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The pharmacological importance of quinoxaline derivatives in antibacterial research is well recognized. This study focuses on the synthesis of new 2,3‐dichloroquinoxaline derivatives containing thioether/ether groups to explore their potential as potent antibacterial agents against various pathogenic bacteria. Most of the compounds exhibited significant antibacterial properties comparable to the standard drug chlorhexidine (CHX). The derivatives of 2‐chloro‐3‐(arylthiol)quinoxaline demonstrated efficacy against Escherichia coli with minimum inhibitory concentrations (MIC) of 2.5 mg/mL and minimum bactericidal concentrations (MBC) of 2.5 to 5.0 mg/mL. These derivatives also showed similar sensitivity to Bacillus pumilus. In addition, molecular docking simulations were performed to investigate the interaction between the synthesized compounds and the DNA gyrase protein (PDB ID: 1KZN), a target for antibiotics. Among the synthesized compounds, 2,3‐bis(3‐nitrophenoxy)quinoxaline exhibited the most favourable docking score of −8.36 kcal/mol, with a binding affinity comparable to that of the reference ligand clorobiocin (−9.3 kcal/mol). [ABSTRACT FROM AUTHOR]

In this study, a new series of quinoxaline derivatives were synthesized by the reaction of 2,3-dichloroquinoxaline with aromatic thiols, leading to the formation of 2,3-bis(arylthiol)quinoxaline, 4-chloro-12H-quinoxalino[2,3-b]1,4-benzothiazine and 5-nitro-1H-benzo[d]imidazole-2-thiol in good to excellent yields. The synthesized quinoxaline derivatives were structurally characterized using infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), elemental analysis and mass spectrometry. Their drug-like properties were evaluated using SwissADME. With the exception of compound 6, all compounds showed significant bioavailability predictions and were subsequently evaluated for their antibacterial activity. The results of the antimicrobial assays showed that the 2,3-bis(arylthiol)quinoxalines exhibited superior inhibitory activity compared to the other synthesized compounds. Further validation was provided by protein-ligand interaction studies using docking analysis. All compounds showed favourable docking values between −7.45 and −8.60 kcal/mol against DNA gyrase subunit B (DNAG) and −7.43 to −8.16 kcal/mol against penicillin-binding protein 1a (PBP1a). Compounds 5 and 6 in particular showed high docking values, confirming the antibacterial in vitro results.

Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor's allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10−12–10−6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs. [ABSTRACT FROM AUTHOR]

Few kinetic parameters, or reaction rates, are known up to date in detail about 1-chloro and 1-fluoro-2,4-dinitrobenzene (ClDNB and FDNB, respectively) with a series of biothiols in aqueous media. These biological nucleophiles with thiol groups have been widely used as a reference in nucleophile reactivity assays due to their prevalence and cellular abundance. The main aim of this study was to elucidate the reaction mechanism based on Brönsted-type plots and reactivity patterns of the electrophile/nucleophile pairs. A complete kinetic study was performed in terms of the comparison of Brönsted-type slope parameters (βnuc) for the reactions and was used for assigning the mechanism and the rate-determining step associated with the reaction route. A mass spectrometry analysis demonstrated that the nucleophilic center of the biothiols is the -SH group and there is only one kinetic product. The kinetic study suggests that the reaction mechanism might be the borderline between concerted and stepwise pathways. An amine–enol equilibrium for the most reactive nucleophiles appears to be the main determining factor controlling the nucleophilic attack in the nucleophilic aromatic substitution reactions investigated, highlighting the anionic form for these nucleophiles. This amine–enol equilibrium involves a hydrogen bond which stabilizes the intermediate species in the reaction pathway. Thus, intramolecular bonds are formed and enhance the nucleophilic strength through the contribution of the solvent surrounding the electrophile/nucleophile pairs. Finally, we highlight the importance of the formation of electrophile/nucleophile adducts that could modify structures and/or functions of biological systems with potential toxic effects. Therefore, it is essential to know all these kinetic and reactivity patterns and their incidence on other studies.

The reactions between 2-chloro-5-nitro pyrimidine with a serie of α-nucleophile derivatives were kinetically evaluated. The kinetic study was carried out in aqueous media and the data shown an unusual split on the Brønsted type-plot, opening a controversial discussion based on reactivities and possible reaction pathways. These split Brønsted type-plots are discussed over the hypothetical transition state (TS) structures associated to concerted or stepwise mechanisms with emphasis on hydrogen bond interactions between electrophile/nucleophile pair able to determine the reactivities and the plausible reaction routes.

Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor’s allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10−12–10−6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs.

