Isolation of a bis-iodurated tetra-THF as a trace product from the oxidation of squalene with RuO₄ and its double ring expansion to a novel bis-THF-bis-THP compound

A novel bis-iodurated polyether compound, based on an unprecedented tetra-THF backbone, has been isolated as a trace by-product of the oxidation of squalene with the catalytic system RuO?(cat.)/NaIO?. The double erythro configuration of the central portion of the molecule furnishes the first indirect support of the previously postulated pathway operating in the oxidative pentacyclization of the isoprenoid substrate. A bidirectional double oxidative bis-cyclization is invoked to explain the formation of this compound. The isolated substance was successfully subjected to a double rearrangement-ring expansion to give a novel bis-THF-bis-THP compound.     

Synthesis and characterization of a novel hydroxypropyl chitosan-graft-β-Cyclodextrin copolymer as potential drug carrier

Abstract

One of the most attractive fields in drug delivery is the design of nanoparticles that could be used to transport drugs into the target place at appropriate time. This paper describes the preparation of a novel hydroxypropyl chitosan-graft-β-cyclodextrin (HPCS-g-β-CD) copolymer using the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) promoted condensation reaction. Structural characterization was finished with FTIR and ¹H NMR spectra, which confirmed the grafting of β-cyclodextrin (β-CD) onto hydroxypropyl chitosan (HPCS). The thermal properties were studied based on DSC and TGA analyses, which revealed the fact that grafting of β-CD onto HPCS resulted in obvious enhancement of the decomposition temperature of the copolymer. Aqueous solution of HPCS-g-β-CD copolymer was stable at pH 7-8 based on the Zeta potential test. The morphological characteristics were investigated by SEM, TEM and AFM analysis, and the results indicated that this copolymer had three-dimensional structure which was suitable for loading drugs.     

Copper methanesulfonate-acetic acid as a novel catalytic system for tetrahydropyranylation of alcohols and phenols

A synergistic catalytic effect between copper methanesulfonate and acetic acid in tetrahydropyranylation of alcohols and phenol at room temperature under solvent free condition has been described. Both alcohols (primary, secondary and tertiary) and phenols reacted with 3,4-dihydro-2H-pyran smoothly to afford the corresponding tetrahydropyranyl ethers in good yields.     

Tautomerism in acyl-pyrazolones and in a novel photolysis product—importance and impact of the accurate localization of hydrogen atoms in crystal structures

Acyl-pyrazolones exist in four different tautomeric forms (two keto and two enol) in crystal structures. Routine crystal structure refinements using an independent atom model and routine isolated-molecule calculations fail in locating the mobile hydrogen atoms accurately in 22 investigated acyl-pyrazolone examples. However, a combination of both within the framework of quantum crystallography represented by the method of Hirshfeld atom refinement accurately locates the mobile hydrogen atom in a resonance-assisted hydrogen bond of title compound 3, a novel photolysis product. The impact of the hydrogen atom position on the resonance system of the non-hydrogen framework of the various tautomers is discussed, and the importance of intermolecular interactions for the positioning of the hydrogen atom is highlighted.     

Preparation of a novel cyclodextrin derivative of benzimido-β-cyclodextrin and its enantioseparation performance in HPLC

A novel cyclodextrin (CD) derivative, mono-6-deoxy-benzimide-β-CD (MB-β-CD), in which a rigid substituent was linked to the narrow edge of the CD with a flexible H(2)C-N group, was successfully synthesized through the condensation of mono-6-deoxy-6-amino-β-cyclodextrin and benzaldehyde. To evaluate its enantioseparation abilities and investigate the role of the CD substituents and linkage in chiral recognition, MB-β-CD and mono-6-deoxyphenylimine-β-CD (MP-β-CD) with a rigid linkage were compared in the separation of 36 chiral compounds in a methanol/water mobile phase. The separation results showed that most of the analytes with rigid structures afforded better enantioresolutions on the MP-β-CD (with a rigid linkage) chiral stationary phase (CSP), while better enantioseparations for analytes with flexible structures and big steric hindrance were obtained on the MB-β-CD (with a flexible linkage) CSP. The former exhibited a specificity for the analyte structures, while the latter was more adaptable. Molecular dynamics simulations were performed to further understand the discrimination process and the function of the CD side arm.     

