Methyl Substitution Research Articles

Enhancing Antileishmanial Activity of Amidoxime-Based Compounds Bearing a 4,5-Dihydrofuran Scaffold: In Vitro Screening Against Leishmania amazonensis.

Leishmaniasis, a protozoan disease affecting humans, exposes significant shortcomings in current treatments. In continuation to our previous findings on amidoxime-based antileishmanial compounds bearing a 4,5-dihydrofuran scaffold, twelve new amidoxime derivatives substituted at position 3 with an amide bearing a nitrogen heterocycle were synthesized. This series was designed to replace the sulfone and aryl group on a previously reported HIT. The synthesis of these compounds involved the following three-step pathway: manganese (III) acetate-based cyclization of a β-ketoester, followed by amidation with LiHMDS and a final reaction with hydroxylamine. Three of them, containing either bromine, chlorine, or methyl substitutions and featuring a pyridine moiety, showed an interesting toxicity-activity relationship in vitro. They exhibited IC50 values of 15.0 µM, 16.0 µM, and 17.0 µM against the promastigote form of the parasite and IC50 values of 0.5 µM, 0.6 µM, and 0.3 µM against the intracellular amastigote form, respectively. A selectivity index (SI) greater than 300 was established between the cytotoxic concentrations (in murine macrophages) and the effective concentrations (against the intracellular form of Leishmania amazonensis). This SI is at least seventy times higher than that observed for Pentamidine and twenty-five times higher than that observed for the reference HIT, as previously reported.

Influence of side-methyl substitution position on the phase state and microwave dielectric properties of triphenylacetylene-based liquid crystals.

Liquid crystal materials are well known in display applications, and their unique birefringence and electrical tunability can be utilised in microwave devices. This innovative technology modulates and filters microwave signals, replacing conventional semiconductors for a broad operational frequency band and tunable phase shift. Although isothiocyanatobiphenylacetylene-based liquid crystals exhibit low viscosity and large dielectric anisotropy, their applications in microwave communication are hampered by their broad near-crystalline phase temperature ranges. To address this limitation, this study designed and synthesized six fluorinated biphenylacetylene liquid crystal compounds with various benzene ring side-methyl substitutions (n = 3-5). The molecular structures, liquid crystal phases, and microwave dielectric properties were evaluated. Our findings indicate that compounds with methyl substitution at the Y2 position exhibited reduced melting points, an expanded nematic phase temperature range (ΔT n ≈ 92.3 °C), and an absence of near-crystalline phases. These compounds still maintain high microwave dielectric constants within the 9-30 GHz frequency band (Δε r = 0.9-1.3) and reduced maximum permittivity losses compared to their non-methyl-substituted counterparts, thereby improving the efficiency in the microwave frequency band. In contrast, the Y1 position substitution results in a significantly narrower nematic phase temperature range (approximately 2.6 °C on average) and a substantial decrease in the dielectric constant, with a Δε r reduction of about 0.3 compared to the Y2 substitution. This work shows that the side-methyl substitution can improve the performance of triphenylacetylene-based liquid crystals in microwave communication, providing valuable insight to aid the discovery of novel microwave liquid crystals.

Effects of Methyl Substitution on the Ultrafast Internal Conversion of Benzene.

The effects of methyl substitution on the ultrafast internal conversion from the S2(1B1u, ππ*) state to the S0 state of benzene were studied using ultrafast extreme-ultraviolet photoelectron spectroscopy and electronic structure calculations. The quantum yield of the internal conversion to the S0 state reached ∼0.69 in benzene, while lower values of 0.35 and 0.12 were obtained for toluene and o-xylene, respectively. These results indicate that methyl substitution makes the conical intersections less accessible to the nuclear wave packet.

Nitrobenzene and Aniline‐Mediated Direct Olefination of Methyl Substituted N‐Heteroarenes With Benzylic Alcohols

AbstractMetal‐free, strong‐base‐free, and solvent‐free synthesis of alkenyl heteroarenes through PhNO2/PhNH2 mediated direct olefination of methyl substituted N‐heteroarenes with benzylic alcohols was described. Detailed mechanistic studies indicated that in situ formed imine was the active intermediate for the olefination. PhNO2 protected benzylic alcohols from overoxidation, and PhNH2 not only acted as the coupling partner for the formation of intermediate imine, but also provides an alkaline condition for the generation of enamine salt. Gram scale reaction and the synthesis of three pharmaceutically relevant conjugated olefins were also successful using this methodology.

Atomic-Level Insights into the Adsorption of Methyl-Substituted Quinoxalinones on Fe(110): A Dispersion-Corrected DFT Analysis.