This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (SNAr) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) 1H-1H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C–H bonds of the electron-poor pyrimidine functions. Our results not only introduce a transition metal-free synthetic methodology to access precision polymers but also demonstrate how interactions between relatively small, neutral aromatic units in the polymers can be utilized as new supramolecular interaction pairs to control the folding of precision macromolecules.

The efficiency of conventional heating energy source compared with Infrared (IR), Ultrasound (US), Microwave and the simultaneous combination US–IR eco-friendly approaches for preparation of new N-(5-R1 -amino-2-nitrophenyl)acetamides and 5-R1-amino-2-nitroaniline by Nucleophilic Aromatic Substitution (SNAr) via addition–elimination reactions on the halogens F, Cl, Br, I, employing amines as nucleophiles were explored. Moreover, phenyldiazenyl derivatives in good yields by an oxidative one-pot SNAr-based amination reaction from an unusual oxidation of 2-phenylhydrazinyl derivatives in DMSO was prepared.

The efficiency of conventional heating energy source compared with Infrared (IR), Ultrasound (US), Microwave and the simultaneous combination US-IR eco-friendly approaches for preparation of new N-(5-R1-amino-2-nitrophenyl)acetamides and 5-R1-amino-2-nitroaniline by Nucleophilic Aromatic Substitution (SNAr) via addition-elimination reactions on the halogens F, Cl, Br, I, employing amines as nucleophiles were explored. Moreover, phenyldiazenyl derivatives in good yields by an oxidative one-pot SNAr-based amination reaction from an unusual oxidation of 2-phenylhydrazinyl derivatives in DMSO was prepared. [ABSTRACT FROM AUTHOR]

The changes of the free energy of activation δ∆ G≠exp and the activation entropy δ∆ S≠ in the framework of the isokinetic relationship δ∆ G≠exp versus ( Tiso − Texp) δ∆ S≠ were explored quantitatively to predict the isokinetic temperature Tiso for the aromatic nucleophilic substitution reactions in solution. [ABSTRACT FROM AUTHOR]

[Display omitted] 2-Arylphenols have been synthesized by KOH/DMSO mediated tandem S N Ar/desulfurization reactions of dibenzothiophene dioxide. Diversely substituted phenols such as 2,4-diarylated and challenging 2,5-diarylated ones are obtained in this transformation. Based on the experimental evidence, a mechanism is proposed. Synthetic utility of sulfinic ester and 2-arylphenol have been showcased. [ABSTRACT FROM AUTHOR]

The title compound, C6H6N6S, crystallized with two independent molecules (A and B) in the asymmetric unit. The conformation of the two molecules differs slightly. While the tetrazole ring is inclined to the pyrimidene ring by 5.48 (7) and 4.24 (7)° in molecules A and B, respectively, the N—C—S—C torsion angles of the thiomethyl groups differ by ca 180°. In the crystal, the A and B molecules are linked via a C—H...N hydrogen bond. They stack along the b-axis direction forming columns within which there are weak π–π interactions present [shortest inter-centroid distance = 3.6933 (13) Å].

2,6-Bis-(1,2,3-triazol-1H-1-yl)purine nucleosides react at C(6) with the N- and S-termini of various amino acids by expelling the corresponding 1,2,3-triazole as a leaving group in nucleophilic aromatic substitution reaction. This gives rise to a novel type of conjugate between purine nucleosides and amino acids. The obtained amino acid-derived 6-amino-2-(1,2,3-triazol-1H-1-yl)-purine derivatives showed useful levels of fluorescence with quantum yields up to 38% and Stokes shifts up to 91 nm. Glutathione and a cysteine-containing nonapeptide selectively reacted with their S-termini and produced the expected C(6) conjugates in good to excellent yields. [ABSTRACT FROM AUTHOR]

An efficient method was developed for the synthesis of 1-naphthols through NaO tBu-promoted SNAr reaction of ortho-haloacetophenones followed by Lewis acid CuI-catalyzed intramolecular condensation and isomerization. 1-Naphthol derivatives were obtained in satisfactory yields from aryl bromide and aryl iodide substrates. [ABSTRACT FROM AUTHOR]

Novel [2n]thiacalixarenepyrazine and [2n]thiacalixarenetriazine systems were synthesised by one-pot SNAr reactions. A screening of the metal-complexing ability of [26]hexathiacalix[3]arene[3]pyrazine revealed its affinity for CuI, CuIIand AgImetal salts. [ABSTRACT FROM AUTHOR]

Highlights: [•] We quantified the electrophilic reactivity for four aromatic triflones. [•] We examined the substitutents effect on the electrophilic strength. [•] Ranking the neutral electro-deficient electrophiles in Mayr's scale. [•] Increasing the scope and the applications of the Mayr equation. [•] Expanding the range of coupling reactions. [Copyright &y& Elsevier]