Identification of novel oxadiazole-based benzothiazole derivatives as potent inhibitors of α-glucosidase and urease: Synthesis,in vitro bio-evaluation and their in silico molecular docking study

This research work represents a synthetic approach for the development of hybrids derivatives of oxadiazole-based benzothiazole (1–17) and diversity in derivatives was achieved using variety of aryl ring of S-substituted benzothiazole to see the effect on the biological activities. All the synthesized derivatives were evaluated for their in vitro α-glucosidase and urease inhibitory potential. The α-glucosidase and urease inhibition profile of the new derivatives represents moderate to good inhibitory potential with IC₅₀ values ranging from 4.60 ± 1.20 µM to 48.40 ± 7.70 µM (α-glucosidase) and 8.90 ± 2.80 to 57.30 ± 7.70 µM (urease) respectively. The results were compared to standard acarbose (38.60 ± 4.50 µM) and thiourea (58.70 ± 6.80 µM) drugs respectively. Among the synthesized series, the analogs 1 having IC₅₀ values of and 4.60 ± 1.20 (α-glucosidase), 8.90 ± 2.80 (urease) and 2 with IC₅₀ values of 5.60 ± 1.60 (α-glucosidase) and 10.90 ± 2.10(urease) were found to be significantly active against targeted α-glucosidase and urease enzymes. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, ¹H- and ¹³C- NMR spectroscopy. The molecular docking studies of the synthesized derivatives showed good correlations with the experimental findings. The binding modes of active compounds and their interactions with active site residues revealed them as possible anti-diabetics and anti-urease leads. The degree of activity and docking studies displayed by the novel innovative structural hybrids of oxadiazole-based benzothiazole moieties make these compounds new active leads and promising candidates for the development of anti-diabetics and anti-urease agents.     

Use of novel cardanol-porphyrin hybrids and their TiO₂-based composites for the photodegradation of 4-nitrophenol in water

Cardanol, a well known hazardous byproduct of the cashew industry, has been used as starting material for the synthesis of useful differently substituted "cardanol-based" porphyrins and their zinc(II), copper(II), cobalt(II) and Fe(III) complexes. Novel composites prepared by impregnation of polycrystalline TiO? powder with an opportune amount of "cardanol-based" porphyrins, which act as sensitizers for the improvement of the photo-catalytic activity of the bare TiO?, have been used in the photodegradation in water of 4-nitrophenol (4-NP), which is a toxic and bio-refractory pollutant, dangerous for ecosystems and human health.     

Tomocomd-Cardd, a novel approach for computer-aided ‘ rational’ drug design: I. Theoretical and experimental assessment of a promising method for computational screening and in silico design of new anthelmintic compounds

Summary In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silicoscreening and several compounds from the Merck Index, Negwers handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (G-1) by an in vivo test coincides fairly well (100) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.     

Synthesis of a polymer-capped palladium nanoparticles and its application as a reusable catalyst in oxidative coupling reaction of α-hydroxyketones and 1,2-diamines for preparation of pyrazines and quinoxalines

A novel method for the synthesis of pyrazines and quinoxalines has been developed using α-hydroxyketones and 1,2-diamines in the presence of cross-linked poly(4-vinylpyridine)-stabilized Pd(0) nanoparticles, [P4-VP]-PdNPs. The catalyst was easily prepared and characterized using various techniques such as FT-IR and UV–Vis spectroscopy, AAS, TEM, FESEM, EDX analysis and XRD. The results confirm a good dispersion of palladium nanoparticles on the polymer support. The catalyst displayed good catalytic activity when applied to the synthesis of quinoxalines via condensation of α-hydroxyketones with 1,2-diamines. A few pyrazine derivatives and various quinoxalines are prepared via coupling reaction of α-hydroxyketones and 1,2-diamines in high–excellent yields (81–99%) with short reaction times. The quinoxalines products were characterized by FT-IR, ¹H and ¹³C NMR spectroscopy, and the physical properties were compared to the literature values of known compounds. The advantages of the present method over conventional classical methods are rapid and very simple work-up, and the catalyst is reusable many times without a significant loss in its activity.     

Synthesis,crystal structure of a novel tetranuclear Cu (Ⅱ) complex and its application in GSH-triggered generation of reactive oxygen species for chemodynamic therapy

A novel tetranuclear copper complex (TCC) has been successfully synthesized and characterized using high resolution mass spectrometry (HRMS), Fourier transform infrared spectroscopy (FTIR) and X-ray single crystal diffraction technique. TCC was capable of triggering by Glutathione (GSH) to produce Cu (Ⅰ), then the resulted Cu (Ⅰ) further converted the overexpression of endogenous H₂O₂ into •OH, a highly cytotoxic reactive oxygen species (ROS), thereby killing the cancer cells. TCC showed high cytotoxicity to 4T1, MCF7, HepG2 cancer cells. Interestingly, the cytotoxicity of TCC to non-cancerous cells is much lower than that of cancer cells. Cell cycle experiments demonstrated that TCC was capable of arresting the cancer cell cycle in the G2/M phase. The apoptosis experiments shown that TCC could induce apoptosis rather than necrosis.     

