Reaction of a hypervalent iodine reagent with bistriflimide efficiently promotes three-component regioselective cyclization of tetrahydrofuro[2,3-d]oxazoles and oxazoles from homopropargyl alcohols bearing a phenyl group, with different substituents on the aryl alkyne compounds affecting the selectivity of the resulting product. Utilizing the hydroxyethyl oxazole derivatives obtained in this research could aid in the development of various peroxisome proliferator-activated receptor agonist derivatives.

We investigated similar compounds to ebselen and tideglusib, which exhibit strong activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using Molecular ACCess System (MACCS) keys. Four candidate compounds were identified. One of them, phenyl-benzothiazol-3-one, showed coronavirus-specific 3C-like (3CL) protease inhibitory activity. The results indicated that a similarity score above 0.81 is a good indicator of activity for ebselen-and-tideglusib-like compounds. Subsequently, we simulated the ring-cleavage Michael reaction of ebselen at the Se center, which is responsible for its 3CL protease inhibitory activity, and determined the activation free energy of the reaction. The results showed that reaction simulation is a useful tool for estimating the activity of inhibitory compounds that undergo Michael addition reactions with the relevant cysteine S atom of 3CL proteases.

MS is a powerful methodology for chemical screening to directly quantify substrates and products of enzymes, but its low throughput has been an issue. Recently, an acoustic liquid-handling apparatus (Echo^®) used for rapid nano-dispensing has been coupled to a high-sensitivity mass spectrometer to create the Echo^® MS system, and we applied this system to screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease inhibitors. Primary screening of 32033 chemical samples was completed in 12 h. Among the hits showing selective, dose-dependent 3CL-inhibitory activity, 8 compounds showed antiviral activity in cell-based assay.

Long-term and constant-release osmotic-pump lorcaserin hydrochloride controlled-release tablets (OP LH CRTs) were prepared, to investigate the influencing factors of LH release and optimize the formulation. The mechanism of release of LH from OP LH CRTs in vitro was investigated. By establishing a high-efficiency method for measuring LH release in vitro, and optimizing it by single-factor and orthogonal experiments, the best formulation of OP LH CRTs was determined. Then, the optimal prescription of OP LH CRTs was: LH = 20.8 mg; mannitol = 100 mg, microcrystalline cellulose = 125 mg; magnesium stearate = 5 mg; cellulose acetate = 3%; polyethylene glycol 400 = 10%; dibutyl phthalate = 10%; Wetting agent and binder was 3% polyvinyl pyrrolidone (PVP) K30 ethanol solution; aperture diameter = 0.8 mm; the coating gained 3% weight. And finally, prepared OP LH CRTs were released at a constant rate in vitro and sustained for 16 h with good reproducibility between batches. Using an orthogonal experimental design, OP LH CRTs with remarkable zero-order release characteristics within 16 h were obtained, and formulation optimization was realized.

Prion diseases are fatal neurodegenerative diseases characterized by the deposition of abnormal prion protein aggregates (PrP^Sc) in the brain. In this study, we developed hydroxyethylamino-substituted styrylchromone (SC) and 2-(2-(pyridin-3-yl)vinyl)-4H-chromen-4-one (VPC) derivatives for single-photon emission computed tomography (SPECT) imaging of PrP^Sc deposits in the brain. The binding affinity of these compounds was evaluated using recombinant mouse prion protein (rMoPrP) aggregates, which resulted in the inhibition constant (K_i) value of 61.5 and 88.0 nM for hydroxyethyl derivative, (E)-2-(4-((2-hydroxyethyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NHEtOH) and (E)-2-(4-((2-hydroxyethyl)(methyl)amino)styryl)-6-iodo-4H-chromen-4-one (SC-NMeEtOH), respectively. However, none of the VPC derivatives showed binding affinity for the rMoPrP aggregates. Fluorescent imaging demonstrated that the accumulation pattern of SC-NHEtOH matched with the presence of PrP^Sc in the brain slices from mouse-adapted bovine spongiform encephalopathy-infected mice. A biodistribution study of normal mice indicated low initial brain uptake of [¹²⁵I]SC-NHEtOH (0.88% injected dose/g (% ID/g) at 2 min) despite favorable washout from the brain (0.26% ID/g, at 180 min) was displayed. [¹²⁵I]SC-NHEtOH exhibited binding affinities to both artificial prion aggregates as well as prion deposits in the brain. However, significant improvement in the binding affinity for PrP^Sc and blood–brain barrier permeability is necessary for the development of successful in vivo imaging probes for the detection of cerebral PrP^Sc in the brain.

We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4′-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4′-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4′-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.

Quantitative proton NMR (qHNMR) methodology was employed for the stoichiometric (free base and the corresponding counterion) assessment of a ticagrelor process impurity, also referred to in the United States Pharmacopeia (USP), Pharmacopeial Forum as Ticagrelor Related Compound A (RC A), [(1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (R)-mandelate], also called as Tica amine mandelate, a critical impurity that, when present during manufacturing, has a limit of not more than 0.0008%. The Tica amine is also a listed impurity E in the Ticagrelor monograph, in European Pharmacopeia. Because there was no existing NMR spectroscopic method in the literature specific to quantify the counterion (mandelic acid) in Ticagrelor RC A, this study aimed to fill the gap. Accurate stoichiometric measurement of this impurity serves to enhance product quality in the manufacturing of the ticagrelor active pharmaceutical ingredient (API). Using ethylene carbonate as an internal standard (IS), the qHNMR analysis on Ticagrelor impurity, revealed many key characteristics of the test mixture composition, including (free base and counterion). The results demonstrate that qHNMR has great potential for addressing several key quality attributes associated with chemical analyses such as detection, identification, quantification, and purity determination, as well as deriving molecular stoichiometry, all from the single proton spectrum.

The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the residual rate of ARIP in the mixed solution decreased to 15.7–17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (−)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.

Heavy atom-containing molecules cause a photoreaction by a direct S₀ → T_n transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365–400 nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S₀ → T_n transition causes the photoreaction to proceed under wavelengths in the blue and green light region.

We previously isolated an aminobutadiene derivative as a by-product in the synthesis of a 1,4-dihydropyridine (1,4-DHP) derivative by the reaction of methyl propiolate with excess ammonium acetate in water, and we proposed that it is an intermediate in the formation of 1,4-DHP. Here, to test this idea and to investigate the reaction mechanism, we selectively synthesized the aminobutadiene derivative in EtOH and examined its reactivity. The yield of the aminobutadiene derivative was increased in the presence of excess ammonium salt. X-Ray crystal structure analysis indicated the presence of an intramolecular hydrogen bond between the terminal amine and ester carbonyl oxygen, together with a short C–N bond length consistent with enamine-imine equilibrium. Direct cyclization of the aminobutadiene derivative with methyl propiolate to afford the 1,4-DHP derivative did not proceed well, but the yield was increased in the presence of morpholine salt as an additive. These results suggest that the predominant reaction pathway from the intermediate to 1,4-DHP in water involves Michael addition of a second amine molecule and reaction with methyl propiolate, followed by intramolecular cyclization and elimination of amine.