Substituent Pattern Research Articles

Synthesis of modified Schiff base appended 1,2,4-triazole hybrids scaffolds: elucidating the invitro and in silico α-amylase and α-glucosidase inhibitors potential.

The current study involves the synthesis of Schiff bases based on 1,2,4-triazoles skeleton and assessing their α-amylase and α-glucosidase profile. Furthermore, the precise structures of the synthesized derivatives were elucidated using various spectroscopic methods such as 1H-NMR, 13C-NMR and HREI-MS. Using glimepiride as the reference standard, the invitro α-glucosidase and α-amylase inhibitory activities of the synthesized compounds were evaluated in order to determine their potential anti-diabetic properties. All analogues showed varied range of inhibitory activity having IC50 values ranging from 17.09±0.72 to 45.34±0.03 μM (α-amylase) and 16.35±0.42 to 42.31±0.09 μM (α-glucosidase), respectively. Specifically, the compounds 1, 7 and 8 were found to be significantly active with IC50 values of 17.09±0.72, 19.73±0.42, and 23.01±0.04 μM (against α-amylase) and 16.35±0.42, 18.55±0.26, and 20.07±0.02 μM (against α-glucosidase) respectively. The obtained results were compared with the Glimepiride reference drug having IC50values of 13.02±0.11 μM (for α-glucosidase) and 15.04±0.02 μM (for α-amylase), respectively. The structure-activity relationship (SAR) studies were conducted based on differences in substituent patterns at varying position of aryl rings A and B may cause to alter the inhibitory activities of both α-amylase and α-glucosidase enzymes. Additionally, the molecular docking study was carried out to explore the binding interactions possessed by most active analogues with the active sites of targeted α-amylase and α-glucosidase enzymes.

Adsorption of Flavonoids in a Transcriptional Regulator TtgR: Relative Binding Free Energies and Intermolecular Interactions.

Antimicrobial resistance in bacteria often arises from their ability to actively identify and expel toxic compounds. The bacterium strain Pseudomonas putida DOT-T1E utilizes its TtgABC efflux pump to confer robust resistance against antibiotics, flavonoids, and organic solvents. This resistance mechanism is intricately regulated at the transcriptional level by the TtgR protein. Through molecular dynamics and alchemical free energy simulations, we systematically examine the binding of seven flavonoids and their derivatives with the TtgR transcriptional regulator. Our simulations reveal distinct binding geometries and free energies for the flavonoids in the active site of the protein, which are driven by a range of noncovalent forces encompassing van der Waals, electrostatic, and hydrogen bonding interactions. The interplay of molecular structures, substituent patterns, and intermolecular interactions effectively stabilizes the bound flavonoids, confining their movements within the TtgR binding pocket. These findings yield valuable insights into the molecular determinants that govern ligand recognition in TtgR and shed light on the mechanism of antimicrobial resistance in P. putida DOT-T1E.

Antiaromaticity of Cycloheptatrienyl Anions: Structure, Acidity, and Magnetic Properties.

Investigations of the nature and degree of antiaromaticity of cycloheptatrienyl anion derivatives using both experimental and computational tools are presented. The ground state of cycloheptatrienyl anion in the gas phase is triplet, planar and Baird-aromatic. In DMSO, it assumes a singlet distorted allylic form with a paratropic ring current. The other derivatives in both phases assume either allylic or diallylic conformations depending on the substituent pattern. A combination of experimental and computational methods was used to determine the pKa values of 16 derivatives in DMSO, which ranged from 36 to -10.7. We revealed that the stronger stabilization of the anionic system, which correlates with acidity, does not necessarily imply a lower degree of antiaromaticity in terms of magnetic properties. Conversely, the substitution pattern first affects the geometry of the ring through the bulkiness of the substituents and their better conjugation with a more distorted system. Consequently, the distortion reduces the cyclic conjugation in the π-system and thereby decreases the paratropic current in a magnetic field, which manifests itself as a decrease in the NICS. The triplet-state geometries and magnetic properties are nearly independent on the substitution pattern, which is typical for simple aromatic systems.

