Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CL^pro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CL^pro. Among them, the representative compound 7a displayed inhibitory activity with an IC₅₀ of 1.28 ± 0.17 μM against SARS-CoV-2 3CL^pro. Molecular docking of 7a against 3CL^pro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CL^pro.     

Synthesis and characterization of the B3-monomer and hyperbranched poly(aryl ether ketone)s

Hyperbranched poly(aryl ether ketone)s were prepared by polymerization of hydroquinone (A₂) and 1,3,5-tris[4-(4-fluorobenzoyl)phenoxy]benzene (B₃). The gelation of hyperbranched poly(aryl ether ketone)s was effectively avoided. Hydroxyl-term inated (HPAEK-OH) and fluoro-terminated (HPAEK-F) hyperbranched poly(aryl ether ketone)s were prepared by using different A₂/B₃ mass ratio. The structure of the B₃ monomer was confirmed by MS, ¹H NMR/IR. The glass transition temperatures of the HPAEK-F and HPAEK-OH are 114°C and 162°C respectively. Thermal stability of HPAEK-F is higher than HPAEK-OH. __________ Translated from Acta Scientianum Naturalium Universitatis Jilinensis, 2005, 5 (in Chinese)     

Synthesis and biological evaluation of novel 2,4,5-triaryl-1 H-pyrazol-3（2H）-ones as inhibitors of ALK5

A series of 2,4,5-triaryl substituted 1H-pyrazol-3（2H）-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1μmol/L and displayed no significant cytotoxicities at 30μmol/L.     

One-step method for synthesis of 2,4-disubstituted quinazoline 3-oxides by reaction of a 2-aminoaryl ketone with a hydroxamic acid using Zn(OTf)2 as the catalyst

A simple and efficient method for the preparation of 2,4-disubstituted quinazoline 3-oxides by reaction of a hydroxamic acid with 2-aminoaryl ketones using zinc(II) triflate as the catalyst is described.     

Four-component synthesis of ferrocene-containing 1,3,4-oxadiazoles from N-isocyaniminotriphenylphosphorane (Ph3PNNC), a primary amine,a cyclic ketone and ferrocene carboxylic acid

The 1:1 imine intermediate created by the addition of a primary amine to a cyclic ketone is trapped by N-isocyaniminotriphenylphosphorane (Ph₃PNNC) in the presence of ferrocene carboxylic acid and the corresponding iminophosphorane intermediate was formed. Afterwards, ferrocene containing 1,3,4-oxadiazole derivatives are formed via intramolecular aza-Wittig reaction of the iminophosphorane intermediate. The reaction proceeded under mild conditions at room temperature.     

Synthesis and biological evaluation of novel 2,4,5-triaryl-1 H-pyrazol-3(2H)-ones as inhibitors of ALK5

A series of 2,4,5-triaryl substituted 1H-pyrazol-3(2H)-ones,as ALK5 inhibitors,were desigened,synthesized and evaluated in vitro.Most compounds exhibited noticeable ALK5 inhibition activities at 1 μmol/L and displayed no significant cytotoxicities at 30 μmol/L.     

Use of 3-(4-hydroxyphenyl)propionic acid as electron donating compound in a potentiometric aflatoxin M1-immunosensor

We developed a potentiometric aflatoxin M₁-immunosensor which utilizes 3-(4-hydroxyphenyl)propionic acid (p-HPPA) as electron donating compound for horseradish peroxidase (HRP; EC 1.11.1.7). The assay system consists of a polypyrrole-surface-working electrode coated with a polyclonal anti-M₁ antibody (pAb-AFM₁), a Ag/AgCl reference electrode and a HRP-aflatoxin B₁ conjugate (HRP-AFB₁ conjugate).To optimize the potentiometric measuring system p-HPPA as well as related compounds serving as electron donating compounds were compared. Also the influence of different buffer systems, varying pH and substrate concentrations on signal intensity was investigated. Our results suggest that reaction conditions that favor the formation of Pummerer's type ketones lead to an increase in signal intensity rather than formation of fluorescent dye. Comparison with commercial ready-to-use HRP electron donating compounds such as 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), o-phenylenediamine (OPD) or 3,3′,5,5′-tetramethylbenzidine (TMB) showed that only 34%, 77% and 49% of the signal intensity of p-HPPA were reached, respectively.The optimized assay had a detection limit of 40 pg mL⁻¹ and allowed detection of 500 pg mL⁻¹ (FDA action limit) aflatoxin M₁ (AFM₁) in pasteurized milk and UHT-milk containing 0.3-3.8% fat within 10 min without any sample treatment. The working range was between 250 and 2000 pg mL⁻¹ AFM₁.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

