Phenyl Research Articles

Highly Selective On‐Surface Dehydrogenative Aromatization of n‐Hexyl to Phenyl Substituents

AbstractDehydrogenative aromatization of alkyl substituents represents a powerful approach to aryl‐substituted functional molecules. However, the inertness of alkyl groups and the need for harsh reaction conditions accompanied by low product selectivity hamper its widespread applications. Here, we demonstrate the highly selective on‐surface thermal aromatization of n‐hexyl substituents on polycyclic aromatic hydrocarbons (PAHs) to their phenyl‐substituted analogues under mild conditions. After depositing two representative precursor molecules, n‐hexyl‐substituted hexaphenylbenzene (HPB‐Hex) and bianthryl octacarboxylic tetraimide (BATI‐Hex), onto a pre‐heated Au(111) substrate, dehydroaromatization of the peripheral n‐hexyl groups into phenyl rings occurs, following the planarization of hexaphenylbenzene and bianthryl core. This process involves sequential intramolecular C−C bond rotations, dehydrogenation, and cyclodehydrogenation reactions, yielding phenyl‐substituted hexabenzocoronene (HBC‐Ph) and bisanthene octacarboxylic tetraimides (BSTI‐Ph). The reaction sequences were monitored using scanning tunneling microscopy (STM) and bond‐resolved non‐contact atomic force microscopy (nc‐AFM), offering structural proof of both intermediates and final products. These experimental techniques were complemented by density functional theory (DFT) simulations, which facilitated the detection of crucial steps in the conversion of n‐hexyl to phenyl groups. Moreover, the effect of alkyl aromatization on the electronic properties of the newly formed aromatic hydrocarbons was elucidated using scanning tunneling spectroscopy (STS).

Cavity induced modulation of intramolecular vibrational energy flow pathways.

Recent experiments in polariton chemistry indicate that reaction rates can be significantly enhanced or suppressed inside an optical cavity. One possible explanation for the rate modulation involves the cavity mode altering the intramolecular vibrational energy redistribution (IVR) pathways by coupling to specific molecular vibrations in the vibrational strong coupling (VSC) regime. However, the mechanism for such a cavity-mediated modulation of IVR is yet to be understood. In a recent study, Ahn et al. [Science 380, 1165 (2023)] observed that the rate of alcoholysis of phenyl isocyanate (PHI) is considerably suppressed when the cavity mode is tuned to be resonant with the isocyanate (NCO) stretching mode of PHI. Here, we analyze the quantum and classical IVR dynamics of a model effective Hamiltonian for PHI involving the high-frequency NCO-stretch mode and two of the key low-frequency phenyl ring modes. We compute various indicators of the extent of IVR in the cavity-molecule system and show that tuning the cavity frequency to the NCO-stretching mode strongly perturbs the cavity-free IVR pathways. Subsequent IVR dynamics involving the cavity and the molecular anharmonic resonances lead to efficient scrambling of an initial NCO-stretching overtone state over the molecular quantum number space. We also show that the hybrid light-matter states of the effective Hamiltonian undergo a localization-delocalization transition in the VSC regime.

Isoreticular Contraction in Dicopper Paddle-Wheel-Based Metal-Organic Frameworks to Enhance C2H2/CO2 Separation.

Achieving a balance between high selectivity and uptake is a formidable challenge for the purification of acetylene from mixtures with carbon dioxide, particularly when seeking to maximize both C2H2 adsorption capacity and C2H2/CO2 separation selectivity in crystalline porous materials. In this study, leveraging the principles of reticular chemistry, we selected two tetracarboxylate-based linkers and combined them with Cu2+ ions to synthesize two isoreticular dicopper paddle-wheel-based metal-organic frameworks (MOFs): Cu-TPTC (terphenyl-3,3',5,5'-tetracarboxylic acid , H4TPTC) and Cu-ABTC (3,3,5,5-azobenzenetetracarboxylic acid, H4ABTC). The structural and sorption analyses revealed that Cu-ABTC, despite having slightly smaller pores due to the strategic replacement of a phenyl ring with an azo group between two tetratopic ligands, maintains high porosity compared to Cu-TPTC. Furthermore, Cu-ABTC outperforms Cu-TPTC in terms of C2H2 adsorption capacity (196 cm3 g-1 at 298 K and 1 bar) and C2H2/CO2 separation selectivity (16.5~5.6). These findings were corroborated by dynamic breakthrough experiments and computational modeling. This research highlights the potential of the isoreticular contraction strategy in enhancing MOFs for sophisticated gas adsorption and separation processes.