Tuning the Emission Properties of 2,1,3-Benzothiadiazoles via Regioselective Substitution.

The 2,1,3-benzothiadiazole (BTD) unit is a prominent building block commonly used in various research areas such as optoelectronics and bioimaging. Despite its great versatility, the development of strategies to elaborate BTD has been largely neglected, including exploring its reactivity and understanding how regioselective functionalization can be used to tune the fluorescence emission. Previous focus has primarily been on C4- or C4,C7-substitutions. Here, a series of unsymmetrical mono - and disubstituted BTDs was synthesized and characterized for their photophysical properties. The reaction scope includes all six possible substituent patterns on the BTD benzoid ring (C4-, C5-, C4,C5-, C4,C6-, C4,C7- and C5,C6-substitution), which comprise arrangements that previously been synthetically challenging to access. By introducing a methoxy and/or a phenyl group we demonstrate that the emissive behavior of BTD derivatives strongly depends on the position of the substituent (s). We show that regioselective substitution on BTD can engender long-lived fluorescence and circumvent strong fluorescence quenching in polar protic solvents, which is a limitation of many previously described BTD derivatives.

Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides

The enantioselective synthesis of S-stereogenic sulfinamides has garnered considerable attention due to their structural and physicochemical properties. However, catalytic asymmetric synthesis of sulfinamides still remains daunting challenges, impeding their broad application in drug discovery and development. Here, we present an approach for the synthesis of S-stereogenic sulfinamides through peptide-mimic phosphonium salt-catalyzed asymmetric skeletal reorganization of simple prochiral and/or racemic sulfoximines. This methodology allows for the facile access to a diverse array of substituted sulfinamides with excellent enantioselectivities, accommodating various substituent patterns through desymmetrization or parallel kinetic resolution process. Mechanistic experiments, coupled with density functional theory calculations, clarify a stepwise pathway involving ring-opening and ring-closing processes, with the ring-opening step identified as crucial for achieving stereoselective control. Given the prevalence of S-stereogenic centers in pharmaceuticals, we anticipate that this protocol will enhance the efficient and precise synthesis of relevant chiral molecules and their analogs, thereby contributing to advancements in drug discovery.

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations.

The cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) structures of the C4H7+ cation have been proposed as intermediates in various reactions forming cyclopropylcarbinyl, cyclobutyl, or homoallyl products. While these cations can react with nucleophiles stereospecifically, in each system there are usually multiple BCB/CPC cations in equilibrium with related cyclobutyl (CB) and homoallyl (HA) cations, from which stereospecificity is jeopardized. Using density functional theory (DFT) and DLPNO-CCSD(T) calculations, we studied the electronic and steric effects on the equilibria between mono- and polysubstituted C4H7+ cations. We find that the shapes of the potential energy surfaces (PESs) vary significantly, with structures that are minima for a given substituent becoming high-energy transition structures for another. Electron-donating groups at C1, C2, or C3/C4 positions favor CPC, BCB/CB, and HA structures, respectively. Electron-withdrawing groups yield shallower PESs where multiple related structures are energetically accessible. Strong Hammett correlations (σ+) are observed for the substituent effects, which appear to be additive. In addition, BCB cations with more substituents are energetically destabilized compared to CPC cations, except with donating substituents at the C2 position. This work allows predictions of the major structures expected in mixtures of CPC/BCB/CB/HA cations for given substituent patterns, and of the major products produced from such cations.

Synthesis of 5-Amino-3(2H)-furanones via S-Methylation/Intramolecular Cyclization of γ-Sulfanylamides.

