Elucidating the intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid-solid interface

Star-shaped 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules self-assemble at the solid–liquid interface into a compact hexagonal nanoarchitecture on graphite. High resolution scanning tunneling microscopy (STM) images of the molecules reveal intramolecular features. Comparison of the experimental data with calculated molecular charge density contours shows that the molecular features in the STM images correspond to molecular LUMO+2.

Intramolecular contrast in the STM images of 2,4,6-tris(4′,4′′,4′′′-trimethylphenyl)-1,3,5-triazine molecules recorded at room-temperature and at the liquid–solid interface.     

Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

2,2′,2′′,4,4′,4′′,6,6′,6′′-Nonanitro-1,1′:3′,1′′-terphenyl (NONA) is currently recognized as an excellent heat-resistant explosive. To improve the atomistic understanding of the thermal decomposition paths of NONA, we performed a series of reactive force field (ReaxFF) molecular dynamics simulations under extreme conditions of temperature and pressure. The results show that two distinct initial decomposition mechanisms are the homolytic cleavage of the C–NO₂ bond and nitro–nitrite (NO₂ → ONO) isomerization followed by NO fission. Bimolecular and fused ring compounds are found in the subsequent decomposition of NONA. The product identification analysis under finite time steps showed that the gaseous products are CO₂, N₂, and H₂O. The amount of CO₂ is energetically more favorable for the system at high temperature or low density. The carbon-containing clusters are a favorable growth pathway at low temperatures, and this process was further demonstrated by the analysis of diffusion coefficients. The increase of the crystal density accelerates the decomposition of NONA judged by the analysis of reaction kinetic parameters and activation barriers. In the endothermic and exothermic stages, a 20% increase in NONA density increases the activation energies by 3.24 and 0.48 kcal mol⁻¹, respectively. The values of activation energies (49.34–49.82 kcal mol⁻¹) agree with the experimental data in the initial decomposition stage.

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.     

Diastereoselective synthesis of dispirooxindoles via [3+2] cycloaddition of azomethine ylides to 3-phenacylideneoxindoles and evaluation of their cytotoxicity

The three-component reaction of 1,2,3,4-tetrahydroisoquinoline, isatins and 3-phenacylideneoxindoles in refluxing ethanol afforded dispiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline-3′,3′-indolines] (4a–4x) in good yields via 1,3-dipolar cycloaddition of in situ generated azomethine ylide with the exocyclic double bond of 3-phenacylideneoxindoles. ¹H NMR spectra and single crystal structures indicated the reaction has high regioselectivity and diastereoselectivity. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation against mouse breast cancer cells 4T1 and human liver cancer cells HepG2 by MTT assay. The results demonstrated that some of the compounds showed cytotoxicities to cell lines of 4T1 and HepG2, and indicated that novel spirooxindoles may become potential lead compounds for further biological screenings of their medicinal applications.

The three-component reaction of 1,2,3,4-tetrahydroisoquinoline, isatins and 3-phenacylideneoxindoles in refluxing ethanol afforded dispiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline-3′,3′-indolines] (4a–4x) in good yields via 1,3-dipolar cycloaddition.     

Base-promoted lipase-catalyzed kinetic resolution of atropisomeric 1,1′-biaryl-2,2′-diols

Herein we report a dramatic acceleration of the lipase-catalyzed kinetic resolution of atropisomeric 1,1′-biaryl-2,2′-diols by the addition of sodium carbonate. This result likely originates from the increased nucleophilicity of the phenolic hydroxyl group toward the acyl-enzyme intermediate. Under these conditions, various substituted C₂-symmetric and non-C₂-symmetric binaphthols and biphenols were efficiently resolved with ∼50% conversion in only 13–30 h with excellent enantioselectivity.

The addition of a stoichiometric amount of Na₂CO₃ dramatically accelerates the lipase-catalyzed kinetic resolution of a range of atropisomeric 1,1′-biaryl-2,2′-diols.     