Corrosion of metallic equipment is a critical issue across various industries, necessitating the development of advanced protective strategies. This study utilized dispersion-corrected density functional theory (DFT) with Becke-Johnson D3(BJ) to examine the atomic-level adsorption of quinoxalinones on Fe(110) surfaces, focusing on optimizing substitution strategies to enhance corrosion inhibition. Three quinoxalinones, quinoxalin-2(1H)-one (QNO), 3-methylquinoxalin-2(1H)-one (QNOM), and 3,7-dimethylquinoxalin-2(1H)-one (QNO2M), were investigated in various configurations and protonation states. Protonated quinoxalinones demonstrated a stronger surface affinity, primarily interacting through oxygen atoms and conjugated systems, with greater energetic stability compared to neutral molecules, driven by enhanced electrostatic interactions and charge transfer mechanisms. The parallel adsorption configuration was more stable than the perpendicular mode, which in some adsorption systems did not form bonds with the iron surface. Notably, the presence of methyl substitutions did not significantly enhance adsorption strength; QNO exhibited higher energetic stability due to reduced steric interference, which maintained its planarity. Projected density of states (PDOS), electron density difference (EDD), and electron localization function (ELF) analyses confirmed the importance of charge transfer between quinoxalinone active sites and the 3d orbitals of iron in stabilizing the adsorption of molecules. These findings underscore the importance of judicious quinoxalinone functionalization to preserve their efficacy as corrosion inhibitors.

Discovery and optimization of anthraquinone derivatives containing substituted bisbenzyloxy groups as a novel scaffold damaged endoplasmic reticulum and against hepatocellular carcinoma cells

This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study.

Insights into Ultrafast Relaxation Dynamics of Electronically Excited Furfural and 5-Methylfurfural.

The ultrafast relaxation dynamics of furfural and 5-methylfurfural following excitation in the ultraviolet range is investigated using the femtosecond time-resolved photoelectron spectroscopy method. Specifically, the pump wavelength-dependent decay dynamics of electronically excited furfural and 5-methylfurfural is discussed on the basis of a detailed analysis of our measured time-resolved photoelectron spectroscopy spectra. Irradiation at all pump wavelengths prepares both furfural and 5-methylfurfural molecules with different vibrational levels in the first optically bright S2 (1ππ*) state, the lifetime of which is measured to be at least hundreds of femtoseconds. Besides the prominent deactivation channels of ring-opening and ring-puckering pathways for the S2(1ππ*) state, we propose that there is a minor decay channel of internal conversion from the initially prepared S2(1ππ*) state to the S1(1nπ*) state. The wavepacket decays out of the Franck-Condon region on the S2(1ππ*) state potential energy surface and bifurcates into different parts somewhere. A small fraction of the wavepacket funnels down to the S1(1nπ*) state via internal conversion. The subsequently populated S1(1nπ*) state contains large vibrational excess energy and decays over a lifetime of 2.5-2.8 ps. One of the deactivation channels of the S1(1nπ*) state is intersystem crossing to the 3ππ* triplet state. In addition, methyl substitution effects on the excited-state dynamics of furfural are also discussed. This experimental study provides new insights into the excitation energy-dependent decay dynamics of photoexcited furfural and 5-methylfurfural.

Maduraflavacins A-E, Unusual Phenyl Polyene Metabolites Produced by a Rare Marine-Derived Actinomadura sp.

Phenyl polyenes comprise a small family of bacterial natural products with broad and potent bioactivities, primarily found in actinobacteria. Here we report the discovery of five new phenyl polyene metabolites, maduraflavacins A-E (1-5), from a rare, marine-derived actinobacteria strain Actinomadura glauciflava NA03286. The structures of these natural products were determined by NMR spectroscopy, HRESIMS, LC-MS/MS, and chemical derivatization. All of these new maduraflavacins feature methyl substitutions at the polyene side chain, and maduraflavacins A-C (1-3) possessed a 1-N-β-d-glucosamine-(3 → 1)-O-β-d-glucopyranosyl-(3 → 1)-O-β-d-glucopyranosyl-(6 → 1)-O-β-d-glucopyranoside tetrasaccharide moiety via an amido linkage with a phenyl polyene skeleton. Compounds 1 and 2 showed weak antibacterial activities against the Gram-positive bacteria Staphylococcus aureus Sau 16339 and Micrococcus luteus, respectively.