The S-methylation/intramolecular cyclization of γ-sulfanylamide is depicted. Different methylating reagents were successfully employed for S-methylation, depending on the substituent pattern of the amide in the starting γ-sulfanylamides; trimethyloxonium tetrafluoroborate was used for N-aryl substituted γ-sulfanylamides, and the combination of methyl iodide and silver(I) tetrafluoroborate was used for N-alkyl substituted γ-sulfanylamides. When the resulting sulfonium salt was treated with DBU, it smoothly underwent intramolecular cyclization to produce a series of N-aryl, N-alkyl, N,N-dialkyl or N-alkyl-N-aryl substituted 5-amino-3(2H)-furanones in 55%-quantitative yields.

Easy Synthetic Access to High‐Melting Sulfurated Copolymers and their Self‐Assembling Diblock Copolymers from Phenylisothiocyanate and Oxetane

AbstractAlthough sulfurated polymers promise unique properties, their controlled synthesis, particularly when it comes to complex and functional architectures, remains challenging. Here, we show that the copolymerization of oxetane and phenyl isothiocyanate selectively yields polythioimidocarbonates as a new class of sulfur containing polymers, with narrow molecular weight distributions (Mn=5–80 kg/mol with Đ≤1.2; Mn,max=124 kg/mol) and high melting points of up to 181 °C. The method tolerates different substituent patterns on both the oxetane and the isothiocyanate. Self‐nucleation experiments reveal that π‐stacking of phenyl substituents, the presence of unsubstituted polymer backbones, and the kinetically controlled linkage selectivity are key factors in maximising melting points. The increased tolerance to macro‐chain transfer agents and the controlled propagation allows the synthesis of double crystalline and amphiphilic diblock copolymers, which can be assembled into micellar‐ and worm‐like structures with amorphous cores in water. In contrast, crystallization driven self‐assembly in ethanol gives cylindrical micelles or platelets.

Easy Synthetic Access to High-Melting Sulfurated Copolymers and their Self-Assembling Diblock Copolymers from Phenylisothiocyanate and Oxetane.

Although sulfurated polymers promise unique properties, their controlled synthesis, particularly when it comes to complex and functional architectures, remains challenging. Here, we show that the copolymerization of oxetane and phenyl isothiocyanate selectively yields polythioimidocarbonates as a new class of sulfur containing polymers, with narrow molecular weight distributions (Mn=5-80 kg/mol with Đ≤1.2; Mn,max=124 kg/mol) and high melting points of up to 181 °C. The method tolerates different substituent patterns on both the oxetane and the isothiocyanate. Self-nucleation experiments reveal that π-stacking of phenyl substituents, the presence of unsubstituted polymer backbones, and the kinetically controlled linkage selectivity are key factors in maximising melting points. The increased tolerance to macro-chain transfer agents and the controlled propagation allows the synthesis of double crystalline and amphiphilic diblock copolymers, which can be assembled into micellar- and worm-like structures with amorphous cores in water. In contrast, crystallization driven self-assembly in ethanol gives cylindrical micelles or platelets.

Synthesis of meta-carbonyl phenols and anilines

Phenols and anilines are of extreme importance for medicinal chemistry and material science. The development of efficient approaches to prepare both compounds has thus long been a vital research topic. The utility of phenols and anilines directly reflects the identity and pattern of substituents on the benzenoid ring. Electrophilic substitutions remain among the most powerful synthetic methods to substituted phenols and anilines, yet in principle achieving ortho- and para-substituted products. Therefore, the selective preparation of meta-substituted phenols and anilines is the most significant challenge. We herein report an efficient copper-catalyzed dehydrogenation strategy to exclusively synthesize meta-carbonyl phenols and anilines from carbonyl substituted cyclohexanes. Mechanistic studies indicate that this transformation undergoes a copper-catalyzed dehydrogenation/allylic hydroxylation or amination/oxidative dehydrogenation/aromatization cascade process.

Sulfone-Functionalized Chichibabin's Hydrocarbons: Stable Diradicaloids with Symmetry Breaking Charge Transfer Contributing to NIR Emission beyond 900 nm.