Uncommon Phosphonylation of Pyrazine‐2,3‐dicarbonitrile Derivatives via C(sp2)‐CN Bond Cleavage

A direct phosphonylation of the sp2C−CN bond under mild catalytic and non‐catalytic reaction conditions is disclosed. Pyrazine‐2,3‐dicarbonitriles are readily coupled with HPO(OEt)2 to produce the corresponding dialkoxyphosphoryl‐substituted pyrazines. The phosphonylation reaction occurs in the presence of a base (Et3N, Cs2CO3) as nucleophilic substitution of the CN groups. The yield of target diphosphonates depends on the nature of substituents in the 5,6‐positions of the pyrazine ring: it exceeds 90% for di‐5,6‐aryl‐substituted pyrazines and is significantly lower when electron‐donating alkyl (n‐propyl) groups are attached to the 5,6‐positions. It should be noted that for pyrazine‐2,3‐dicarbonitriles bearing vicinal 4‐bromophenyl groups, the nucleophilic phosphonylation leading to C‐‐CN/P‐‐H coupling in the pyrazine ring is predominant over Pd‐catalyzed Hirao’s C‐‐Br/P‐‐H coupling reaction in phenyl rings. Detailed structural characterization, both in solution by means of 1H, 13C and 31P NMR spectroscopy and in the solid state by single crystal X‐ray diffraction, of a series of newly synthesized pyrazine phosphonates is reported.

Design And Synthesis Of Novel Thiazole Linked Tetrahydropyridine Analogues As Anticancer Agents.

A library of new thiazole linked tetrahydropyridines (6a-q) synthesized and screened for their invitro anticancer activity against human breast adeno carcinoma cell viz. MCF-7 and MDA-MB-231. The two compounds 6d containing -F and -Cl functions in para and meta position of phenyl ring (9.94 ± 1.02µM, 9.78 ± 1.08µM) and 6e with -Cl and -NH2 functions on pyridine ring (9.72 ± 0.91 µM,9.54 ± 0.95µM) demonstrated outstanding activity against both the cell lines when compared to Doxorubicin. The benzofuran analogue 6o presented good activity with an IC50 value of 12.19 ± 1.03µM (MCF-7) and 12.22 ± 1.07µM (MDA-MB-231). The molecular docking study of potent molecule 6e against crystal structure of breast tumor kinase presented promising docking score and binding interactions. Predicted pharmacokinetics properties of compounds 6a-q and presented boiled diagram of compounds 6d and 6e implied favourable drug-likeness properties.

Side Chain Phenyl Isomerization-Induced Spatial Conjugation for Achieving Efficient NIR-II Phototheranostic Agents.

The contradiction of near-infrared II (NIR-II) emission and photothermal effects limits the development of phototheranostic agents (PTAs) in many emerging cutting-edge applications. Organic aggregates present a promising opportunity for the balance of competitive relaxation processes through the manipulation of molecular structure and packing. Herein, side chain phenyl isomerization-induced spatial conjugation was proposed for constructing A-D-A type NIR-II PTAs with simultaneous enhancement of fluorescence brightness and photothermal properties. Three pairs of mutually isomeric fluorophores, whose phenyls respectively located at the outside (o-series) and inside (i-series) of the side chain, were designed and synthesized. The positional isomerization of the phenyl endows the o-series crystals with strong spatial conjugation between the phenyl group on the side chain and the backbone, as well as interlocked planar network, which is different to that observed in the i-series. Thus, all o-series nanoparticles (NPs) exhibit red-shifted absorption, enhanced NIR-II emission, and superior photothermal properties than their i-series counterparts. A prominent member of the o-series, o-ITNP NPs, demonstrated efficacy in facilitating NIR-II angiography, tumor localization, and NIR-II imaging-guided tumor photothermal therapy. The success of this side chain phenyl isomerization strategy paves the way for precise control of the aggregation behavior and for further development of efficient NIR-II PTAs.