Regioselectivity and physical nature of the interactions between (methyl)guanine with HCl and CH3OH

A comprehensive study of the hydrogen bonding interactions between guanine (G) and methyl guanine derivatives (MGs) in the presence of HCl and MeOH is carried out at B3LYP, B3LYP-D3 and M062X/6–311 + + G(d.p) levels using molecular electrostatic potential, natural bond orbital, and symmetry adapted perturbation theory. Making use of these state-of-the-art techniques, this study attempts to elucidate the chemical bonding, regioselectivity, and physical nature of the interactions responsible for the stability of (M)G…L (L = HCl, MeOH) acid–base complexes. Our calculations reveal that 1-G, 3-MG, and 5-MG interact more strongly with MeOH than HCl due to the positive hydrogen bond cooperativity. Furthermore, the carbonyl site on G is found to be the most reactive site, while methyl substitution increases the basicity of the nucleobase, thus yieding more stable complexes. The strongest H-bond interaction in G-complexes is found when HCl and MeOH attack the carbonyl group in anti-position. Finally, energy decomposition analyses through the symmetry-adapted perturbation theory reveal that most complexes are mainly stabilized via electrostatic interactions. The energy difference between complex isomers shows a competition between 3-HCl-G (MG) and 4-HCl-G (MG) at ∆G level where thermal, BSSE and entropy terms are included.

Benzimidazole based electron-transport hosts for efficient pure blue narrowband OLED device

Two electron-transport host materials are synthesized by linking anthracene with benzimidazole derivatives through a unit of methyl substituted phenyl. The methyl substitution generates a large dihedral angle between the benzimidazole plane and bridging phenyl, keeping the excited state distribution and energy levels of T1 and S1 unchanged. The electron-only devices reveal that the two hosts have obviously enhanced electron transport ability than that of Ph-AN-MBP without benzimidazole. As a result, the devices with Ph-AN-BIZ and N1-AN-BIZ as hosts and a blue multiple resonance material of tBuCz-DABNA as emitter exhibit high external quantum efficiency of 10.1 % and 9.1 %, respectively, and low turn-on voltage of 2.7 V, which is better than those of Ph-AN-MBP based device (7.9 %, 3.4 V). And their electroluminescence spectra have a very small full-width at half-maximum of 16.2 nm and pure blue color with CIE coordinates of (0.12, 0.11).

Substitution, Elimination, and Integration of Methyl Groups in Terpenes Initiated by C-H Bond Functionalization.

Methyl groups are ubiquitous in natural products and biologically active compounds, but methods for their selective transformation in such structures are limited. For example, terpenoids contain many methyl groups, due to their biosynthetic pathways, but few reactions of these groups in such structures have been reported. We demonstrate that the combination of methyl C-H silylation and oxidation proximal to native hydroxyl or carbonyl groups occurs in a range of terpenoids and show that the installed hydroxyl group serves as a toehold to enable substitution, elimination, or integration of the methyl carbon into the terpenoid skeleton by the cleavage of C-C bonds. In one case, substitution of the entire methyl group occurs by further oxidation and decarboxylative coupling. In a second, substitution of the methyl group with hydrogen occurs by photochemical hydrodecarboxylation or epimerization by retro-Claisen condensation. In a third, photocatalytic decarboxyolefination formally eliminates methane from the starting structure to generate a terminal olefin for further transformations. Finally, a Dowd-Beckwith-type rearrangement cleaves a nearby C-C bond and integrates the methyl group into a ring, forming derivatives with unusual and difficult-to-access expanded rings. This strategy to transform a methyl group into a synthon marks a distinct approach to restructuring the skeletons of complex architectures and adding functional groups relevant to medicinal chemistry.

Simple Modulation of thermally activated delayed fluorescent emitter by steric methyl substitution

Methyl subsitituion is considered as a simple and effetive method to finely tune the photophysical properties of thermally activated delayed fluorescent (TADF) emitters. Herein, we develop two compounds to fully showcase the impact on methyl on TADF features. MeICP with methyl exhibits favorable quasi-equatorial geometry and shorter delayed lifetime, while ICP without methyl possesses higher radative decay and photoluminescent quantum yield. Consequently, ICP-based devices show higher external quantum efficiency of 20.6 % and relieved efficiency roll-off.

