Benzyl Side Chain Research Articles

Chlorination of benzyl group on the terminal unit of A2-A1-D-A1-A2 type nonfullerene acceptor for high-voltage organic solar cells

Benzotriazole (BTA)-based A2-A1-D-A1-A2 type wide-bandgap (WBG) non-fullerene acceptors (NFAs) have shown promising potential in indoor photovoltaic, and in-depth investigation of their structure-property relationship is of great significance. Herein, we explored the chlorination effect of the side chain on the terminals. We introduced Cl atoms into the benzyl side chains in parent BTA5 to synthesize two NFAs, BTA5-Cl with mono-chlorinated benzyl groups and BTA5-2Cl containing bi-chlorinated benzyl groups. We chose D18-Cl with deep-energy levels and strong crystallinity to pair with these three acceptors, affording high photovoltage and photocurrent. With the stepwise chlorination, the open-circuit voltage (VOC) values decrease from 1.28, 1.22, to 1.20 V, while the corresponding power conversion efficiencies (PCEs) improve from 5.07 %, 9.15 %, to 10.96 %. Compared with BTA5-based OSCs, introducing Cl atoms downshifts the energy levels and slightly increases the non-radiative energy loss (0.14 < 0.17 < 0.19 eV), resulting in a sequential decrease in VOC. However, more chlorine atom replacements produce more effective exciton dissociation, higher charge transfer, and balanced carrier mobility in the blend films, ultimately achieving better PCEs. This work indicates that chlorination of the benzyl group on the terminals can improve the device's performance, implying good application potential in indoor photovoltaics.

Highly Efficient Separation of BTEX via Amide Naphthotube Cavity-Confined Tandem C/N-H···π Interactions.

The separation of BTEX [benzene, toluene, ethylbenzene (EB), and xylene isomers] poses a huge challenge in the industry, attributed to their similar structures and physical properties. Supramolecular compounds show great promise for hydrocarbon separation. Herein, we designed two pairs of endo-functionalized amide naphthotubes with methyl and benzyl side chains, which were first employed as chromatographic separation materials and exhibited high shape-selectivity for BTEX. In particular, the amide naphthotubes with methyl side chains provided complete separation toward BTEX and anti-3a showed high selectivity for the p-xylene over other isomers with αPX/OX = 9.34, αPX/MX = 5.50, and αPX/EB = 4.30. The mechanism of BTEX separation originates from the synergistic effect of specially confined tandem N-H···π and C-H···π interactions toward aromatic compounds. The findings of this research show promise for practical applications in efficiently separating crucial aromatic isomers.

Discovery and optimization of spirocyclic lactams that inhibit acyl-ACP thioesterase.

There are various methods to control weeds, that represent considerable challenges for farmers around the globe, although applying small molecular compounds is still the most effective and versatile technology to date. In the search for novel chemical entities with new modes-of-action that can control weeds displaying resistance, we have investigated two spirocyclic classes of acyl-ACP thioesterase inhibitors based on X-ray co-crystal structures and subsequent modelling studies. By exploiting scaffold-hopping and isostere concepts, we were able to identify new spirolactam-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. The present work covers a series of novel herbicidal lead structures that contain a spirocyclic lactam as a structural key feature carrying ortho-substituted benzyl or heteroarylmethylene side chains. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity. Glasshouse trials showed that the spirolactams outlined herein display promising control of grass-weed species in pre-emergence application combined with dose-response windows that enable partial selectivity in wheat and corn. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors showed efficacy against resistant grass weeds such as Alopecurus myosuroides and Lolium spp. on competitive levels compared with commercial standards. © 2024 Society of Chemical Industry.

Increasing the functional density of threose nucleic acid.