Side Chain Phenyl Isomerization‐Induced Spatial Conjugation for Achieving Efficient NIR‐II Phototheranostic Agents

The contradiction of near‐infrared II (NIR‐II) emission and photothermal effects limits the development of phototheranostic agents (PTAs) in many emerging cutting‐edge applications. Organic aggregates present a promising opportunity for the balance of competitive relaxation processes through the manipulation of molecular structure and packing. Herein, side chain phenyl isomerization‐induced spatial conjugation was proposed for constructing A‐D‐A type NIR‐II PTAs with simultaneous enhancement of fluorescence brightness and photothermal properties. Three pairs of mutually isomeric fluorophores, whose phenyls respectively located at the outside (o‐series) and inside (i‐series) of the side chain, were designed and synthesized. The positional isomerization of the phenyl endows the o‐series crystals with strong spatial conjugation between the phenyl group on the side chain and the backbone, as well as interlocked planar network, which is different to that observed in the i‐series. Thus, all o‐series nanoparticles (NPs) exhibit red‐shifted absorption, enhanced NIR‐II emission, and superior photothermal properties than their i‐series counterparts. A prominent member of the o‐series, o‐ITNP NPs, demonstrated efficacy in facilitating NIR‐II angiography, tumor localization, and NIR‐II imaging‐guided tumor photothermal therapy. The success of this side chain phenyl isomerization strategy paves the way for precise control of the aggregation behavior and for further development of efficient NIR‐II PTAs.

Highly Selective On-Surface Dehydrogenative Aromatization of n-Hexyl to Phenyl Substituents.

Dehydrogenative aromatization of alkyl substituents represents a powerful approach to aryl-substituted functional molecules. However, the inertness of alkyl groups and the need for harsh reaction conditions accompanied by low product selectivity hamper its widespread applications. Here, we demonstrate the highly selective on-surface thermal aromatization of n-hexyl substituents on polycyclic aromatic hydrocarbons (PAHs) to their phenyl-substituted analogues under mild conditions. After depositing two representative precursor molecules, n-hexyl-substituted hexaphenylbenzene (HPB-Hex) and bianthryl octacarboxylic tetraimide (BATI-Hex), onto a pre-heated Au(111) substrate, dehydroaromatization of the peripheral n-hexyl groups into phenyl rings occurs, following the planarization of hexaphenylbenzene and bianthryl core. This process involves sequential intramolecular C-C bond rotations, dehydrogenation, and cyclodehydrogenation reactions, yielding phenyl-substituted hexabenzocoronene (HBC-Ph) and bisanthene octacarboxylic tetraimides (BSTI-Ph). The reaction sequences were monitored using scanning tunneling microscopy (STM) and bond-resolved non-contact atomic force microscopy (nc-AFM), offering structural proof of both intermediates and final products. These experimental techniques were complemented by density functional theory (DFT) simulations, which facilitated the detection of crucial steps in the conversion of n-hexyl to phenyl groups. Moreover, the effect of alkyl aromatization on the electronic properties of the newly formed aromatic hydrocarbons was elucidated using scanning tunneling spectroscopy (STS).

QSAR prediction of toxicity for a new 1,2,4-triazole derivatives with 2-bromo-5-methoxyphenyl fragment

New derivatives of 1,2,4-triazole are promising research targets due to their unique biological properties, including antimicrobial, antifungal, antitumor, and antioxidant activities. The introduction of the 2-bromo-5-methoxyphenyl fragment into the triazole structure potentially enhances these properties. However, the issue of toxicity for such compounds remains a critical factor for their further application. To reduce experimental costs and time, QSAR (Quantitative Structure-Activity Relationship) methods are widely applied, allowing to predict compounds toxicity based on their molecular structure. The aim of this study was to evaluate the toxicity of new derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols, their acids, and esters using the QSAR method to predict parameters of acute toxicity (LD50) and to assess the influence of various radicals on the toxicity of the compounds. Materials and methods. The objects of this study were derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols, synthesized at the Department of Toxicological and Inorganic Chemistry of Zaporizhzhia State Medical and Pharmaceutical University. The nearest neighbor method was used for toxicity evaluation, applying the Toxicity Estimation Software Tool (TEST). The prediction of rats lethal dose (LD50) was based on the structural similarity of the studied compounds with known substances that have experimental toxicity data. Results. The QSAR analysis revealed that structural modifications in the derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols significantly influence their toxicity. Specifically, increasing the size of the radicals, especially through the introduction of aromatic fragments, contributed to the enhanced safety of the compounds, as evidenced by the increase in LD50 values. The highest LD50 values were observed for compounds containing phenyl radicals. Conclusions. The results of this study indicate the feasibility of using QSAR models to predict the toxicity of 1,2,4-triazole derivatives containing a 2-bromo-5-methoxyphenyl fragment. The observed trend of increasing safety with the introduction of larger aromatic radicals can be used for the rational design of new compounds with improved toxicological properties.

