion) and 1’-(m-phenylene-N-maleimidido)-2a’,5a’-dihydro-1’H-spiroindole-3,3’-pyrrolo[3,4-c]pyrrole-5’-methyl-2,2’,6’(1H,1’H,5’H)-trione by modification of the NH-group of the pyrrole fragment in position 4’ (nitrosation) or the NH-group of the indole fragment in position 1 (alkylation), or acylation at once in two positions. The structure of the compounds obtained has been reliably confirmed by instrumental methods. Data from the microbiological screening show a high biological effect of the compounds synthesized in relation to gram-positive (Staphylococcus aureus, Bacillus subtilis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris) and fungi (Candida albicans).Experimental part. The synthesis of the initial and target compounds in classical preparative conditions was performed; instrumental methods for determining the structure of organic compounds, the agar diffusion method in the modification of wells were used.Conclusions. The chemical modification of mono- and bis-derivatives of spiro-2-oxindole[3,3’]pyrrole has been performed: new functionalized nitroso derivatives have been synthesized, the alkylation reaction has been performed, and the reaction of acylation has been studied. It has been shown that the acylation occurs immediately in two positions – by the secondary amino group of the pyrrole and indole fragments, while the alkylation proceeds by the indole fragment. The structure of the compounds obtained has been proven. The antimicrobial effect of the compounds synthesized has been studied.

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

Separation of enantiomers of chiral sulfoxides in high-performance liquid chromatography with cellulose-based chiral selectors using acetonitrile and acetonitrile-water mixtures as mobile phases

The separation of 14 chiral sulfoxides was systematically studied on 12 cellulose-based chiral columns in acetonitrile and acetonitrile-water mobile phases. Out of all monosubstituted methylphenylcarbamates of cellulose the one having a methyl moiety in position 3 showed more universal chiral resolving ability compared to 2- and 4-substituted derivatives. Out of disubstituted phenylcarbamates of cellulose the ones with methyl substituents showed higher enantiomer resolving ability compared to chloro-substituted ones and substitution in positions 3 of the phenyl moiety was clearly advantageous. From disubstituted derivatives those possessing a combination of methyl- and chloro-substituents were advantageous compared to the ones having dimethyl- or dichloro-substituents. Chiral recognition ability of most chiral selectors towards studied sulfoxides was higher in pure acetonitrile compared to previously studied methanol. The effect of water addition to the mobile phase on analyte retention and enantioseparation was also quite different from that observed with methanol. In particular, with aqueous methanol by increasing the water content in the mobile phase retention increased in most cases and the separation factor improved. In contrast, with aqueous acetonitrile retention and separation factors decreased up to a certain water content in the mobile phase and then started to recover again for most of the studied analytes.