While monoradical emitters have emerged as a new route toward efficient organic light-emitting diodes, the luminescence property of organic diradicaloids is still scarcely explored. Herein, by devising a novel radical-radical coupling-based synthetic approach, we report a new class of sulfone-functionalized Chichibabin's hydrocarbon derivatives, SD-1-3, featuring varied substituent patterns and moderate to high diradical characters of 0.44-0.70, as highly stable diradicaloids with rarely seen NIR emission beyond 900 nm. Via comprehensive experimental and theoretical investigations, we reveal that the optoelectronic and magnetic properties of these materials are significantly tuned by the variations of substitutions (H/CF3/OMe) on the molecular skeletons. More importantly, quantum chemical computations indicate that the embedding of sulfone groups has contributed to a breaking of their quasi-C2 symmetry of these diradicaloid molecules and results in an excited-state charge transfer character. Therefore, a remarkably deep NIR emissive wavelength of up to 998 nm, together with a large Stokes shift (∼386 nm), is achieved for the CF3-based SD-2 molecule in tetrahydrofuran. To the best of our knowledge, such a luminescent wavelength of SD-2 has represented the longest wavelengths among the currently reported organic fluorescent radicals. Overall, our work not only establishes a new synthetic approach toward stable Chichibabin's hydrocarbons but also paves the way for designing NIR emissive open-shell materials with both fundamental understanding and feasible control of their luminescent properties.

Catalytic Asymmetric Oxidation of Amines to Hydroxylamines.

Chiral hydroxylamines are increasingly common structural elements in pharmaceuticals and agrochemicals, but their asymmetric synthesis remains challenging. Although enantioselective oxidation is the most straightforward method to prepare chiral oxides with a higher oxidation state, asymmetric and even nonasymmetric amine oxidation to hydroxylamines has been poorly addressed. We report a titanium-catalyzed asymmetric oxidation of racemic amines providing a broad range of structurally diverse chiral hydroxylamines with excellent chemo- and enantioselectivity. Notably, hydroxylamines bearing diverse substituent patterns on the stereocenters, including α,α-ester-alkyl, α,α-amide-alkyl, α,α-aryl-alkyl, α,α-alkynyl-alkyl, and α,α-dialkyl, are well tolerated with good functional group compatibility. Catalyst turnover numbers up to 5000 and selectivity factors up to 278 are observed. This finding offers a democratized platform to chiral hydroxylamines as design elements for drug discovery and provides insights into metal-catalyzed asymmetric oxidation of challenging substrates.

Discovery of Novel Carboxamide Derivatives Containing Biphenyl Pharmacophore as Potential Fungicidal Agents Used for Resistance Management.

Natural products are one of the main sources of drug and agrochemicals discovery. Biphenyls skeleton are ubiquitous structures in many classes of natural products, which indicate extensive biological activities. So, in order to investigate the potential applications for natural biphenyl derivatives, a series of novel carboxamide derivatives with diverse substituent patterns were designed and synthesized based on active pharmacophore from natural biphenyl lignans, and their in vitro antifungal activities against several typical plant pathogens belonging to oomycetes, ascomycete, deuteromycetes, and basidiomycetes were fully investigated. The highly potential compounds were further tested in vivo assay against Botrytis cinerea Pers. of cucumber to demonstrate a practical application for controlling common plant diseases, which indicated four compounds could effectively control the resistant strains of carbendazim, rutamycin, and pyrazolidide. The potential modes of action for compound B12 against B. cinerea were also explored using molecular docking, microscopic technology, and label-free quantitative proteomics analysis. The results show that compound B12 may be a potential novel fungicidal agent used for gray mold resistance control, which can influence the protein synthesis of B. cinerea. These findings can provide a certain theoretical basis for the development of novel biphenyl derivatives as potential green antifungal agents.

Ceramicines U-Z from Chisocheton ceramicus and structure-antimalarial activity relationship study.