Determination of comprehensive in silico determinants as a strategy for identification of novel PI3Kα inhibitors

Structural Chemistry - The PI3KCA gene functions by activating cascade signaling pathways leading to cell proliferation, survival, and growth. Being one of the frequently aberrant kinase in various...     

Synthesis and characterization of a novel organic–inorganic hybrid supramolecular recognition material and its selective adsorption for cesium

To separate Cs(I) from highly active liquid waste, a macroporous silica-based 25, 27-bis(iso-propyloxy)calix[4]arene-26,28-crown-6 (BiPCalix[4]C6) supramolecular recognition material, BiPCalix[4]C6/SiO₂–P, was synthesized and characterized by SEM, FT-IR, and TG-DSC. The adsorption properties of BiPCalix[4]C6/SiO₂–P and a macroporous polymer-based supramolecular recognition composite, BiPCalix[4]C6/XAD-7, were compared. It was found that BiPCalix[4]C6/SiO₂–P exhibited better adsorption ability and faster adsorption dynamics than BiPCalix[4]C6/XAD-7. The adsorption isotherm of Cs(I) onto BiPCalix[4]C6/SiO₂–P was studied at 298 K and it was well described by Langmuir isotherm model. The complex composition between BiPCalix[4]C6/SiO₂–P and Cs(I) was determined as 1:1 type by investigating the effect of the concentrations of BiPCalix[4]C6, Cs(I), and H⁺ on the adsorption. Meanwhile, the selectivity of BiPCalix[4]C6/SiO₂–P towards Na(I), K(I), Rb(I), Cs(I), Sr(II), Ba(II), Ru(III), Mo(VI), La(III), and Y(III) was investigated.     

Synthesis and characterization of a colloidal novel folic acid?C??-cyclodextrin conjugate for targeted drug delivery

A novel folic acid?C??-cyclodextrin (??-CD) conjugate was synthesized and preliminarily characterized by ¹H NMR, ESI-MS, and MALDI-MS. ¹H NMR shows the presence of ??- and ??-conjugates which are generated by ??-CD linkage in turn with both carboxylic functions of folic acid. Moreover ROESY evidences supramolecular interactions between the benzene ring of the folic acid and the ??-CD cavity. DOSY suggests that ethylenediamine derived ??-CD?Cfolic acid forms a colloidal dispersion difficult to purify from free folic acid. An analysis of self-diffusion coefficient (D_s) of the three species (??-, ??-conjugates, and free folic acid) and relaxation times (T₁ and T₂) is reported to tentatively explain the colloidal behaviour of the new species in an aqueous solution.     

Synthesis and characterization of a novel Fe3O4@SiO2/bipyridinium dichloride nanocomposite and its application as a magnetic and recyclable phase-transfer catalyst in the preparation of β-azidoalcohols, β-cyanohydrins,and β-acetoxy alcohols

β-Azidoalcohols, β-cyanohydrins, and β-acetoxy alcohols have been synthesized in the presence of a Fe₃O₄@SiO₂/bipyridinium nanocomposite (Fe₃O₄@SiO₂/BNC) as a novel magnetic and recyclable phase-transfer catalyst (PTC) in water. The catalyst was characterized with FT–IR, SEM, XRD, VSM, and TGA. This methodology offers several advantages, including easy work-up procedure, excellent regioselectivity, high yields, short reaction times, recyclable catalyst, easy separation of the catalyst through an external magnet and eco-friendly procedure.     

Development of a novel quality by design–enabled stability-indicating HPLC method and its validation for the quantification of nirmatrelvir in bulk and pharmaceutical dosage forms

A systematic and novel quality by design–enabled, rapid, simple, and economic stability–indicating HPLC method for quantifying nirmatrelvir (NMT) was successfully developed and validated. An analytical target profile (ATP) was established, and critical analytical attributes (CAAs) were allocated to meet the ATP requirements. The method used chromatographic separation using a Purosphere column with a 4.6 mm inner diameter × 250 mm (2.5 μm). The analysis occurred at 50°C with a flow rate of 1.2 mL/min and detection at 220 nm. A 10 μL sample was injected, and the mobile phase consisted of two components: mobile phase A, containing 0.1% formic acid in water (20%), and mobile phase B, containing 0.1% formic acid in acetonitrile (80%). The diluent was prepared by mixing acetonitrile and water at a 90:10 v/v ratio. The retention time for the analyte was determined to be 2.78 min. Accuracy exceeded 99%, and the correlation coefficient was greater than 0.999. The validated HPLC method was characterized as precise, accurate, and robust. Significantly, NMT was found to be susceptible to alkaline, acidic, and peroxide conditions during forced degradation testing. The stability-indicating method developed effectively separated the degradation products formed during stress testing, underlining its effectiveness in stability testing and offering accuracy, reliability, and sensitivity in determining NMT.     