Crystal structures and circular dichroism of {2,2′-[(1S,2S)-1,2-diphenylethane-1,2-diylbis(nitrilophenylmethanylylidene)]diphenolato}nickel(II) and its ethanol solvate

The title compound, [Ni(C40H30N2O2)] (1), with an optically active Schiff base ligand derived from 2-hydroxybenzophenone and (1S,2S)-1,2-diphenylethylenediamine, was crystallized as the solvent-free and ethanol solvate forms (1 and 1·2C2H5OH). In both structures, the two phenyl groups on the stereogenic centers of the O,N,N,O-tetradentate ligand are axially oriented, and the conformation of the central diamine chelate ring is λ. The circular dichroism (CD) spectra of 1 and the analogous nickel(II) complex [Ni(C30H26N2O2)] (2) in solution show partially similar patterns in the 350–450 nm range, but are mirror images in the longer wavelength region (450–650 nm). In the latter region, the sign of CD for these complexes is sensitive to the substituents on the C=N carbon atoms (phenyl for 1 and methyl for 2) rather than the diamine chelate ring conformation.

Tetrazaisoindigos:Serpentine Syntheses and Their Expected and Unexpected Photophysical and Electronic Properties.

Isoindigo, an electron-withdrawing building block for polymeric field-effect transistors, has long been considered to be non-fluorescent. Moreover, using electron-deficient heterocycle to replace the phenyl ring in the isoindigo core for better electron transport behaviour is synthetically challenging. Here we report the syntheses of a series of tetrazaisoindigos, including pyrazinoisoindigo (PyrII), pyrimidoisoindigo (PymII) and their hybrid (PyrPymII), and the investigation on their photophysical and electric properties. Proper flanking groups need to be chosen to stabilize these highly electron-deficient bislactams. Both PyrII and PymII derivatives show lower LUMO energy levels than that of naphthalene bisimide (NDI). Interestingly, PyrII is instinctively unstable and can be easily reduced, while both PymII derivatives are stable. More surprisingly, PymII derivatives are highly fluorescent and their photoluminescence quantum yields are around 40 %, 133 times higher than that of reported isoindigo derivatives. UV-vis spectroscopic results and theoretical calculations show that strong intramolecular hydrogen-bond exists in PymII, which prohibits it from non-radiative decay and accounts for its fluorescent behaviour. PymII derivatives are n-type semiconductors, while Ph-PyrII and the hybrid show balanced ambipolar charge transport behaviour, all among the best isoindigo derivatives. Our study not only discloses the structure-property relationship of tetrazaisoindigos, but also provides novel electron-deficient monomers for conjugated polymers.

Synthesis of Novel 3,4-Dihydropyrimidine Derivatives, Cytotoxic Activity Evaluation, Apoptosis, Molecular Docking Studies, and MD Simulations.

In this study, twelve 3,4-dihydropyrimidines derivatives were synthesized through Biginelli multi-component reaction. The efficacy of these compounds against MCF-7, A549, and HeLa cells was evaluated using the MTT method. The results showed that designed derivatives were more effective against A549 cancer cells than MCF-7 and HeLa cells. Compound 5l (bearing 4-Cl-phenyl at C4 of 3, 4-dihydropyrimidin-2(1H)-one ring) was the most potent analogue (A549: 18.65±1.87 μM, HeLa: 26.59±2.71 μM, MCF-7: 31.82±2.64 μM). The presence of an electron-withdrawing group with optimum lipophilicity at the C4 position of the phenyl ring increased the cytotoxic effect. The flow cytometry findings indicated that compound 5l induced apoptosis in A549 cancer cells in a dose-dependent manner. Eg5 and AKT1 were selected as molecular modeling target by applying pharmacology network analyses. The molecular docking results indicated that both enantiomers of compound 5l had significant interactions with key residues in both Eg5 (Gly117 and Glu116) and AKT1 (Ala123 and Glu121) active sites. However, MD simulation revealed that the R enantiomer had a more stable complex and a higher binding affinity to the Eg5 enzyme active site than the S-enantiomer. The affinity of 5l (R enantiomer) to Eg5 was predicted more than AKT1.