Synthesis and characterization of some novel cadmium(II) complexes with 3-hydroxypicolinic acid (3-OHpicH): Crystal and molecular structures of [CdI(3-OHpic)(3-OHpicH)(H2O)]2, [Cd(3-OHpic)2(H2O)2] and [Cd(3-OHpic)2]n

Cadmium(II) complexes of 3-hydroxypicolinic acid, namely [CdI(3-OHpic)(3-OHpicH)(H₂O)]₂ (1), [Cd(3-OHpic)₂(H₂O)₂] (2) and [Cd(3-OHpic)₂]_n (3) were prepared and characterized by spectroscopic methods (IR, NMR) and their molecular and crystal structures were determined by X-ray crystal structure analysis. Complexes 1 and 2 were prepared in similar reaction conditions using different cadmium(II) salts: cadmium(II) iodide and cadmium(II) acetate dihydrate, respectively, while 3 was prepared by recrystallization of 2 from N,N-dimethylformamide solution. Various coordination modes of 3-OHpicH in 1–3 were established in the solid state: bidentate N,O-chelated mode in 1 and 2, monodentate mode through the carboxylate O atom from zwitterionic ligand in 1 and bidentate N,O-chelated and bridging mode in 3. In the DMF solution of all prepared complexes, only monodentate mode of 3-OHpicH binding to cadmium(II) through the carboxylate O atom was established by ¹H, ¹³C, ¹⁵N and ¹¹³Cd NMR spectroscopy.     

Synthesis and crystal structure of a pyrazole derivative of artemisia ketone

The oxime of artemisia ketone is smoothly converted to the pyrazole derivative by sodium nitrite and acetic acid in CHCl₃. The structure of the pyrazole was found by x-ray structural analysis. The PMR and¹³C NMR spectra were interpreted using two-dimensional¹H–¹³C NMR (COSY, COLOC).Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 121–123, March–April, 2000.     

Spin-spin coupling constant 3JH,F of the 1,1,2,2-tetrafluoroethyl group as a useful tool for recognition of regioisomeric and tautomeric pairs of organofluoric compounds

The spin-spin coupling constant ³ J _H,F of the H(CF₂)₂ group varies within 1.6—6.5 Hz (in CDCl₃) depending on the structure of the molecular fragment, which is linked with the group, and can be used for the recognition of regioisomeric and tautomeric pairs of organofluoric compounds.     

N-Chlorophthalimide as a mild and efficient chlorination reagent in the Gassman ortho alkylation of aromatic amines. Synthesis of 3-(methylthio)oxindoles

A practical modification of the Gassman 3-(methylthio)oxindole synthesis is reported. In our method, substituted anilines and 2-(methylthio)acetamide were reacted under mild reaction conditions, in the presence of N-chlorophthalimide as a chlorinating agent to give α-amidosulfides, which, in the next step of the process, were cyclized to give 3-(methylthio)oxindoles. The method was successfully applied for the synthesis of the key intermediate, 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide, in the process of the preparation of nepafenac, a commonly used ophthalmic drug.     

Synthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[¹⁸F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([¹⁸F]F-γ-T-3) was prepared for this purpose. [¹⁸F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [¹⁸F]fluoride in DMF/K₂₂₂. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [¹⁸F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [¹⁸F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [¹⁸F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.     

