Benzyl Substituents Research Articles

Study of the Mechanism of Biological Activity Enhancement of Benzylpenicillin Sodium Salt after Treatment with Pulsed Magnetic Field of High Intensity

Magnetic field is able to change the biological activity of drugs, which can be used in medicine. Literature data on the increase in biological activity of prepared drugs under the influence of pulsed magnetic fields immediately before their administration have not been found. This article presents data on the increase in antibacterial activity of benzylpenicillin sodium salt after its treatment with pulsed magnetic field. The aim of the work is to investigate the reasons for the increase in biological activity of benzylpenicillin, to show the changes that occur in the molecule under the influence of a pulsed magnetic field. Exposure to magnetic field was carried out on powdered antibiotic on magnetic-pulse unit with magnetic field strength H = (0.09÷0.82) × 106 A/m. The pulse shape was a damped sinusoid with frequency response f = 40 kHz and f = 51 kHz. Experimental methods of NMR-spectroscopy and IR-Fourier-spectroscopy were used in the studies. The shift in the value of chemical shifts (δH) and spin-spin interaction constants (2JHH) of the signals of methylene protons of the benzyl substituent as a result of the magnetic field was found. The changes in the absorption bands of the N–H and C=O bonds of the amide grouping and the carbonyl group of the lactam cycle were detected by FTIR spectroscopy. The obtained spectral data allow us to conclude that the geometry of the benzylpenicillin sodium salt molecule in the amide fragment has changed under the influence of a pulsed magnetic field, which is probably the reason for the increase in antibacterial activity of the antibiotic.

Synthesis, Characterization and Biological Activities of Novel Chiral Bis 1,2-diolcarbothioamides

2,2'-[(2R,3R)-2,3-dihydroxy-1,4-dioxobutane-1,4-diyl]bis(N-aryl-alkylhydrazine-1-carbothioamide (T1–5) were obtained by the interaction of (2R,3R)-2,3-dihydroxybutanedihydrazide (1) with five different isothiocyanate alkyl(aryl) derivatives. The structures of the final compounds were confirmed by elemental analyses, FT-IR, ¹H-NMR and ¹³C-NMR. The antioxidant, antimicrobial and anticancer properties of the synthesized compounds were also investigated. Three of the triazole derivatives with p-tolyl, benzyl and phenyl substituents (T3–5) displayed good antioxidant and anticancer activity in comparison to the standards.

Mechanism-Guided Development of Bifunctional Cyclooctenes as Active, Practical, and Light-Gated Bromination Catalysts.

Most molecular catalysts have been developed employing polar functional groups as catalytic sites. However, the use of non-polar functional groups for catalysis has received less attention due to their modest molecular interactions while the bioorthogonal reactivity of non-polar alkenes as substrates is frequently used in click chemistry. In this study, we conducted mechanistic studies on the catalysis of trans-cyclooctene (TCO) derivatives with the strained olefin as the catalytic site using kinetic and computational analyses to aid the design of more active olefin catalysts. The analysis reveals the significant role of the benzyl substituents in accelerating the generation of bromonium species through dispersion interaction in the rate-determining step. Guided by the mechanistic insights, we developed bifunctional TCO catalysts bearing a functionalized benzyl group, taking advantage of the remarkable substituent effects. Experimental studies confirmed the theoretical model and revealed that TCO with a para-hydroxybenzyl group provided excellent catalytic activity. Furthermore, inclusion of the functionalized benzyl groups allowed more readily available and robust cis-cyclooctenes to be used as active catalysts, expanding the practical utility of the olefin catalysts. By using a photochemically labile masking group on the para-hydroxybenzyl substituent, the first light-gated bromination catalyst was developed, enabling spatiotemporal control of the transformation.