Tactfully regulating the ESIPT and TICT mechanism in the AIE-active multifunctional triphenylamine Schiff-base compound (TPASB) by methyl substitution

The triphenylamine Schiff-base (TPASB) with dual proton transfer sites (N1…H1–O1 [R1] and N2…H2–O2 [R2]), which is crucial in the field of optoelectronic materials. Herein, a novel molecular design strategy for preparing of TPASB-1 and TPASB-2 via the selective methylation of the hydroxyl group at the R2 or R1 position was proposed. The analysis of electronic structures and potential energy surfaces revealed that a single excited state intramolecular proton transfer (ESIPT) process of TPASB occurs only at R1. Nevertheless, the ESIPT process of TPASB-2 was successfully turned on at R2. More noteworthy is that compared to TPASB, the methylation of hydroxyl group at the R2 position triggers the TICT process of TPASB-1, effectively reducing the potential barrier of ESIPT at the R1 position. This theoretical study explains the role of the substituent effect in regulating ESIPT behaviour, and provides valuable guidance for synthesising efficacious ESIPT-active compounds.

Synthesis and characterization of oligonucleotides containing 2′-O,4′-C-methyleneoxy-bridged 5-methyluridine with an unsubstituted bridge

In this study, a 2′-O,4′-C-methyleneoxy-bridged 5-methyluridine with three consecutive acetal groups (TaNA with a thymine base) was synthesized. The synthesized TaNA was incorporated into oligonucleotides (ONs), and their properties were compared with those of ONs containing the 7′-methylated analog (Me-TaNA) modifications previously reported by us. The duplex stability of TaNA with single-stranded RNA was comparable to that of Me-TaNA. However, the triplex stability of TaNA-modified ONs with double-stranded DNA was slightly lower than that of Me-TaNA-modified ONs. Additionally, the enzymatic stability of TaNA-modified ONs was lower than that of Me-TaNA-modified ONs. These results suggest that the 7′-methyl substitution on the TaNA structure is crucial for enhancing the properties of modified ONs.

Photophysical mechanism study of photophysical properties of new red BODIPY chromophores with or without methyl substitution

The relationship between the photophysical properties and structure of BODIPY derivatives always has attracted much attention. Two new BODIPY derivative chromophores with phenyl group substitutions at meso-/6- positions, with or without methyl substitutions at 1/3/5/7 positions were investigated by ways of combination of multiple experimental techniques and theoretical methods. The chromophore without methyl substitutions has a larger Stokes shift and better viscosity sensitivity compared to the other one. The intrinsic reason is that considerable charge transfer between the BODIPY core and the 6- position group is achieved in chromophore. However, this charge transfer process is severely weakened, if 1-/3-/5-/7- methyl substitutions existing, via restricting rotation between the core and side groups. At the same time, the non-radiative process is amplified significantly in chromophore without methyl substitution and the fluorescence efficiency decrease from 51.7% (with methyl substitutions) to 1.84% (without methyl substitutions) in DMSO. Quantum calculations indicate the presence or absence of methyl substitution can change both the shape and height of the torsional potential energy curve of the side groups, thereby affecting the fluorescence quantum yield and viscosity response performance of chromophores. Our work can provide foundation and ideas for designing and optimizing BODIPY derivatives with objective photophysical properties.

How Do the Position and Number of Methyl Substituents Affect the Photochemical Process of Criegee Intermediate? Trajectory Surface-Hopping Dynamics of Four-Carbon CIs.

Electronic-structure calculations combined with nonadiabatic trajectory surface-hopping (TSH) dynamic simulations were carried out on two alkenyl-substituted Criegee intermediates (CIs), i.e., propenyl-substituted CI (PCI) and 1-methyl-propenyl substituted CI (MPCI), in order to investigate the influence of the position and number of substituents on the photochemical process of CI in S1 states. It is found that they play critical roles in the reactivity, dominant product channel, and mechanism of the CIs. More specifically, introducing a methyl group on either C1 (α-C) or C3 (γ-C) position of a vinyl-substituted CI (VCI) skeleton facilitates the rotation of the C1═O1 bond and leads to the formation of a three-membered dioxirane ring; meanwhile, it evidently enhances the reactively of the S1-state molecule. Meanwhile, methyl substitution on the vinyl moiety [i.e., C2 (β-C) and C3 (γ-C) positions] is beneficial for the rotation of the C2═C3 bond and thus facilitates the formation of the five-membered 1,2-dioxole ring, and the substitution on C2 site decreases the reactivity. The cosubstitution of C2 and C3 atoms by methyl groups well balances the features of VCI in the sense of high reactivity, consistently predominant channel, and possible dioxole side-product. The findings here not only deepen the knowledge on the photochemical processes of the CI but also inspire the rethinking of the "old" concept of substitution effect.

Silver Complex Bearing N-Heterocyclic Carbene Bidentate Chelating Ligand as an Efficient Catalyst in Solvent-Free KA2 Coupling.

