BMC Chemistry最新文献

Bruton’s tyrosine kinase (BTK) inhibitors play a critical role in the treatment of mantle cell lymphoma (MCL). pirtobrutinib, a new, highly selective, non-covalent BTK inhibitor, was approved by the FDA for the treatment of MCL, chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL). In this study, we established a robust and reliable method for the quantitation of pirtobrutinib in rat plasma using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Acetonitrile and 0.1% formic acid served as the mobile phase, with zanubrutinib as the internal standard (IS). Detection ion transitions were m/z 480.12→294.05 for pirtobrutinib and m/z 472.20→ 289.96 for Zanubrutinib. The intra‐day and inter‐day relative standard deviation (RSD%) values of pirtobrutinib were less than 9.8% and 10.3%, respectively. Recovery and matrix effects ranged from 95.1 to 101.5% and 91.7-100.4%. In addition, the test sample stability was confirmed under various storage conditions, and this method was successfully applied to a pharmacokinetic study of pirtobrutinib at a dose of 10 mg·kg^− 1.

To elucidate the mechanism by which choline-based ionic liquids potentially can enhance the sugar conversion to bioethanol, this work was conducted to study the thermodynamic behavior of D( +)-glucose in aqueous solutions of choline-based ionic liquids, choline salicylate [Ch][Sal], choline formate [Ch][For], and choline acetate [Ch][Ace]. This study involved measuring density, speed of sound, viscosity, and electrical conductivity at various concentrations and temperatures. Analysis of the calculated parameters, including apparent molar volume, V_φ, apparent molar isentropic compressibility (κ_φ), viscosity B-coefficient, and molar conductivity (Λ) values provide deep insights into intermolecular interactions between the components of the solutions studied. The standard partial molar volume values ((V_{varphi }^{0})) of D( +)-glucose, show stronger interactions between D( +)-glucose and the [Ch][Sal]. The computed transfer volume values ((Delta_{tr} V_{varphi }^{0})), with the help of co-sphere overlap model confirm intensified hydrophilic-hydrophilic interactions in [Ch][Sal] [(1.99 to 2.08) cm³·mol⁻¹] solutions. Hepler's constants suggest that D( +)-glucose acts as a structure-maker in the presence of choline-based ILs, especially in [Ch][Sal] solutions. Also, the DFT-COSMO calculations result in [Ch][Sal] the most favorable interactions among the other choline based ILs. Apparent specific volume (ASV), and apparent specific isentropic compressibility, (ASIC), values revealed that D( +)-glucose exhibits the taste behavior with [Ch][Sal]. The hydration number of D( +)-glucose diminishes as the temperature rises due to weakened hydrogen bonds between D( +)-glucose and water molecules. These findings suggest that [Ch][Sal] could be a promising candidate for accelerating sugar conversion to bioethanol.

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A successful methodology for the copper-catalyzed dehydrogenated methylsulfonylation of alkenes utilizing CH₃SSO₃Na in conjunction with hypervalent iodine reagents was successfully established. This method offers a practical avenue to obtain allyl methyl sulfones and alkenyl methyl sulfones by forming C-S bonds. Using the C-H bond oxidation sulfonylation strategy with alkenes and Bunte salts, we successfully synthesized a total of twenty two compounds, including four examples of deuterium-substituted molecules, and demonstrated one example of a scale-up reaction.

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A new series of 1-substiuted-5,6-dichloro-2-(4-methoxyphenyl)-1H-benzo[d]imidazoles 10a–p was designed and synthesized to target both BRAF_WT and BRAF_V600E. The design strategy ensures that these derivatives would effectively occupy the ATP binding pocket of BRAF_WT/V600E kinase domains and extend over the gate area interacting through hydrogen bonding with the surrounding key amino acids Glu500 and Asp593 and to finally occupy the allosteric hydrophobic back pocket. Some synthesized derivatives demonstrated impressive potency against BRAF_WT with % inhibition approaching 91% at a concentration of 10 µM. The most potent candidate 10h demonstrated IC₅₀ values of 1.72 and 2.76 µM on BRAF_WT and BRAF_V600E, respectively. At the same time, the synthesized benzimidazoles 10a–p were examined for their growth inhibitory activity on NCI-60 cancer cell lines. Again, compound 10h revealed a potent GI₅₀ across a range of cancer cell lines. Moreover, it arrested cell cycle progression in HT29 colon cancer cell line at G2/M phase and induced apoptosis in the same cell line. Molecular dynamics simulations supported the validity of the design assumption, simultaneously, ADME prediction study displayed that the designed benzimidazoles exhibit promising physiochemical and drug-likeness properties as anticancer agents.