Regioselective [3 + 2] Cycloaddition Between Ynamides and Pyridine‐N‐Aminides Catalyzed by PicAuCl2 Anchored Onto SBA‐15

ABSTRACTA dichloro(2‐pyridinecarboxylato)gold complex anchored on SBA‐15 (SBA‐15‐PicAuCl2) was conveniently prepared through the addition reaction between triethoxy(3‐isocyanatopropyl)silane and dichloro(3‐hydroxy‐2‐pyridinecarboxylato)gold complex and subsequent condensation with SBA‐15. The new heterogenized PicAuCl2 complex was fully characterized by using various analytic methods. In the existence of 5 mol% of SBA‐15‐PicAuCl2, the regioselective [3 + 2] cycloaddition reaction between ynamides and pyridine‐N‐aminides proceeded in toluene at 100°C for 1–24 h to deliver a wide array of functionalized trisubstituted 1,3‐oxazoles in 57%–95% yields. Ynamides with alkyl, benzyl, and aryl substituents as well as different sulfonyl groups at the nitrogen atom and the oxazolidinone‐derived ynamides were well‐tolerated. A wide range of pyridine‐N‐aminides bearing aroyl, naphthoyl, furoyl, vinylcarbonyl, alkylcarbonyl, and methoxycarbonyl were also allowed in the reaction. Moreover, SBA‐15‐PicAuCl2 is easy to recover through a simple centrifugation and recyclable at least seven cycles with only a slight drop in catalytic activity.

Oxidation State and Halogen Influence on the NHC‐Gold‐Halide‐Catalyzed Cyclization of Propargylic Amides

The homogeneously catalyzed cycloisomerization reaction of propargylic amides was tested as benchmark reaction for two homologous series of Au(I) and Au(III) complexes with NHC ligands. This reaction is known to afford either aromatic oxazoles or dihydrooxazoles, depending on the oxidation state of the applied gold catalysts. For this purpose, symmetric and unsymmetric NHC ligands with mixed alkyl or benzyl substituents (1,3‐dimethyl‐imidazolyl‐2yl or 1‐benzyl‐3‐methyl‐imidazolyl‐2‐yl) and the corresponding Au(I) and Au(III) derivatives were prepared and characterized by analytical methods, IR and 1H and 13C NMR spectroscopies, and by X‐ray diffraction methods. Ten NHC‐gold(I) and NHC‐gold(III) complexes were tested on the cyclization reactions by adding gold catalysts in the presence and absence of AgPF6.Noteworthy, only the 1‐benzyl‐3‐methyl‐gold(III) trichloride was able to give selectively the aromatic oxazole without the addition of the silver salt. Interestingly, on contrary to what is reported in the literature, the use of gold(I) or gold(III) complexes does not influence the chemoselectivity of the cyclization reaction, while the halide bound to the metal does. In this regard, a mechanism purposing the dihydrooxazole as an intermediate for the formation of aromatic oxazole is proposed.

Electrochromic behaviors and applications of tetrasubstituted thienoviologen derivatives

Electrochromic materials have been widely used in various parts of life due to their advantages of energy conservation and rich colors. In this work, a series of novel viologen derivatives (tetrasubstituted thienoviologen derivatives, a–f) were designed and synthesized as electrochromic materials by decorating 4,4′,4″,4‴-(thiophene-2,3,4,5-tetrayl)tetrapyridine with different N-substituents (alkyl, benzyl and aryl). Electrochromic devices based on a–f exhibited a low working voltage of −1.4 V. The N-substituents markedly affected their electrochromic performance. The compounds with alkyl and benzyl substituents performed better than the compound with aryl substituent. Among them, compound c with benzyl substituent performed best with a high optical contrast (66 %), a high coloration efficiency (389 cm2/C), good cycling stability, and fast response time. Besides, compound c was also applicable to sodium carboxymethyl cellulose hydrogel ECD with good cycling stability and a broad absorption band (500–700 nm) in the visible region. The applications of compound c in electronic tags, functional displays and smart windows were explored, indicating it's a promising ECM with wide application prospects.

Chiral versus achiral crystal structures of 4-benzyl-1H-pyrazole and its 3,5-di-amino derivative.