Synthesis of 1-O-R-5-deoxy-β-D-ribofuranosides with (CH3)2As and (CH3)2AsO as substituents at the 5-position and a methyl or 2′,3′-dihydroxypropyl group as the aglycone in the 1-position

Six arsenic-containing β-D -ribofuranosides, including the naturally occurring (2′R)-dimethyl[1-O-(2′,3′-dihydroxypropyl)-5-deoxy-β-D -ribofuranos-5-yl]arsine oxide, were prepared in multi-step reactions from D -ribose and tetramethyldiarsine. The synthetic procedure uses the early substitution of the hydroxy group with bromine at C5, subsequent attachment of a chiral three-carbon aglycone at C1, and final delivery of arsenic at C5. The synthesis provides a viable route for the preparation of multigram quantities of the natural product.     

Synthesis, crystal structure and thermochemical behaviour of a barium complex [Ba(5-OH-BDC)(H2O)3] [5-OH-H2BDC = 5-hydroxyisophtalic acid]

A novel complex [Ba(5-OH-BDC)(H₂O)₃] [5-OH-H₂BDC = 5-hydroxyisophtalic acid] was synthesized and characterized by X-ray crystallography. The complex is Monoclinic P2₁/c, a = 11.1069(4), b = 14.8192(6), c = 6.5005(2) Å, β = 103.465(3)° and Z = 4, which exhibits a three-dimensional framework formed by linkage of adjacent two-dimensional (6, 3) layers via intermolecular hydrogen bonds. The title complex has been studied by IR spectrum and TG-DTG. The constant-volume combustion energy of the complex, Δ_cU, was determined as being (−3210.45 ± 1.41) kJ mol⁻¹ by a precise rotating-bomb calorimeter at 298.15 K. The standard enthalpy of combustion, , and the standard enthalpy of formation, , were calculated as being (−3207.97 ± 1.41) and (−1922.80 ± 1.76) kJ mol⁻¹, respectively. A calculation model for determining the specific heat capacity of the complex with an improved RD496-III microcalorimeter is also derived. The specific heat capacity of the complex was (6158.387 ± 0.187) J mol⁻¹ K⁻¹.     

Pheromone synthesis. Part 244: Synthesis of the racemate and enantiomers of (11Z,19Z)-CH503 (3-acetoxy-11,19-octacosadien-1-ol), a new sex pheromone of male Drosophila melanogaster to show its (S)-isomer and racemate as bioactive

The enantiomers of (11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol were synthesized from the enantiomers of 3,4-epoxy-1-butanol PMB ether. Its racemate was also synthesized. Its (S)-isomer and racemate were shown to possess the same pheromone activity as CH503, a long-lived inhibitor of male courtship in Drosophila melanogaster, although the racemate was less active.     

Biosensors and rapid diagnostic tests on the frontier between analytical and clinical chemistry for biomolecular diagnosis of dengue disease: a review

The past decades have witnessed enormous technological improvements towards the development of simple, cost-effective and accurate rapid diagnostic tests for detection and identification of infectious pathogens. Among them is dengue virus, the etiologic agent of the mosquito-borne dengue disease, one of the most important emerging infectious pathologies of nowadays. Dengue fever may cause potentially deadly hemorrhagic symptoms and is endemic in the tropical and sub-tropical world, being also a serious threat to temperate countries in the developed world. Effective diagnostics for dengue should be able to discriminate among the four antigenically related dengue serotypes and fulfill the requirements for successful decentralized (point-of-care) testing in the harsh environmental conditions found in most tropical regions. The accurate identification of circulating serotypes is crucial for the successful implementation of vector control programs based on reliable epidemiological predictions. This paper briefly summarizes the limitations of the main conventional techniques for biomolecular diagnosis of dengue disease and critically reviews some of the most relevant biosensors and rapid diagnostic tests developed, implemented and reported so far for point-of-care testing of dengue infections. The invaluable contributions of microfluidics and nanotechnology encompass the whole paper, while evaluation concerns of rapid diagnostic tests and foreseen technological improvements in this field are also overviewed for the diagnosis of dengue and other infectious and tropical diseases as well.