Copper-catalyzed intramolecular cross dehydrogenative coupling approach to coumestans from 2′-hydroxyl-3-arylcoumarins

A copper-catalyzed intramolecular cross dehydrogenative C–O coupling reaction of 2′-hydroxyl-3-arylcoumarins was developed. This protocol provided a facile and efficient strategy for the construction of natural coumestans and derivatives in moderate to high yields. This transformation exhibited good functional group compatibility and was amenable to substrates with free phenolic hydroxyl groups.

A copper-catalyzed intramolecular cross dehydrogenative C–O coupling reaction of 2′-hydroxyl-3-arylcoumarins was developed.     

Anti-inflammatory butenolide derivatives from the coral-derived fungus Aspergillus terreus and structure revisions of aspernolides D and G,butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4). The new structures were characterized on the basis of comprehensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS data. Compounds 1 and 2 were a pair of rare C-8′′ epimers with vicinal diol motifs. The absolute configurations of 1–4 were determined via [Mo₂(AcO)₄] induced circular dichroism (ICD) spectra and comparison of their experimental ECD spectra. Importantly, the structures of reported aspernolides D and G, butyrolactone VI and 4′,8′′-diacetoxy butyrolactone VI have been correspondingly revised via a combined strategy of experimental validations, ¹³C NMR predictions by ACD/Labs software, and ¹³C NMR calculations. Herein we provide valuable referenced ¹³C NMR data (C-7′′, C-8′′, and C-9′′) for the structure elucidations of butenolide derivatives with 1-(2-hydroxyphenyl)-3-methylbutane-2,3-diol, 2-(2,3-dihydrobenzofuran-2-yl)propan-2-ol, or 2,2-dimethylchroman-3-ol motifs. Additionally, all the isolates (1–10) were assessed for anti-inflammatory activity by measuring the amount of NO production in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages, and compound 10 showed an even stronger inhibitory effect than the postive control indomethacin, presenting it as a promising lead compound for the development of new anti-inflammatory agents.

Chemical investigation of the coral-derived fungus Aspergillus terreus led to the discovery of ten butenolide derivatives (1–10), including four new ones (1–4).     

Synthesis of 8′,11′-dihydrospiro[cyclohexane-1,2′-oxepino[2,3-h] chromen]-4′(3′H)-ones with ring closing metathesis as a key step

A series of novel hybrid molecular entities incorporating various spiro chromanone scaffolds onto the benzannulated oxepine core moiety were synthesised using allylation, Claisen rearrangement, Kabbe condensation and Ring Closing Metathesis (RCM) as a key step. During the synthesis we found that the nitrogen functionality in the substrate influences significantly the catalyst load due to electronic effects. Several iterations have been carried out to achieve complete conversion to products 6a–6e.

We successfully synthesized these type of angular tetracyclic frameworks.     

Synthesis,cytotoxicity evaluation and molecular docking studies on 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone derivatives

2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC, 1) was isolated from seeds of Syzygium nervosum A.Cunn. ex DC. exhibiting intriguing biological activities. Herein, thirty three DMC derivatives including 4′-O-monosubstituted-DMC (2), 7-O-acylated-4-hydroxycoumarin derivatives (3), stilbene–coumarin derivatives (4), 2′,4′-disubstituted-DMC (5), and flavanone derivatives (6), were synthesised through acylation, alkylations, and sulfonylation. These semi-synthetic DMC derivatives were evaluated for in vitro cytotoxicity against six carcinoma cell lines. It was found that most derivatives exhibited higher cytotoxicity than DMC. In particular, 4′-O-caproylated-DMC (2b) and 4′-O-methylated-DMC (2g) displayed the strongest cytotoxicity against SH-SY5Y with IC₅₀ values of 5.20 and 7.52 μM, respectively. Additionally, 4′-O-benzylated-DMC (2h) demonstrated the strongest cytotoxicity against A-549 and FaDu with IC₅₀ values of 9.99 and 13.98 μM, respectively. Our structure–activity relationship (SAR) highlights the importance of 2′-OH and the derivatisation pattern of 4′-OH. Furthermore, molecular docking simulation studies shed further light on how these bioactive compounds interact with cyclin-dependent kinase 2 (CDK2).

Semi-synthetic DMC derivatives were synthesised and displayed biological potency against various cancer cell lines.      