The crystal structures of 4-benzyl-1H-pyrazole (C10H10N2, 1) and 3,5-di-amino-4-benzyl-1H-pyrazole (C10H12N4, 2) were measured at 150 K. Although its different conformers and atropenanti-omers easily inter-convert in solution by annular tautomerism and/or rotation of the benzyl substituent around the C(pyrazole)-C(CH2) single bond (as revealed by 1H NMR spectroscopy), 1 crystallizes in the non-centrosymmetric space group P21. Within its crystal structure, the pyrazole and phenyl aromatic moieties are organized into alternating bilayers. Both pyrazole and phenyl layers consist of aromatic rings stacked into columns in two orthogonal directions. Within the pyrazole layer, the pyrazole rings form parallel catemers by N-H⋯N hydrogen bonding. Compound 2 adopts a similar bilayer structure, albeit in the centrosymmetric space group P21/c, with pyrazole N-H protons as donors in N-H⋯π hydrogen bonds with neighboring pyrazole rings, and NH2 protons as donors in N-H⋯N hydrogen bonds with adjacent pyrazoles and other NH2 moieties. The crystal structures and supra-molecular features of 1 and 2 are contrasted with the two known structures of their analogs, 3,5-dimethyl-4-benzyl-1H-pyrazole and 3,5-diphenyl-4-benzyl-1H-pyrazole.

Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.

Novel binuclear copper(II) complexes with sulfanylpyrazole ligands: synthesis, crystal structure, fungicidal, cytostatic, and cytotoxic activity.

New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents. An in vitro evaluation of the cytotoxic properties of Cu chelates against HEK293, Jurkat, MCF-7, and THP-1 cells identified the Cu complex with the cyclohexylsulfanyl substituent in the pyrazole core as the lead compound, whereas the Cu complex without a sulfur atom in the pyrazole ligand had virtually no cytotoxic or fungicidal activity. The lead Cu(II) complex was more active than cisplatin. Effect of the S-containing Cu complex on apoptosis and cell cycle distribution has been investigated as well.

Reactivity and zinc affinity of dipyrromethenes as colorimetric sensors: structural and solvation effects

A wide range of dipyrromethenes (17 objects) with different nature, number, and attachment positions of alkyl, aryl, and meso-aza substituents was synthesized, and the effect of molecular structure features on their spectral properties was analyzed. It is shown that, chromophores absorb in a wide spectral range from ∼ 420 to ∼ 600 nm due to the structural modification of the dipyrromethene ligand backbone. Partially alkylated dipyrromethenes containing 4–5 methyl substituents absorb in the region from 421 to 436 nm. For fully alkylated dipyrromethenes, the band maximum position shifts to the region from 437 to 446 nm for ligands with 4,4′-substituents in the sequence: methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl. The most significant spectral responses in the form of a red shift of 100 nm (in DMF) are observed when four methyl substituents in the 3,3′,5,5′-positions are replaced by phenyl groups. The replacement of the methine meso-spacer by a nitrogen atom leads to an additional red shift by another 70 nm. Particular attention is paid to the comparative analysis of the effect of structural factors on the coloristic and spectral responses of the complexation of dipyrromethene ligands with zinc(II) acetate and the stability of the resulting complexes [ZnL2], for which the lgKo values are varied from 6.4 to 10.9. The auxochromic action of Zn2+ cations shifts the band maxima of electronic absorption spectra to the long wavelength region by 20–76 nm relative to the spectra of the ligands. The highest complexation constant lgKo is 10.9 was obtained for the reaction of Zn(AcO)2 with hexamethylsubstituted dipyrromethene. Ligands with partially methylated pyrrole nuclei and extended alkyl and benzyl substituents form less stable complexes. The greatest effect of lowering the [ZnL2] stability is produced by the introduction of an electron-withdrawing aryl substituent into the meso-spacer of the dipyrromethene ligand (lgKo is 6.4).

Discovery of New Antimicrobial Metabolites in the Coculture of Medicinal Mushrooms.