Ceramicines are a series of limonoids which were isolated from the barks of Malaysian Chisocheton ceramicus (Meliaceae), and were known to show various biological activity. Six new limonoids, ceramicines U-Z (1-6), with a cyclopentanone[α]phenanthrene ring system with a β-furyl ring at C-17 were isolated from the barks of C. ceramicus. Their structures were determined on the basis of the 1D and 2D NMR analyses, and their absolute configurations were investigated by CD spectroscopy. Ceramicine W (3) exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC50 value of 1.2µM. In addition, the structure-antimalarial activity relationship (SAR) of the ceramicines was investigated to identify substituent patterns that may enhance activity. It appears that ring B and the functional groups in the vicinity of rings B and C are critical for the antimalarial activity of the ceramicines. In particular, bulky ester substituents with equatorial orientation at C-7 and C-12 greatly increase the antimalarial activity.

Synthesis of Silolide Dianions via Reduction of Dichlorosiloles: Important Role of the Solvent

AbstractThe reduction of 1,1‐dichloro‐2,5‐bistrimethylsilyl‐3,4‐diphenylsilole to silolide dianion by alkali metals was investigated. As previously demonstrated, the outcome of the reaction depends strongly on the applied alkali metal, solvent, reaction conditions, and substituent pattern. We showed that lithium is a powerful reducing agent in THF or DME solvents, the reaction is even faster than the same reaction with sodium. The X‐ray structures of the corresponding dilithio and disodium silolide dianion were investigated, interestingly recrystallization of the dilithio salt results in a coordination polymer. In order to support the synthetic work DFT calculations were performed.

Dual and Panchromatic Emission from N-Aryl-phenanthridinones: Extension of the Seesaw Photophysical Model with a Slight Twist.

White-light emission from a single organic molecule, known as a single white-light emitter, is a rare phenomenon and desirable property for a class of materials with potential future applications in white lighting. Since N-aryl-naphthalimides (NANs) have been shown to follow excited state behavior and unique dual or panchromatic emission through a substituent pattern prescribed via a seesaw photophysical model, this study investigates the substituent effects on the fluorescence emission of structurally related N-aryl-phenanthridinones (NAPs) dyes. Following a similar placement prescription of an electron-releasing group (ERG) and electron-withdrawing group (EWG) at the phenanthridinone core and N-aryl moiety, we discovered from time-dependent density functional theory (TD-DFT) results that NAPs show a substitution pattern opposite to NANs in order to promote S2 and higher excited states. Interestingly, 2-methoxy-5-[4-nitro-3(trifluoromethyl)phenyl]phenanthridin-6(5H)-one 6e displayed a pronounced dual and panchromatic fluorescence dye depending on the solvent. For the six dyes included in the study, full spectral information in a variety of solvents, as well as fluorescence quantum yield and lifetime are reported. TD-DFT calculations support the predicted optical behavior via mixing of S2 and S6 excited states via anti-Kasha type of emission behavior.

Atomically precise gold nanoclusters at the molecular-to-metallic transition with intrinsic chirality from surface layers

The advances in determining the total structure of atomically precise metal nanoclusters have prompted extensive exploration into the origins of chirality in nanoscale systems. While chirality is generally transferrable from the surface layer to the metal–ligand interface and kernel, we present here an alternative type of gold nanoclusters (138 gold core atoms with 48 2,4-dimethylbenzenethiolate surface ligands) whose inner structures are not asymmetrically induced by chiral patterns of the outermost aromatic substituents. This phenomenon can be explained by the highly dynamic behaviors of aromatic rings in the thiolates assembled via π − π stacking and C − H···π interactions. In addition to being a thiolate-protected nanocluster with uncoordinated surface gold atoms, the reported Au138 motif expands the size range of gold nanoclusters having both molecular and metallic properties. Our current work introduces an important class of nanoclusters with intrinsic chirality from surface layers rather than inner structures and will aid in elucidating the transition of gold nanoclusters from their molecular to metallic states.

Liquid Structures and Diffusion Dynamics of Alkyl-Pyrene Liquids Studied by Molecular Dynamics Simulations.