Design and synthesis of pyridine-bridged benzothiazole-based D-A system for SRAM memory devices

This study focused on designing small donor-acceptor (D-A) frameworks for resistive memory devices. We synthesized five new organic molecules using pyridine bridged to benzothiazole and various donor moieties (triphenylamine, naphthalene, benzothiophene, t-butyl phenyl, and mesityl group) via Suzuki cross-coupling to study their memory performance. The compounds with triphenylamine and naphthalene exhibited good semiconductor behavior, with a band gap of 3.11 eV and 3.44 eV, respectively. The benzothiazole moiety, employed as a shallow trap in the acceptor segment, demonstrated the SRAM characteristics of all devices. This study examined how varying the potency of electron-donating substituents impacts charge transfer and volatile memory behavior in a small D-A system. Memory devices with triphenylamine and naphthalene donors showed binary SRAM behavior with high ON/OFF ratios of 2.82 × 103 and 2.36 × 103, while t-butylphenyl and mesityl donors exhibited lower ratios of 1.43 × 101 and 4.08 × 101, respectively. All the compounds exhibited switching characteristics at a low threshold voltage of −1 to −1.3 V. The analysis of HOMO, LUMO energy levels, and ESP images of all compounds from the DFT study, collectively indicate charge transfer and trapping are the operative mechanisms in volatile SRAM devices.

Cyclometalated Iridium(III) Complex with Substituted Benzimidazole: pH Directed Organelle-Specific Localization Within Lysosome.

We report the synthesis and pH dependent emission spectral behaviour of four emissive iridium(III) complexes (Ir1-Ir4) with two isomeric pairs of bis-trifluoromethyl appended benzimidazole ligands. The imidazolyl hydrogen(N-H) has been replaced by phenyl groups (N-Ph) in two ligands to understand the impact of hydrogen bonding on the photophysical properties of the complexes and it indeed plays interesting role in the charge-transfer dynamics. The pH dependent electronic spectral change is observed for two of the complexes. The enhancement of emission intensity is observed at different wavelength for pH<7 and pH>7 for Ir1 and Ir3. The emission sensing of biogenic amines with pka values ranging from 5.80-9.74 is reported along with cellular imaging. The complex Ir1 specifically localizes within lysosome (pH=4.5-5) and thus image this organelle with great precision. The detail electronic spectra and electrochemical behaviour were reported here along with TDDFT results.

Absorption, Fluorescence, and Two-Photon Excitation Ability of 5-o-Tolyl-11 (or 13)-o-tolylisoindolo[2,1-a]quinolines Prepared by Ring-Closing Metathesis and [2+3] Cycloaddition.

We have successfully improved the fluorescence quantum yield of isoindolo[2,1-a]quinoline derivatives by suppressing the rotation of the phenyl groups at positions 5 and 11 (or 13). Additionally, we found that the planarity of these phenyl groups at positions 5 and 13 of isoindolo[2,1-a]quinoline derivatives is crucial for two-photon absorption properties.

Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents

The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [3H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.

Comparing the linear and non-linear optical properties of keto-enol forms of N-alkyl, N-aryl, and O-alkyl substituted 2-Hydroxybenzophenone

The Geometrical, electronical, spectral, linear, and non-linear optical properties (NLO) of keto-enol forms of 2-hydroxybenzophenone (2-HBp) derivatives were examined. Ten pairs of 2-HBp derivatives having D-π-A framework with N-alkyl (ethyl, julolidine), N-aryl (phenyl), O-methyl, groups as donor, phenyl ring as aspacer, and carbonyl group linked to phenyl ring consisting of either mono or dicarboxylic acid group as acceptor, were selected. DFT results suggest thatthe keto form is stablein the S0 and S1 states. Further, IR spectra, CV analysis, experimental absorption maxima, and TD-DFT results support the existence of 2-HBp derivatives in keto form. Thermogravimetric analysis shows that 2-HBp derivatives have remarkable thermal stability (∼200 °C), enabling their practical application in NLO. Further, DFT and TD-DFT results show that theketo form of 2-HBp derivatives with lower BLA, higher μ, ω, η, Γ, and hyperpolarizability exhibits superior NLO properties compared to theenol form of 2-HBp derivatives.