Synthesis and photophysical properties of N-alkyl dithieno[3,2-b:2′,3′-d]pyrrole based donor/acceptor-π-conjugated copolymers for solar-cell application

Two kinds of donor–acceptor π-conjugated copolymer based on poly{[N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-2,6-diyl]alt-[isoindigo]} (PDTP-IID) and poly{[N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-2,6-diyl]alt-[thiazol-2,5-diyl]} (PDTP-Thz) were investigated. These copolymers were synthesized via a Stille coupling reaction. The results showed the structure–property relationships of different donor–acceptor (D–A) combinations. The polymer structures and photophysical properties were characterized by ¹H NMR, TGA, DSC, UV-vis absorption spectroscopy, AFM, CV, and XRD measurement. Through UV-vis absorption and cyclic voltammetry (CV) measurements, it showed that the copolymers exhibit not only a low bandgap of 1.29 eV and 1.51 eV but also a deep highest occupied molecular orbital (HOMO) of −5.49 and −5.11 eV. Moreover, photovoltaic properties in combination with the fullerene derivatives were investigated. The device based on the copolymers with PC₇₁BM exhibited higher maximum power conversion efficiency and higher maximum short-circuit current density of 0.23% with 1.64 mA cm⁻² of PDTP-IID:PC₇₁BM and 0.13% with 1.11 mA cm⁻² of PDTP-Thz:PC₇₁BM than those of the copolymers with PC₆₁BM. Measurements performed for N-hexyl-dithieno(3,2-b:2′,3′-d)pyrrole-based copolymers proved the potential of these polymers to be applied in optoelectronic applications.

The relationships between the structure and the property of donor–acceptor copolymers based on dithieno[3,2-b:2′,3′-d]pyrrole as a strong donor unit and isoindigo or thiazole as acceptor units are successfully studied.     

Facile access to regio- and stereoselective synthesis of highly functionalized spiro[indoline-3,2′-pyrrolidines] incorporating a pyrene moiety: experimental,photophysical and theoretical approach

The regio- and stereochemical polar [3 + 2] cycloaddition of azomethine ylides, which were generated in situ by the reaction of isatin and sarcosine or benzylamine, with (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones as dipolarophiles, was studied using experimental and theoretical methods. The chemical structures and relative configurations of all products have been fully established by 1D and 2D homonuclear and heteronuclear correlation NMR spectrometry. The effects of the electronic and steric factors of the reactions were discussed. The photophysical properties of the synthesized spiro[indoline-3,2′-pyrrolidin]-2-ones and 5′-phenyl-spiro[indoline-3,2′-pyrrolidin]-2-ones were studied. The mechanism of the reactions was investigated using global and local reactivity indices and frontier molecular orbital (FMO) analysis at the B3LYP/6-31G level of theory. The relationship between the electrophilicity index ω of the dipolarophiles and the Hammett constant σ_p has been studied. The theoretical scale of reactivity correctly explains the electrophilic activation/deactivation effects promoted by electron-withdrawing and electron-releasing substituents in the para-position of the dipolarophiles.

The regio- and stereochemical polar [3 + 2] cycloaddition of azomethine ylides with (E)-3-aryl-1-(pyren-1-yl)prop-2-en-1-ones as dipolarophiles, was studied using experimental and theoretical methods.     

The synthesis of N,N′-disulfanediyl-bis(N′-((E)-benzylidene)acetohydrazide) from (E)-N′-benzylideneacetohydrazide and S8

Herein we report an oxidative coupling reaction for N–S/S–S bond formation from (E)-N′-benzylideneacetohydrazide and S₈ to furnish substituted N,N′-disulfanediyl-bis(N′-((E)-benzylidene) acetohydrazide). It provides a direct approach for the synthesis of disulfides with good yields.

Herein we report an oxidative coupling reaction for N–S/S–S bond formation substituted N,N′-disulfanediyl bis(N′-((E)-benzylidene)acetohydrazide). It provides a direct approach for the synthesis of disulfides with good yields.     