Chemical strategies that augment genetic polymers with amino acid residues that are overrepresented on the paratope surface of an antibody offer a promising route for enhancing the binding properties of nucleic acid aptamers. Here, we describe the chemical synthesis of α-l-threofuranosyl cytidine nucleoside triphosphate (tCTP) carrying either a benzyl or phenylpropyl side chain at the pyrimidine C-5 position. Polymerase recognition studies indicate that both substrates are readily incorporated into a full-length α-l-threofuranosyl nucleic acid (TNA) product by extension of a DNA primer-template duplex with an engineered TNA polymerase. Similar primer extension reactions performed using nucleoside triphosphate mixtures containing both C-5 modified tCTP and C-5 modified tUTP substrates enable the production of doubly modified TNA strands for a panel of 20 chemotype combinations. Kinetic measurements reveal faster on-rates (kon) and tighter binding affinity constants (Kd) for engineered versions of TNA aptamers carrying chemotypes at both pyrimidine positions as compared to their singly modified counterparts. These findings expand the chemical space of evolvable non-natural genetic polymers by offering a path for improving the quality of biologically stable TNA aptamers for future clinical applications.

A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

Structure–Function Relationship within Cu-Peptoid Electrocatalysts for Water Oxidation

Water oxidation (WO) is the first step in the water-splitting process aiming at the production of hydrogen as a green renewable fuel. To successfully perform WO, potent strategies for overcoming the high energetic barrier and slow kinetics of this reaction are urgently required. One such strategy is the use of molecular catalysis. Specifically, Cu-based catalysts have been highlighted over the last decade due to their stability and fast kinetics. Among them, Cu-peptoids, where peptoids are peptidomimetics akin to peptides and are N-substituted glycine oligomers, can act as stable and active catalysts for oxidation transformations including electrocatalytic WO. Previously, we suggested that a benzyl group incorporated as a side chain near the catalytic site within a Cu-peptoid electrocatalyst for WO has a structural role in the activity of the electrocatalyst in phosphate buffer (PBS). Herein, we aimed to test this hypothesis and understand how an incorporated structural element side chain affects WO. To this aim, we prepared a set of peptoid trimers each with a different structural element replacing the benzyl group by either naphthyl, cyclohexyl, benzyl, propyl chloride, or propyl side chains as well as a peptoid lacking a structural element. We studied the structure of their Cu complexes and tested these complexes as electrocatalysts for WO. We discovered that while all the peptoids self-assemble to form dinuclear Cu-peptoid complexes, the duplex that has no structural side chain, Cu2(BE)2, is structurally different from the others in the solid state. Moreover, Cu2(BE)2 remains dinuclear in a PBS at pH 11, while all the other duplexes are mononuclear in the PBS. Finally, though most of the complexes showed low electrocatalytic activity for WO, the dinuclear complex Cu2(BE)2 performed with the highest turnover frequency of 484 s−1. Nevertheless, this dinuclear complex slowly decomposes to the corresponding mononuclear complex as a more stable species during WO, while the other mononuclear complexes retain their structure in solution but display much slower kinetics (ca. 5 to 8 s−1) under the same conditions. Overall, our results demonstrate that bulkier side chains hamper the stability of dinuclear Cu-peptoids in a PBS, and hence, their efficiency as WO electrocatalysts is also hampered.

Building-up an interrelationship between isomeric benzyl inner side chains within nonfullerene acceptors and isomeric xylene solvents for non-chlorinated solvent-processed organic solar cells

Three isomeric BzY-series NFAs are developed by introducing inner benzyl side chains. Among the BzY-series NFA-based OSCs processed with non-chlorinated xylene solvents, PM6 : m-BzY exhibits PCE over 16% without an additive and thermal annealing process.

Amphiphilic Graft Copolymers for Time-Delayed Release of Hydrophobic Fragrances.