Formulation and preclinical evaluation of 99mTc–gemcitabine as a novel radiopharmaceutical for solid tumor imaging

The aim of this study is the formulation of a new radiopharmaceutical for imaging solid tumor bearing. Gemcitabine is a nucleoside analogue used as chemotherapeutic agent. Gemcitabine was formulated and radiolabeled with one of the most important diagnostic radioactive isotopes (technetium-99m) to be investigated in solid tumor imaging. The labeling parameters such as gemcitabine amount, stannous chloride amount, pH of the reaction mixture, and reaction time were optimized. ^99mTc–gemcitabine was prepared at pH 9 with a maximum labeling yield of 96 ± 0.3 % without any notable decomposition at room temperature over a period of 8 h. The preclinical evaluation and biodistribution in solid tumor bearing mice showed that ^99mTc–gemcitabine had solid tumor selectivity, preclinical high biological accumulation in tumor cells and high retention. Tumor/normal muscle (T/NT) ratios increased with time showing high T/NT ratio (T/NT = 4.9 ± 0.27 at 120 min post injection) and high Tumor/Blood ratio (3.4 ± 0.06), suggesting ^99mTc–gemcitabine as a novel solid tumor imaging agent.     

Reaction of zirconocene dichloride with alkyllithiums or alkyl grignard reagents as a convenient method for generating a “zirconocene” equivalant and its use in zirconium-promoted cyclization of alkenes,alkynes, dienes,enynes, and diynes

Treatment of Cl₂ZrCp₂ with 2 equiv of alkylmetals (RM) containing Li or Mg, e.g., n-BuLi, in THF produces organozirconium species that act as sources of “ZrCp₂,” the latter product being a convenient reagent for preparing zirconacycles.     

Hyphenation of reverse-phase HPLC and ICP-MS for metabolite profiling—application to a novel antituberculosis compound as a case study

In this study, a high-performance liquid chromatography (HPLC) inductively coupled plasma (ICP) mass spectrometry (MS) method was developed intended for use in metabolism studies of bromine-containing drugs, administered to test animals (or test persons). As a case study, the method was applied to a new antituberculosis compound, the bromine-containing diarylquinoline R207910. A method has been proposed to overcome the incompatibilities between the high organic solvent content (45%CH₃OH and 45% CH₃CN) used in the reverse-phase liquid chromatography (LC) separation on one hand and the limitations of the ICP on the other hand. Therefore, several instrument modifications had to be made. For the introduction of the column effluent, a combination of a perfluoroalkoxy LC nebulizer with a PC³ Peltier-cooled inlet system (operated at 2 °C) was used. Additionally, the standard injector tube (internal diameter 2 mm) was replaced by an injector tube with an internal diameter of 1 mm and to avoid carbon build-up on the interface cones and the torch, the nebulizer gas was admixed with 6% v/v of oxygen. After optimization of the method, HPLC-ICP-MS was applied for metabolite profiling of faeces samples after dosing of ¹⁴C-radiolabelled R207910 to dogs and rats. To evaluate the method developed, the HPLC-ICP-MS results were compared with those of HPLC with UV spectrophotometric and ¹⁴C radiochemical detection. As the HPLC-ICP-MS method gave rise to a higher selectivity than HPLC with UV detection and to a better detection limit (5 ng R207910) than the method with radiochemical detection (65 ng R207910), it can be concluded that ICP-MS can be used as a good alternative to the more traditional detection methods, even when a mobile phase with high organic solvent content has to be used in the LC separation.     

Design and efficient synthesis of novel haptens and complete antigens for the AOZ, a toxic metabolite of furazolidone

A good strategy was brought forward for designing efficient haptens and complete antigens for 3-amino-2-oxazolidinone (AOZ). Haptens designed newly were achieved facilely in good yield by using LiCI-N(Et)_3 as new catalysis system,the structure of which was elucidated by spectroscopy analysis,such as NMR and MS.Novel antigens for AOZ were prepared successfully by convenient active ester method.The ratios of haptens 3 and 4 to carrier proteins were proven respectively as 41:1(5a),39:1(6a),11:1(5b) and 9:1(6b) by trinitrobenzene sulfonic acid(TNBS) method.The results of indirect competitive ELISA (ic-ELISA) of antiserums indicated that the haptens with a short unsaturated side chain can evoke specific immune response effectively.