2′-Fluoro-c-di-GMP as an oral vaccine adjuvant

Bis-(3′–5′)-cyclic dimeric 2′-deoxy-2′-fluoroguanosine monophosphate (2′-F-c-di-GMP) was synthesized through the modified H-phosphonate chemistry. Oral immunization of C57BL/6 mice with Helicobacter pylori cell-free sonicate extract adjuvanted with 2′-F-c-di-GMP led to the production of antigen-specific antibodies in feces and sera, and lowered bacterial counts in the stomach upon post-vaccination infections in immunized mice. Similarly, oral vaccination of BALB/c mice with flagillin proteins from Clostridium difficile and Listeria monocytogenes adjuvanted with 2′-F-c-di-GMP led to production of antigen-specific antibodies both systemically and mucosally. The adjuvanticity of 2′-F-c-di-GMP is associated with the enhanced induction of interferon γ. These results demonstrated the excellent oral adjuvanticity of 2′-F-c-di-GMP.

2′-F-c-di-GMP was synthesized through the modified H-phosphonate chemistry. 2′-F-c-di-GMP was found to be an effective mucosal vaccine adjuvant, both intranasally and orally.     

Inhibitory potential of nitrogen,oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

Heterocycles are the key structures in organic chemistry owing to their immense applications in the biological, chemical, and pharmaceutical fields. Heterocyclic compounds perform various noteworthy functions in nature, medication, innovation etc. Most frequently, pure nitrogen heterocycles or various positional combinations of nitrogen, oxygen, and sulfur atoms in five or six-membered rings can be found. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes is a popular strategy for the management of numerous mental diseases. In this context, cholinesterase inhibitors are utilized to relieve the symptoms of neurological illnesses like dementia and Alzheimer''s disease (AD). The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD. Moreover, a detailed structure–activity relationship (SAR) has been established for the future discovery of novel drugs for the treatment of AD. Most of the heterocyclic motifs have been used in the design of new potent cholinesterase inhibitors. In this regard, this review is an endeavor to summarize the biological and chemical studies over the past decade (2010–2022) describing the pursuit of new N, O and S containing heterocycles which can offer a rich supply of promising AChE and BChE inhibitory activities.

The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD.     

Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes. Under similar conditions, the one-pot reaction of tryptamines, alkyl propiolates and β-nitroalkenes resulted in functionalized tetrahydroindolizino[8,7-b]indoles. The reaction mechanism involved sequential generation of β-enamino ester, Michael addition, Pictet–Spengler reaction and annulation process. The reaction showed high atomic economy and met the goals of sustainable chemistry.

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes.     

The antitumor activity of 4,4′-bipyridinium amphiphiles

A series of 4,4′-bipyridinium amphiphiles were synthesized and their anticancer activities were further evaluated. MTT assay showed that the cytotoxicity first increased and then decreased with the growth of carbon chains (8–16 C) at both ends of bipyridyl. Specifically, compounds with saturated carbon chains consisting of 13 carbons at both ends of bipyridyl displayed the best cell inhibitory activity with IC₅₀ values in the low-micromolar range, which were even superior to that of cisplatin, against all the tested human cancer cells and cisplatin-resistant A549 cancer cells in vitro. In addition, compound 6 could evidently arrest the G2/M phase of the cell cycle in a dose-dependent manner. Moreover, this study demonstrates the potent performance of compound 6 in cell growth inhibition and apoptosis induction via a conceivable approach of membrane damage.

The cell growth inhibition and apoptosis induction of 4,4′-bipyridinium amphiphiles.     

Isolation of 5′-O-sulfamyladenosine and related 3′-O-β-glucosylated adenosines from the nucleocidin producer Streptomyces calvus

The isolation of three adenosine based metabolites 6–8 from Streptomyces calvus is reported. The metabolites are structurally related to the fluorine containing antibiotic nucleocidin 1 and two recently identified glycosylated fluoroadenosines 2 and 3, however in this case the three metabolites do not contain a fluorine, suggesting that the biosynthetic enzymes to the fluorometabolites also process their non-fluorinated counterparts.

The isolation of three adenosine based metabolites 6–8 from Streptomyces calvus is reported.     