Bioactivity screening revealed that the antifungal activities of EtOAc extracts from coculture broths of Trametes versicolor SY630 with either Vanderbylia robiniophila SY341 or Ganoderma gibbosum SY1001 were significantly improved compared to that of monocultures. Activity-guided isolation led to the discovery of five aromatic compounds (1-5) from the coculture broth of T. versicolor SY630 and V. robiniophila SY341 and two sphingolipids (6 and 7) from the coculture broth of T. versicolor SY630 and G. gibbosum SY1001. Tramevandins A-C (1-3) and 17-ene-1-deoxyPS (6) are new compounds, while 1-deoxyPS (7) is a new natural product. Notably, compound 2 represents a novel scaffold, wherein the highly modified p-terphenyl bears a benzyl substituent. The absolute configurations of those new compounds were elucidated by X-ray diffraction, ECD calculations, and analysis of physicochemical constants. Compounds 1, 2, and 5-7 exhibited different degrees of antimicrobial activity, and the antifungal activities of compounds 6 and 7 against Candida albicans and Cryptococcus neoformans are comparable to those of fluconazole, nystatin, and sphingosine, respectively. Transcriptome analysis, propidium iodide staining, ergosterol quantification, and feeding assays showed that the isolated sphingolipids can extensively downregulate the late biosynthetic pathway of ergosterol in C. albicans, representing a promising mechanism to combat antibiotic-resistant fungi.

Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity.

A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4c and 4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained with N-methylation of SGC-CK2-2, but α-methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound 4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and 4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and 4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.

Tuning the Structure of 4‐Aminopyridine Catalysts for Improved Activity and Selectivity in Functionalization of Alcohols

AbstractSeeking to improve the site selectivity in the catalytic phosphorylation and acylation of a model amphiphilic substrate, further increasing the preference for the apolar domain, which we recently disclosed, we attempted to augment the nucleophilicity of the 4‐aminopyridine core unit used in our catalysts, while simultaneously preserving or even increasing the density of their lipophilic outer‐sphere components. Of the three approaches to the new catalyst design, the most promising, in the case of phosphorylation, was that placing two benzyl moieties, substituted with long apolar alkoxy groups in the ortho positions, on the amine nitrogen of the core. This modification also substantially improved the activity of the catalyst in both reactions. Although this approach reduced the selectivity in the acylation reaction, we demonstrated that by altering the geometry of the benzyl substituents (e. g., by restricting the degree of their freedom), the higher selectivity can be regained.

Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines.

A novel and efficient base-catalyzed, transition-metal-free method for the synthesis of diheterocyclic compounds connected by an amidine linker, including apart from the common 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various N-monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides. The developed method has a broad scope and can be applied to obtain a variety of N-heteroaryl-1,2,3-triazole-4-carbimidamides with alkyl, allyl, propargyl, benzyl, cycloalkyl, and indolyl substituents at the N1 position .

Decaging-to-labeling: Development and investigation of quinone methide warhead for protein labeling

Biomolecule labeling in living systems is crucial for understanding biological processes and discovering therapeutic targets. A variety of labeling warheads have been developed for multiple biological applications, including proteomics, bioimaging, sequencing, and drug development. Quinone methides (QMs), a class of highly reactive Michael receptors, have recently emerged as prominent warheads for on-demand biomolecule labeling. Their highly flexible functionality and tunability allow for diverse biological applications, but remain poorly explored at present. In this regard, we designed, synthesized, and evaluated a series of new QM probes with a trifluoromethyl group at the benzyl position and substituents on the aromatic ring to manipulate their chemical properties for biomolecule labeling. The engineered QM warhead efficiently labeled proteins both in vitro and under living cell conditions, with significantly enhanced activity compared to previous QM warheads. We further analyzed the labeling efficacy with the assistance of density functional theory (DFT) calculations, which revealed that the QM generation process, rather than the reactivity of QM, contributes more predominantly to the labeling efficacy. Noteworthy, twelve nucleophilic residues on the BSA were labeled by the probe, including Cys, Asp, Glu, His, Lys, Asn, Gln, Arg, Ser, Thr, Trp and Tyr. Given their high efficiency and tunability, these new QM warheads may hold great promise for a broad range of applications, especially spatiotemporal proteomic profiling for in-depth biological studies.