Abstract: Previously unknown 2,5-bis-sulfonylpyrazines are prepared and their SNAr reactions are investigated. When 2equiv of thiols are employed, the corresponding bis-thiopyrazines are obtained exclusively. However, phenols or alkoxides gave rise to only the corresponding mono-substituted aryloxy- or alkoxy-sulfonylpyrazines in excellent yields. A carbon nucleophile prepared by treating malonate with NaH also produced the corresponding mono-sulfonylpyrazines. Aliphatic amines and anilines only provided the mono-anilino-sulfonylpyrazines in poor to moderate yields. [Copyright &y& Elsevier]

On the basis of the changes of the activation parameters [ABSTRACT FROM AUTHOR]

Few kinetic parameters, or reaction rates, are known up to date in detail about 1-chloro and 1-fluoro-2,4-dinitrobenzene (ClDNB and FDNB, respectively) with a series of biothiols in aqueous media. These biological nucleophiles with thiol groups have been widely used as a reference in nucleophile reactivity assays due to their prevalence and cellular abundance. The main aim of this study was to elucidate the reaction mechanism based on Brönsted-type plots and reactivity patterns of the electrophile/nucleophile pairs. A complete kinetic study was performed in terms of the comparison of Brönsted-type slope parameters ( β nuc ) for the reactions and was used for assigning the mechanism and the rate-determining step associated with the reaction route. A mass spectrometry analysis demonstrated that the nucleophilic center of the biothiols is the -SH group and there is only one kinetic product. The kinetic study suggests that the reaction mechanism might be the borderline between concerted and stepwise pathways. An amine-enol equilibrium for the most reactive nucleophiles appears to be the main determining factor controlling the nucleophilic attack in the nucleophilic aromatic substitution reactions investigated, highlighting the anionic form for these nucleophiles. This amine-enol equilibrium involves a hydrogen bond which stabilizes the intermediate species in the reaction pathway. Thus, intramolecular bonds are formed and enhance the nucleophilic strength through the contribution of the solvent surrounding the electrophile/nucleophile pairs. Finally, we highlight the importance of the formation of electrophile/nucleophile adducts that could modify structures and/or functions of biological systems with potential toxic effects. Therefore, it is essential to know all these kinetic and reactivity patterns and their incidence on other studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campodónico, Alarcón-Espósito and Olivares.)

Abstract: 2,4,6-Trinitrotoluene readily reacts with 1-nitroso-2-naphthol to afford 9,11-dinitrobenzo[f]naphtho[2,1-b][1,4]oxazepine. The nitro groups of the latter undergo displacement by O- and S-nucleophiles with preferential substitution of the 11-NO2 (peri-nitro group). The structures of the substitution products are confirmed by X-ray diffraction and 1H NMR NOE experiments. [Copyright &y& Elsevier]

The reactions between 2-chloro-5-nitro pyrimidine with a serie of α-nucleophile derivatives were kinetically evaluated. The kinetic study was carried out in aqueous media and the data shown an unusual split on the Brønsted type-plot, opening a controversial discussion based on reactivities and possible reaction pathways. These split Brønsted type-plots are discussed over the hypothetical transition state (TS) structures associated to concerted or stepwise mechanisms with emphasis on hydrogen bond interactions between electrophile/nucleophile pair able to determine the reactivities and the plausible reaction routes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campodónico, Tapia and Suárez-Rozas.)

Abstract: The reaction of 2-iodo-3-nitro-1-(phenylsulfonyl)indole (2) with amines affords the corresponding 2-amino-3-nitroindoles in excellent yields via nucleophilic aromatic substitution. [Copyright &y& Elsevier]

This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (S N Ar) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) 1 H- 1 H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C-H bonds of the electron-poor pyrimidine functions. Our results not only introduce a transition metal-free synthetic methodology to access precision polymers but also demonstrate how interactions between relatively small, neutral aromatic units in the polymers can be utilized as new supramolecular interaction pairs to control the folding of precision macromolecules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jaynes, Sharafi, Campbell, Bocanegra, McKay, Little, Osadchey Brown, Gray, Woods, Li and Schneebeli.)

The title compound, C6H6N6S, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The conformation of the two mol-ecules differs slightly. While the tetra-zole ring is inclined to the pyrim-idene ring by 5.48 (7) and 4.24 (7)° in mol-ecules A and B, respectively, the N-C-S-C torsion angles of the thio-methyl groups differ by ca 180°. In the crystal, the A and B mol-ecules are linked via a C-H⋯N hydrogen bond. They stack along the b-axis direction forming columns within which there are weak π-π inter-actions present [shortest inter-centroid distance = 3.6933 (13) Å].