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Large volume bone defects that do not spontaneously heal despite surgical stabilization (“critical-sized” defects) remain a challenge to treat clinically. Recent research investigating bone regenerative implants made from 3D printed materials have shown promise as a potential alternative to current treatment methods, such as autografting, allografting, and multi-step surgical interventions. Recent work has shown that implanting 3D printed calcium phosphate cement (CPC) scaffolds loaded with bone morphogenetic protein-2 (BMP-2) can provide a one-step surgical intervention that has similar bone healing outcomes to a popular two-step intervention: the Masquelet technique. The aim of this study was to investigate whether a 3D printed CPC scaffold loaded with a lyophilized polyplex gene-delivery formulation could serve as an alternative to loading BMP-2 protein onto such scaffolds. We 3D printed CPC scaffolds, hardened them with multiple methods, and explored the impact of these hardening methods on surface texture, mechanical strength, osteogenic differentiation, and ion flux. We then gene-activated these materials with cationic polyplexes containing plasmid DNA encoding reporter genes to investigate transfection from the gene-activated scaffolds. We found that incubating CPC scaffolds in aqueous solutions after initial hardening in a humid environment could enhance scaffold mechanical strength (compressive strength of 21.28 MPa vs. 6.54 MPa) and osteogenic differentiation. We also found that when we increased the total surface area of the CPC material exposed to polyplex solutions, there was a reduction in transfection via adsorption of polyplexes to the CPC surface. This study shows that 3D printed, gene-activated CPC scaffolds are a promising avenue for future exploration in the field of bone regeneration, though the level of gene expression induced by the scaffolds must be improved.

In this study, new tetrahydroisoquinoline compounds were synthesized by reaction of 7-Acetyl-4-cyano-1,6-dimethyl-6-hydroxy-8- (3-nitrophenyl or 4-nitrophenyl)-5,6,7,8-tetrahydrosoquinoline-3(2H)-thiones with methyl iodide, chloro acetonitrile, ethyl chloroacetate to produce compounds 3–5 and reacted with N-arylchloroacetamides reagents to gave tetrahydroisoquinolin-3-ylthio) acetamides compounds 6a–c, 8a–b which can cyclized to 6,7,8,9-tetrahydrothieno[2,3-c]Isoquinoline-2-carboxamides compounds 7a–c, 9a–b. Also react with N-(benzthiazol-2-yl)-2-chloroacetamideto give compound 10. The structures of all newly synthesized compounds were characterized by elemental and spectral analyses. Also, most of the synthesized compounds were evaluated for their anticancer activities aganist MCF7 and HEPG2 cell lines. From the result we found that the most active compound against the MCF7 cell lines was compound 8b, and the most active compound against HEPG2 cell lines was compound 3. Then the effects of compound 3 on the HEPG2 cell line was investigated using an apoptotic Annexin V-FITC test and flow cytometry. Compound 3 induced a 59-fold increase in HEPG2 cell line apoptosis and cell cycle arrested at the G0-G1, G2/M phases. Moreover, the molecular docking study was applied and the result showed that compounds 8b bind to the RET enzyme with binding energies of − 6.8 kcal/mol in comparison with standard alectinib, which exhibits a binding energy of − 7.2 kcal/mol. Compound 3 can bind with HSP 90 with a binding energy (ΔG) of − 6.8 kcal/mol, which was comparable to the standard Onalespib (− 7.1 kcal/mol).

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A significant variable in the genesis of peptic ulcers is Helicobacter pylori, which could be eliminated through several strategies. Amid them, there is a strategy based on receptor histamine-2 (e.g., famotidine) antagonist in conjunction with metronidazole and amoxicillin as antibiotics. This research used UV spectrophotometry paired with chemometrics to clarify the concurrent analysis of famotidine (FAM), amoxicillin (AMX) and metronidazole (MET) in bulk powder and mixed tablet formulations. The first derivative was calculated for determining FAM and MET. Nonetheless, the methods of double divisor ratio spectra and Fourier functions were incorporated for determining each of the three medications. The methods linearity was fine in the strength ranges of 3–20 µg mL⁻¹ (FAM), 12–40 µg mL⁻¹ (AMX) and 4 -20 µg mL⁻¹ (MET), as shown by the correlation coefficient (0.9999). Analyzing the triple therapy of FAM, AMX and MET helped in the determination of the techniques' accuracy and precision which were done for both their synthetic and combined tablet mixture solutions, as well as in their combined tablet mixture solutions in simulated stomach fluid. Adopting UV spectrophotometry was advantageous over HPLC and HPTLC techniques for FAM, AMX and MET simultaneous determination. This can be attributed to better cost and time efficiency, lack of sophistication, less amounts of reagents and wastes and therefore better greenness when talking about UV spectrophotometry. Upon co-formulation of FAM, AMX and MET triple therapy, their routine analysis could benefit from the presented methodologies in quality control labs. Green Analytical Chemistry (GAC) as well as White Analytical Chemistry (WAC) were both employed for assessing the UV spectrophotometric methods that were described with an emphasis on the cost-effectiveness and environmental friendliness of the suggested techniques. Moreover, the method was practically appraised employing Blue Applicability Grade Index (BAGI).