When a controlled or retarded release of perfumes is required such as in cosmetics or cleaning products, polymers can be applied as encapsulation agents. With regard to such applications, we investigated two amphiphilic graft copolymers featuring a polydehydroalanine (PDha) backbone and different hydrophobic side chains. Hereby, grafting of aliphatic octyl side chains (PDha-g-EOct) enabled the adsorption of the aliphatic fragrance tetrahydrolinalool with moderate loads, whereas benzyl side chains (PDha-g-BGE) allowed taking up aromatic fragrances, for example, amylsalicylate-n with exceptionally high loads of up to 8 g g-1. The side-chain density was studied as well but had no significant influence on the loading. In addition, the characterization and quantification of the load by NMR and thermogravimetric analysis were compared, and it was also possible to load the aromatic model fragrance into the graft copolymer with aliphatic side chains. After 3 months, the load had decreased by 40-50% and, hence, such systems are of interest for a long-term release of perfumes over months. Although this study is a proof-of-concept, we foresee that such polyampholytic graft copolymers can be tailored for the adsorption of a variety of hydrophobic perfumes simply by altering polarity and chemistry of the side chain.

Using a Johnson‐Claisen Rearrangement Strategy to Construct Azaindoles – A Streamlined and Concise Route for the Commercial Process of Fevipiprant

AbstractA novel and concise synthesis of the DP2 receptor antagonist Fevipiprant (NVP‐QAW039) was developed. The initial research route was suffering from a long reaction sequence to the functionalized 7‐aza‐indole core followed by a poorly selective N(1)‐alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early by reductive amination between the functionalized aldehyde and 2‐amino‐3‐bromopyridine. The Sonogashira coupling with prop‐2‐yn‐1‐ol introduces the 3 missing carbon atoms to build the 7‐aza‐indole core and sets the stage for the innovative Johnson‐Claisen key step. The reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate led to a reactive allene intermediate which spontaneously and selectively cyclizes to the 7‐aza‐indole QAW039‐methyl ester. QAW039 was isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated.

Benzyl side-chain engineering of non-fullerene acceptors for efficient organic solar cells

Side-chain engineering is one of the most promising ways to develop non-fullerene acceptors (NFAs) for organic solar cells. In this work, we designed and synthesized a novel acceptor IT-BnC6-4F by introducing methylene group between the phenyl group and the sp3 hybrid carbon atoms of central conjugated cores to form benzyl side chains. IT-BnC6-4F shows broader absorption spectrum and higher crystallinity than those of its analogue, IT-4F. When blended with PT2, the IT-BnC6-4F based device achieved a high power conversion efficiency (PCE) of 13.36 %, with an open-circuit voltage (Voc) of 0.87 V and a short-circuit current density (Jsc) of 20.99 mA cm−2.

Dual-Site Binding of Quaternary Ammonium Ions as Internal K+-Ion Channel Blockers: Nonclassical (C-H···O) H Bonding vs Dispersive (C-H···H-C) Interaction.

A molecular-level study of the influence of the alkyl chain length of quaternary ammonium ions (QAs) on the blocking action and the mode of binding with the bacterial KcsA K+-ion channel is carried out by molecular dynamics (MD) simulations as well as quantum mechanics/molecular mechanics (QM/MM) methods. The present work unveils distinct modes of binding for different QAs, due to differences in size and hydrophobicity. The QAs bind near the channel gate as well as at the central cavity, leading to a possible dual-site blocking action. Small-sized tetraethylammonium (TEA) and tetrabutylammonium (TBA) ions enter inside the channel cavity in the open state of KcsA but bind strongly in the closed state. TEA binds to the polar hydroxyl group of threonine residues situated at the channel gate via nonclassical H-bonding interaction (C-H···O), while TBA binds to a second binding site, the central cavity, with hydrophobic benzyl and sec-butyl side chains of phenylalanine and isoleucine residues via alkyl-π and hydrophobic interactions (C-H···H-C). On the contrary, large tetrahexylammonium (THA) and tetraoctylammonium (TOA) ions bind the hydrophobic side-chain methyl and isopropyl of alanine and valine at the channel gate both in the open and closed states, thereby restricting the free movement of large QAs toward the center of the cavity. However, the binding to the hydrophobic benzyl and sec-butyl side chains of phenylalanine and isoleucine residues in the closed state is thermodynamically preferable. Also, the binding energy is found to increase with an increase in the alkyl chain length from ethyl (-16.4 kcal/mol) to octyl (-65.5 kcal/mol), due to an almost linear increase in dispersive interaction.