Synthesis of 1,3-diaryl-spiro[azetidine-2,3′-indoline]-2′,4-diones via the Staudinger reaction: cis- or trans-diastereoselectivity with different addition modes

A new synthetic approach for realizing biologically relevant bis-aryl spiro[azetidine-2,3′-indoline]-2′,4-diones was developed based on Staudinger ketene–imine cycloaddition through the one-pot reaction of substituted acetic acids and Schiff bases in the presence of oxalyl chloride and an organic base. A series of [azetidine-2,3′-indoline]-2′,4-diones were synthesized using this method. For comparison, the same compounds were obtained using a known technique, where ketene is generated from pre-synthesized acyl chloride. It was shown that the use of oxalyl chloride for ketene generation in the one-pot reaction at room temperature allows for the reversal of the diastereoselectivity of spiro-lactam formation, unlike previously described procedures.

Two experimental techniques of the ketene–imine Staudinger reaction allowed different diastereomers of spiro-indolinone-β-lactams to be obtained.     

Supported l-tryptophan on Fe3O4@SiO2 as an efficient and magnetically separable catalyst for one-pot construction of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives

In this work, l-tryptophan functionalized silica-coated magnetic nanoparticles were readily prepared and evaluated as a recyclable magnetic nanocatalyst for the synthesis of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives through the one-pot four-component reaction of malononitrile, cyclohexanone, aromatic aldehydes, and 1,3-indandione. This novel magnetic nanocatalyst was confirmed to be effective and provide products in moderate to excellent yields under reflux conditions. The structure of obtained nanoparticles was characterized using FT-IR, XRD, VSM, EDX, elemental mapping, FE-SEM, and TGA. This synthetic protocol provides several benefits such as excellent yields in short reaction times (64–91%), saving costs, reusability of the catalyst using an external magnet (seven runs), and low catalyst loading.

l-Tryptophan functionalized silica-coated magnetic nanoparticles were prepared and evaluated as a magnetic nanocatalyst for the synthesis of spiro[indene-2,2′-naphthalene]-4′-carbonitrile derivatives through the one-pot four-component reaction.     

Direct enantioseparation of axially chiral 1,1′-biaryl-2,2′-diols using amidine-based resolving agents

Amidine-based optically active resolving agents for enantiomer separation of axially chiral 1,1′-biaryl-2,2′-diols have been developed. A strongly basic amidine bearing no substituents on its nitrogen atoms enables the formation of their diastereomeric salts upon being mixed with weakly acidic phenol derivatives. Enantiopure 1,1′-biaryl-2,2′-diols can be obtained in high yields after only one crystallization of their salts with the chiral amidine derived from dehydroabietic acid. X-ray crystallography revealed that the amidine moiety forms a salt with the phenol group and additional intermolecular NH/π interactions contribute to the efficient chiral recognition process.

Enantioseparation of atropisomeric biphenols using a chiral amidine derived from dehydroabietic acid was reported. Only one crystallization of their mixture gave pure diastereomeric salts of biphenols from racemate.     

Microbial transformations of 4′-methylchalcones as an efficient method of obtaining novel alcohol and dihydrochalcone derivatives with antimicrobial activity

Biotransformations are an alternative method of receiving dihydrochalcones as a result of the reduction of α,β-unsaturated ketones – chalcones. In presented research, two strains of bacteria – Gordonia sp. DSM44456 and Rhodococcus sp. DSM364 – were selected as effective biocatalysts that are able to transform chalcones in a short period of time. As a result of our investigation 3 new dihydrochalcones and one novel alcohol were obtained with high isolated yields. All 4′-methylchalcone derivatives and biotransformations products were tested for antimicrobial activity against Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957. The best inhibitory effect was observed for all chalcones against E. coli ATCC10536 – compounds 1–6 and 8 prevented thorough growth of this strain (ΔOD = 0). Moreover, dihydrochalcones showed about 2–3 times stronger inhibitory effect against S. aureus DSM799 in comparison to their chalcones. Excluding the E. coli ATCC10536 strain, 3-(4-carboxyphenyl)-1-(4-methylphenyl)propan-1-ol (8b) had weaker biological activity than 4-carboxy-4′-methyl-α,β-dihydrochalcone (8a).

Biotransformations of 4′-methylchalcones using whole cells of bacteria allowed to obtain dihydrochalcones and alcohol with high isolated yields. The antimicrobial activity of all derivatives was evaluated against selected bacteria and fungi strains.