We report a synthesis of silver complexes bearing chelating bidentate N-heterocyclic carbene, with various substitutions at the terminal positions of the imidazole moiety of the NHC units. The long aliphatic substituents proved to be beneficial in terms of the synthetic efficiency of the complexes, compared to previously reported methyl substitution. The complexes demonstrated excellent suitability for the KA2 coupling reaction, providing quaternary carbon-containing propargylic amines in yields up to 95 %, under solvent-free conditions. The method showed high tolerance for a wide range of substrates, including naturally occurring ketones, underscoring its practicality. To our knowledge, this represents the first use of a well-defined silver species in KA2 coupling, marking an advancement in the field.

Mesomorphic and optical properties of azo-ester liquid crystalline reactive mesogens with enhanced thermal stability

A series of azo-ester-linked polymerizable liquid crystalline compounds M1-M3, containing lateral methyl substitution and different terminal alkoxy substituents, e.g., −OCH3, −OCH2CH3, and −OCH2CH2CH3 have successfully been synthesized and characterized. The chemical structures of the prepared compounds were confirmed by different spectroscopic techniques. Thermogravimetric analysis revealed that all the compounds exhibited excellent thermal stability and showed two-staged decomposition patterns. The optical microscopic study revealed that all compounds displayed only the nematic phase and lateral substituent played a crucial role in the formation of single mesophase. The broad X-ray scattering peaks for M1, M2, and M3 in the 2.5–5.5 nm−1 region was observed at temperatures of 154 °C, 85 °C, and 129 °C, respectively, upon cooling from the isotropic liquid, confirming the existence of nematic mesophase. The electronic spectra of M1-M3 showed two main absorption bands with λmax ranges of 263–266 and 369–377 nm. The E-Z photoisomerization study of M1-M3 showcased that the processes followed the first-order kinetic, and the isomerization rate decreased as the alkoxy chain length increased. On the contrary, the Z-E thermal isomerization rates for M1-M3 showed insignificant changes as the alkoxy chain length increased.

Optimization and Effect of Substituents on the Transformation of 3-(Substituted acetoxy)azetidin-2-ones to Chiral 3-Hydroxyazetidin-2-ones, Molecular Docking and Enantiomeric Excess Determination

Abstract: The enantioselective synthesis of chiral cis-3-hydroxyazetidin-2-ones mediated by Porcine Pancreatic Lipase (PPL) via hydrolysis of cis-3-(chloro acetoxy) azetidin-2-ones in the presence of a phosphate buffer (0.1M, pH = 7.2) in acetonitrile at a temperature range of 25-35 °C was optimized. Under the optimized reaction conditions, the influence of various electron withdrawing/donating/neutral groups on ester functionality of cis-3-(substituted acetoxy)azetidin-2- ones towards hydrolysis was extensively studied, and the bromoacetoxy, propanyloxy, and formyloxy groups provided moderate to good yields of 90%, 91%, and 81%, respectively. Moreover, the chiral cis-3-hydroxyazetidin-2-ones underwent acetylation, and their enantiomeric excess was assessed using the 1H NMR technique, employing chiral shift reagents. To gain insights into the active sites of the biocatalyst, molecular docking studies of compounds 5(a-i) with pancreatic lipase (PDB ID: 1LBS) were carried out. Additionally, the proposed interaction of substituents with the biocatalyst established the absolute stereochemistry of the target chiral cis-3-hydroxyazetidin-2-ones using Seebach's model in comparison to Jone's models.

Engineering Lipophilic Aggregation of Adapalene and Adamantane-Based Cocrystals via van der Waals Forces and Hydrogen Bonding.

Lipophilic aggregation using adamantanes is a widely exploited molecular property in medicinal and materials chemistry. Adamantanes are traditionally installed to molecular units via covalent bonds. However, the noncovalent installation of adamantanes has been relatively underexplored and presents the potential to bring properties associated with adamantanes to molecules without affecting their intrinsic properties (e.g., pharmacophores). Here, we systematically study a series of adamantanecarboxylic acids with varying substitution levels of methyl groups and their cocrystals with bipyridines. Specifically, single-crystal X-ray diffraction shows that while the directionality of single-component adamantanes is notably sensitive to changes in methyl substitution, hydrogen-bonded cocrystals with bipyridines show consistent and robust packing due to π-stacking predominance. Our observations are supported by Hirshfeld surface and energy framework analyses. The applicability of cocrystal formation of adamantanes bearing carboxylic acids was used to generate the first cocrystals of adapalene, an adamantane-bearing retinoid used for treating acne vulgaris. We envisage our study to inspire noncovalent (i.e., cocrystal) installation of adamantanes to generate lipophilic aggregation in multicomponent systems.