Synthesis of Branched Peptides via a Side-Chain Benzyl Ester.

Branched peptide as an attractive mimic of natural peptide is widely used in structural design of functional or therapeutic peptides, to improve their biological activity, stability, and pharmacokinetic properties. In this protocol, we employ a function group of side-chain benzyl ester as the precursor of hydrazide, which could be conveniently used to assemble a branch peptide by native chemical ligation or direct amidation. This method is convergent and efficient, and facilitates the synthesis and application of branched peptides.

Antimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL – CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character

The rapid emergence and spread of multi-resistant bacteria have created an urgent need for new antimicrobial agents. We report here a series of amphipathic α,α-disubstituted β-amino amide derivatives with activity against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase – carbapenemase (ESBL-CARBA) production. A variety of halogenated aromatic side-chains were investigated to improve antimicrobial potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative 4e with 3,5-di-brominated benzylic side-chains. Derivative 4e displayed minimum inhibitory concentrations (MIC) of 0.25–8 μg/mL against Gram-positive and Gram-negative reference strains, and 2–32 μg/mL against multi-resistant clinical isolates. Derivative 4e showed also low toxicity against human red blood cells (EC50 > 200 μg/mL), human hepatocyte carcinoma cells (HepG2: EC50 > 64 μg/mL), and human lung fibroblast cells (MRC-5: EC50 > 64 μg/mL). The broad-spectrum antimicrobial activity and low toxicity of diguanylated derivatives such as 4e make them attractive as lead compounds for development of novel antimicrobial drugs.

Biomimetic polypeptoids with para-oligo(ethylene glycol) benzyl side-chains synthesized from α-Amino acids

A series of N-alkylated glycine and l-alanine bearing oligoethylene glycol (OEG) and benzyl side chains, i.e., N-(4-oligoethylene glycol)benzyl glycine and N-(4-oligoethylene glycol)benzyl alanine (NMe(OEt)xOBnG and NMe(OEt)xOBnA, x = 1–3), have been readily synthesized via schiff base and reductive amination reactions. The successful ring opening polymerization (ROP) of N-substituted glycine N-carboxyanhydrides (NCA) results in three types of peptoid oligomers (PNMe(OEt)xOBnG, x = 1–3). Depending on the length of OEG side chains, PNMe(OEt)xOBnG show different solubility in water. Particularly, the as-prepared oligomers containing three ethylene glycol units (PNMe(OEt)3OBnG) display interesting thermoresponsive aggregation behaviors in water. DSC results reveal that all the oligomers show crystalline behaviors with melting temperatures decreasing as the OEG side chain length is increased. Both live-dead and MTT assays indicate low cytotoxicity of PNMe(OEt)2OBnG and PNMe(OEt)3OBnG toward HeLa cells, comparable to benchmark PEG. Concerning thermoresponsive and crystalline properties, the as-prepared peptoid oligomers are potentially promising building blocks for stimuli-responsive bioinspired materials and hierarchical self-assembly.

Studies on acid stability and solid-phase block synthesis of peptide-peptoid hybrids: ligands for formyl peptide receptors.

α-Peptoids as well as peptide/α-peptoid hybrids and peptide/β-peptoid hybrids constitute major classes of proteolytically stable peptidomimetics that have been extensively investigated as mimetics of biologically active peptides. Representatives of lipidated peptide/β-peptoid hybrids have been identified as promising immunomodulatory lead compounds, and hence access to these via protocols suitable for gram-scale synthesis is warranted to enable animal in vivo studies. Recent observations indicated that several byproducts appear in crude mixtures of relatively short benzyl-based peptide/β-peptoid oligomers, and that these were most predominant when the β-peptoid units displayed an α-chiral benzyl side chain. This prompted an investigation of their stability under acidic conditions. Simultaneous deprotection and cleavage of peptidomimetics containing either α-chiral α- or β-peptoid residues required treatment with strong acid only for a short time to minimize the formation of partially debenzylated byproducts. The initial work on peptide/β-peptoid oligomers with an alternating design established that it was beneficial to form the amide bond between the carboxyl group of the α-amino acid and the congested amino functionality of the β-peptoid residue in solution. To further simplify oligomer assembly on solid phase, we now present a protocol for purification-free solid-phase synthesis of tetramericbuilding blocks. Next, syntheses of peptidomimetic ligands via manual solid-phase methodologies involving tetramericbuilding blocks were found to give more readily purified products as compared to those obtained with dimericbuilding blocks. Moreover, the tetramericbuilding blocks could be utilized in automated synthesis with microwave-assisted heating, albeit the purity of the crude products was not increased.