Thermally active delayed fluorescence (TADF) of experimentally synthesized anthracene derivatives is studied. The studied compounds are named as 9-cyano-10-diphenylamino-anthracene (Cy-Anth-1), 9-(N-carbazolyl)-10-cyanoanthracene (Cy-Anth-2), 10-(benzofuro[2,3-b] pyridin-6-yl)-N, N-diphenylanthracen-9-amine (Benzo4-Anth-1), 6-(10-(9H-carbazol-9-yl) anthracen-9-yl) benzofuro[2,3-b] pyridine (Benzo4-Anth-2). Chemical characterization and the structure-TADF relationship were determined using the DFT and TD-DFT techniques. The analysis of frontier molecular orbitals and molecular electrostatic potential indicated that the Benzo4-Anth-1 derivative is a good candidate for TADF due to its spatially separated donor and acceptor groups. The energy gap ΔE (S₁-T₂) of Cy-Anth-1, Cy-Anth-2, Benzo4-Anth-1, and Benzo4-Anth-2 is 0.0057, -0.026, 0.0528, and -0.0635 eV, respectively. While ΔE (T₂-T₁) for Cy-Anth-1, Cy-Anth-2, Benzo4-Anth-1, and Benzo4-Anth-2 is 0.759, 0.790, 1.019, and 0.926 eV, respectively. Donor (D = (N, N-diphenyl)) and acceptor (A = (10-(benzofuro[2,3-b] pyridin-6-yl)) in D-π-A system enhances the ΔE (S₁-S₀) up to 2.837 eV and decreases ΔE (S₁-T₂) to -0.0635 eV by making it good TADF material. Thermodynamic investigation revealed that the rise in temperature from 50–500 K, CV, CP, internal energy (U), enthalpy (H), entropy (S), and ln (Q) increases, but Gibbs free energy (G) decreases.

Recently, microencapsulation has developed in various industries with its versatile applications. Its profound impact is particularly notable in the chemical, food, and pharmaceutical sectors. Among its research areas, the microencapsulation of drugs using phase change materials (PCMs) stands out as a groundbreaking advancement in drug delivery systems. This innovative approach involves encasing drugs within a PCM shell, significantly enhancing their stability and delivery regulation. The focus of our study is the microencapsulation of certain drugs with poor water solubility namely, cyclosporine, baclofen, and biotin within a bio-based PCM. It has identified PCMs with phase transition temperatures near human body temperature ( 310 K) as ideal candidates for this purpose. A eutectic mixture of stearic-lauric acid in a 1:3 mole ratio was selected for its optimal phase change properties to create microcapsules with core–shell morphology in spherical form. Our comprehensive characterization of the microcapsules, validated by FT-IR and SEM techniques, confirms their proper formation. All studied drugs microencapsulated with the PCM exhibited an excellent thermal stability at working temperature from thermal stability analysis based on TGA results. Furthermore, differential scanning calorimetry (DSC) tests conducted on the microencapsulated drugs obtained the melting point of all three microencapsulated drugs near the melting point of PCM. Also, the release behavior of drugs from drug delivery method was investigated in PBS (pH 7.4) and two temperatures (310.15 and 318.15) K. Drug release occurred sustainably, such that 50% and about 60% of the total of each drug was released from the microcapsules at mentioned temperatures respectively during 24 h.

The developed method for simultaneous detection of levodopa and carbidopa was able to separate the peaks of the drug and sodium bisulfite in the in-vitro release samples and stability samples. Levodopa (LD), a pro-drug of dopamine, is used as the gold standard treatment for Parkinson’s disease. It is usually prescribed with carbidopa (CD) to prevent the conversion of levodopa to dopamine peripherally, thus reducing undesirable side effects. Both drugs are unstable at pH 7.4 beyond 24 h due to their oxidation, therefore 0.2% sodium bisulfite is added to the formulation as an antioxidant. The separation was performed by gradient elution using the Luna-C18 column (250 × 4.6 mm, 5 µm) at a flow rate of 1 ml/min. The mobile phase was composed of mobile phase A 30 mM potassium phosphate and acetonitrile (95:5, v/v) with 35 mM tetrabutylammonium hydrogen sulphate and mobile phase B containing 30 mM potassium phosphate and acetonitrile (50:50 v/v). Drug peaks were detected at 280 nm with retention times of 3.05 ± 0.001 min for LD and 3.64 ± 0.001 min for CD. The validation of the method according to US FDA guidelines and results were found to be within acceptable limits. The method was linear from 10–100 µg/ml (r² = 0.999) and 10–100 µg/ml (r² = 0.999) for LD and CD, respectively. The developed method was applied to studying the drug release from in-situ gel. The environmental impact of the developed method was evaluated using various greenness assessment tools.

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