New ATP-competitive inhibitors of E. coli GyrB obtained from the mapping of the hydrophobic floor at the binding site: synthesis and biological evaluation.

We mapped the hydrophobic floor, an interesting subsite at the active site of DNA gyrase B (GyrB) from E. coli. We synthesized three new compounds with pendant groups targeting the hydrophobic floor and evaluated their inhibitory activities on DNA gyrase. A new benzothiazole derivative with a benzyl substituent at position 3 of the benzothiazole ring exhibited strong inhibitory activity against E. coli DNA gyrase (IC50 = 19 ± 3 nM). An exhaustive conformational study using potential energy surfaces (PESs) allowed us to map the new subsite evaluating all critical points on the surface and conformational interconversion pathways. We analyzed the molecular interactions using QTAIM calculations. Our data provide insights into the mechanism of action of these new ligands at the molecular level. Theoretical and experimental data suggest that new ligand optimization strategies should focus on strengthening interactions at the hydrophobic floor while preserving the binding mode of the main scaffold.

Highly efficient platinum(ii) complexes overcoming Pt–Pt interactions and their applications in organic light-emitting diodes

By introducing the methyl substituent acetylacetone and benzyl substituents, Pt(ii) complexes restrain Pt–Pt interactions in pure films and maintain nearly identical PL spectra with dilute solution. The maximum EQE of non-doped OLED reaches 19.6%.

Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity.

The design and synthesis of leu-enkephalin analogs by replacing the glycine residues with N-(2-thioethyl)glycines and opening the cyclisation potential is presented. The cyclization (stapling) was achieved using bifunctional reagents (hexafluorobenzene and trithiocyanuric acid derivatives). The CD conformational studies of the stapled analogs suggest that the peptides adopt the type I β-turn conformation, which is in agreement with the theoretical analysis. The analog containing a trithiocyanuric acid derivative with a benzyl substituent shows potent analgesic activity.

Tuning CH Hydrogen Bond-Based Receptors toward Picomolar Anion Affinity via the Inductive Effect of Distant Substituents.

Inspired by nature, artificial hydrogen bond-based anion receptors have been developed to achieve high anion selectivity; however, their binding affinity is usually low. The potency of these receptors is usually increased by the introduction of aryl substituents, which withdraw electrons from their binding site through the resonance effect. Here, we show that the polarization of the C(sp3 )-H binding site of bambusuril receptors, and thus their potency to bind anions, can be modulated by the inductive effect. The presence of electron-withdrawing groups on benzyl substituents of bambusurils significantly increases their binding affinities to halides, resulting in the strongest iodide receptor reported to date with an association constant greater than 1013 M-1 in acetonitrile. A Hammett plot showed that while the bambusuril affinity toward halides linearly increases with the electron-withdrawing power of their substituents, their binding selectivity remains essentially unchanged.

Tuning CH Hydrogen Bond‐Based Receptors toward Picomolar Anion Affinity via the Inductive Effect of Distant Substituents

AbstractInspired by nature, artificial hydrogen bond‐based anion receptors have been developed to achieve high anion selectivity; however, their binding affinity is usually low. The potency of these receptors is usually increased by the introduction of aryl substituents, which withdraw electrons from their binding site through the resonance effect. Here, we show that the polarization of the C(sp3)‐H binding site of bambusuril receptors, and thus their potency to bind anions, can be modulated by the inductive effect. The presence of electron‐withdrawing groups on benzyl substituents of bambusurils significantly increases their binding affinities to halides, resulting in the strongest iodide receptor reported to date with an association constant greater than 1013 M−1 in acetonitrile. A Hammett plot showed that while the bambusuril affinity toward halides linearly increases with the electron‐withdrawing power of their substituents, their binding selectivity remains essentially unchanged.