Functional molecular liquids (FMLs) based on alkylated π-conjugated molecules have attracted attention as solvent-free and nonvolatile liquid materials with prominent optoelectronic features. Recently, novel FML compounds containing pyrene as the functional core were synthesized, and their rheological and photochemical properties were investigated. Although the molecules differ only in the number of alkyl chain substituents and their substitution positions, their viscosity coefficients are largely different beyond the Stokes-Einstein relation on the assumption of identical microscopic friction, indicating that local microscopic molecular interactions are crucial for the macroscopic rheological properties. Here, we report a theoretical study on the rheological properties of the alkyl-pyrene liquids by means of atomistic molecular dynamics (MD) simulations. We performed long-time MD simulations for tens of microseconds to obtain ample statistical samples of the alkyl-pyrene liquids and analyzed their liquid structures and diffusion dynamics based on spatiotemporal correlation functions. We found the formation of characteristic local liquid structures of π-π stacking of the pyrene moieties and locally anisotropic and anomalous diffusion dynamics, which remarkably vary depending on the alkyl substituent patterns. The present results provide an atomistic insight into the macroscopic rheological properties of alkyl-π FMLs and molecular design strategy for them.

Highly Chemoselective Synthesis of Indole Derivatives.

A facile and efficient synthesis of polysubstituted indoles from α-arylamino-β-hydroxy-2-enamides, α-arylamino-β-oxo-amides, or their tautomeric mixture via electrophilic activation strategy is described. The salient feature of this methodology is the use of either combined Hendrickson reagent and triflic anhydride (Tf2O) or triflic acid (TfOH) to control the chemoselectivity in the intramolecular cyclodehydration to provide a predictable approach to these valuable indoles with flexible substituent patterns. Moreover, the mild reaction conditions, simple execution, high chemoselectivity, excellent yields, and wide range of synthetic potential of products make this protocol much attractive for academic research and practical applications.

Halochromic Silk Fabric as a Reversible pH-Sensor Based on a Novel 2-Aminoimidazole Azo Dye

Textiles are important components for the development of lightweight and flexible displays useful in smart materials. In particular, halochromic textiles are fibrous materials with a color-changing ability triggered by pH variations mainly based on pH-sensitive dye molecules. Recently, a novel class of 2-aminoimidazole azo dyes was developed with distinct substituent patterns. In this work, silk fabric was functionalized through exhaustion for the first time with one of these dyes (AzoIz.Pip). The halochromic properties of the dye were assessed in an aqueous solution and after silk functionalization. The solutions and the fabrics were thoroughly analyzed by ultraviolet-visible (UV-vis) spectra, color strength (K/S), color difference (∆E), CIE L*a*b* coordinates, and the ultraviolet protection factor (UPF). The dyeing process was optimized, and the halochromic performance (and reversibility) was assessed in universal Britton-Robinson buffers (ranging from pH 3 to 12) and artificial body fluids (acid and alkaline perspiration, and wound exudate). AzoIz.Pip showed vibrant colors and attractive halochromic properties with a hypsochromic shift from blue (557 nm) to magenta (536 nm) in aqueous buffered solutions. Similarly, the functionalized silk showed a shift in wavelength of the maximum K/S value from 590 nm to 560 nm when pH increases. The silk fabric showed a high affinity to AzoIz.Pip, and promoted additional color stabilization of the dye, avoiding color loss as observed when the dye is in solution at alkaline pH after 24 h. The color reversibility was effective up to the fourth cycle and the fastness tests denoted suitable results, except washing fastness. The cytotoxicity of the silk fabric extracts was assessed, depicting reduced viability of HaCaT cells to <70% only when the dye concentration in the fabric is higher or equal to 64 μg·mL-1. Nevertheless, lower concentrations were also very effective for the halochromic performance in silk. These materials can thus be a helpful tool for developing sensors in several sectors such as biomedicine, packaging, filtration, agriculture, protective apparel, sports, camouflage, architecture, and design.