Preparation of a new reusable magnetic organocatalyst to synthesis of polyhydroquinoline derivatives as cytotoxic Agents: Synthesis and biological evaluation

One of the most important ways to practice environmental stewardship is to turn waste materials into useful nanomaterials through ecological recycling. This work introduces a magnetic organocatalyst made from red mud waste, adding to the “greening” of global chemical processes.The new composite (Fe3O4@SiO2@(CH2)3@4-(2-Aminoethyl)-morpholine) is introduced and characterized by different spectroscopic methods such as fourier transform infrared (FT-IR), X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), mapping, thermogravimetric analysis (TGA) and vibrating-sample magnetometers (VSM). Catalytic activity of the catalyst was evaluated in production of some polyhydroquinoline derivatives and the results showed efficiency. Nine polyhydroquinoline derivatives were synthesized (M1-M9) and their cytotoxic properties evaluated against two human-cancerous cell lines (Hep-G2 and SW480) by MTT assay. Most of the compounds exhibited high inhibitory activity against two studied cell lines. M2 bearing 2-chloro substitution on phenyl ring was exhibited appropriate activity (IC50 = 14.70 ± 3.11 µM) against SW480 cell line in comparison to cisplatin as positive control.

Design, Synthesis, Biological and Computational Analysis of Isatin-based bis-Thiourea Analogues as Anti-diabetic and Anti-nematode Agents

A new series of isatin derivatives were synthesized, characterized by 1HNMR, 13CNMR and HREI-MS, and screened for α-glucosidase and alpha amylase inhibition. All the analogues were found to be dual inhibitors and showed good inhibitory potentials with IC50 values ranging from 5.28 ± 0.10 to 38.66 ± 0.30 µM (against alpha-amylase), and 5.45 ± 0.10 to 39.25 ± 0.50 µM (against alpha-glucosidase), as compared to the standard drug acarbose (IC50 = 11.12 ± 0.15 and 11.29 ± 0.07 µM, respectively). The most potent inhibitor among the series was analogue 24 (IC50 = 5.28 ± 0.10 for alpha-amylase and IC50 = 5.46 ± 0.10 µM for alpha-glucosidase), which has a nitro group attached at the meta-position of the phenyl ring A and the para position of phenyl ring B. Structure-activity relationship has been established mainly based on the position, nature and number of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analog with the active site of an enzyme, molecular docking studies were carried out. To study the drug-likeness properties, the ADME study was also carried out. The most active compounds engage most of the amino acids composing the active site and display maximum interactions. These interactions majorly include formation of strong hydrogen bonds, which might be due to the presence of highly electronegative heteroatoms on aromatic rings. All the analogues were also tested for in vivo anti-nematodal activity against C. elegans to assess their cytotoxicity in comparison to the reference Levamisole. The cytotoxicity profile demonstrated that analogues 2, 7, 20 and 22 displayed minimum cytotoxicity at every concentration.

The role of intra and intermolecular interactions on the conformational dynamics of 2-halo-1-phenylpropanols: Structure and solvent effects

Experimental and theoretical 3JHH scalar coupling constants allowed the identification of the conformational landscape of erythro (eX) and threo (tX) 2-halo-1-phenylpropanols (halo = F, Cl, and Br). NMR scalar coupling constants captured dynamics of the OC-C-X dihedral and OH rotameric states, in a dynamic and solvent-dependent equilibrium. The erythro series revealed a particular halogen-dependent equilibrium, which showed different sensitivity to the media, especially in acetone, where the eF populations were completely shifted. At the same time, threo showed a highly solvent-sensitive equilibrium. NBO calculations showed the importance of electron delocalization over steric and electrostatic effects to stabilize the preferred synclinal conformer in both diastereomers. A Principal Component Analysis (PCA) on the NBO stabilization energies pointed to a complex mixture of electronic delocalization happening simultaneously. Hyperconjugative interactions are significant, but they are not the only important effect. Non-covalent interactions were also identified through NCI surfaces. Hydrogen bonds and intramolecular C-X···π and CH···π interactions were proved to act differently in the two diastereomers, affecting their equilibria in different ways. Nuclear Overhauser (NOE) NMR experiments point to an intramolecular CH···π contact, while 1H NMR of the aromatic hydrogens evidence an intermolecular effect of acetone and DMSO on the phenyl ring. DFT with explicit solvation shows a solvent shell favoring intermolecular CH···π contacts, in agreement with the experiments. This thorough analysis revealed that intra- and intermolecular factors contribute to the preference for the synclinal conformer in the studied compounds.