Kirmse-Doyle- and Stevens-Type Rearrangements of Glutarate-Derived Oxonium Ylides.

A novel chemoenzymatic synthetic cascade enables the preparation of densely decorated tetrahydrofuran building blocks. Here, the lipase-catalyzed desymmetrization of 3-alkoxyglutarates renders highly enantioenriched carboxylic acid intermediates, whose subsequent activation and oxonium ylide rearrangement by means of rhodium or copper complexes furnishes functionalized O-heterocycles with excellent diastereoselectivity. The two-step protocol offers a streamlined and flexible synthesis of tetrahydrofuranones bearing different benzylic, allylic or allenylic side chains with full control over multiple stereogenic centers.

Comparison of the Self-Assembly Behavior of Fmoc-Phenylalanine and Corresponding Peptoid Derivatives

Fluorenylmethoxycarbonyl-protected phenylalanine (Fmoc-Phe) derivatives are a privileged class of low molecular weight amino acid hydrogelators that undergo spontaneous self-assembly in water to form one-dimensional (1D) fibril networks. Structural studies indicate that these fibrils feature unidirectional hydrogen bonding and parallel π–π interactions (Fmoc–Fmoc and side chain benzyl–benzyl), which stabilize the 1D fibrils. However, the relative contribution of hydrogen bonding vs π–π interactions in these assemblies is not understood. Herein, we compare the self-assembly of Fmoc-Phe amino acids with corresponding Fmoc-protected peptoid derivatives. The N-benzyl glycine-derived peptoid analogues exhibit altered hydrogen bonding ability and benzyl side chain presentation geometry relative to the parent Fmoc-Phe molecules. We found that Fmoc-peptoid analogues preferentially assemble into two-dimensional (2D) nano- and microsheets that ultimately adopt crystalline states, whereas the Fmoc-Phe amino acids as...

Benzyl and fluorinated benzyl side chains for perylene diimide non-fullerene acceptors

The synthesis, characterization, and photovoltaic performance of three N-annulated perylene diimide dimers with benzyl based side-chains is reported.

Phenylalanine and derivatives as versatile low-molecular-weight gelators: design, structure and tailored function.

Phenylalanine (Phe) is an essential amino acid classified as neutral and nonpolar due to the hydrophobic nature of the benzyl side chain. In the field of materials science, the chemical modification of phenylalanine at C or N terminus has enabled to synthesize a large number of low-molecular-weight gelators over the past decade. Thus, many physical (or supramolecular) softgel materials have been fabricated by self-assembly of Phe-derived building blocks, which can be programmed with atomic level information and modification. The process of self-assembly and gelation must balance the parameters that influence the solubility as well as the contrasting forces that dictate epitaxial growth into entangled fibrillar aggregates. Gelator-gelator and solvent-gelator interactions are known to be highly important for the gelation process, and the non-covalent nature of these interactions provides physical gels with important properties such as reversible phase transitions and responsiveness towards external stimuli. Among other applications, these gels have been used for drug delivery, as extracellular matrix for tissue engineering, for oil spills recovery, removal of dyes, extraction of heavy metals or pollutants, and for the detection of explosives. In this tutorial review, we highlight the advances in the design, synthesis and applications of supramolecular gels made of Phe and derivatives.

Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer.

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure-activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.