The different states of water incorporated in wet granules were studied by a low-field benchtop ¹H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin–spin relaxation time (T₂) was measured using the NMR relaxation technique. The experimental T₂ relaxation curves were analyzed by the two-component curve fitting, and then the individual T₂ relaxation behaviors of solid and water in wet granules were identified. According to the observed T₂ values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.

A number of clinical trials demonstrated that tigecycline was effective and well tolerated in the treatment of patients with various bacterial infections, but few literatures had shown the coagulopathy induced by tigecycline. To address this concern, we performed a retrospective analysis to assess the impact of tigecycline treatment on coagulation parameters in 50 patients with bacterial infections in our hospital (Shandong Provincial Hospital, China). These patients were treated with tigecycline at Shandong Provincial Hospital in 2015–2016 at either a recommended (50 mg q12h) or a higher dose (100 mg q12h). Coagulation parameters, including Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT) and D-dimer, were evaluated in order to assess the impact of tigecycline treatment in these severely infected patients. What we found was that the plasma fibrinogen (FIB) level was 4.63 ± 1.56 g/L before tigecycline treatment, and decreased to 2.92 ± 1.23 g/L during treatment, which was statistically significant (p < 0.001). The mean values of aPTT and PT were significantly increased from 39.58 ± 8.72 to 44.05 ± 10.45 s (p = 0.002), and from 15.37 ± 1.53 to 16.37 ± 2.64 s (p = 0.004), respectively. This study demonstrates that treatment of tigecycline could reduce FIB, prolong aPTT and PT. In conclusion, we advise that it is necessary for practitioners routinely monitor coagulation level in at-rick patient populations treated with tigecycline.

When a neutral solution of a nucleoside mixture was irradiated with UV light having wavelength longer than 300 nm, addition of salicylic acid to the solution greatly accelerated the reaction of thymidine. The UV light irradiation of thymidine solution in the presence of salicylic acid resulted in four major product peaks in HPLC. All the products were identified as isomers of cyclobutane thymidine dimers by MS and NMR. The cyclobutane thymidine dimers were generated from thymidine almost exclusively. UV irradiation with the longer wavelength of 350 nm induced almost no reaction. The results indicate that salicylic acid is a photosensitizer for thymidine dimerization excited by UV light of wavelength 300 to 350 nm.

Orally disintegrating tablets (ODTs), which are administered without water, are beneficial for elderly patients and patients with dysphagia. Masking the unpleasant taste of a drug is an important factor associated with adherence of patients consuming ODTs. We prepared cocoa powder-containing ODTs of bitter-tasting rebamipide (rebamipide chocolet) and evaluated their clinical palatability. We prepared rebamipide ODTs by adding a sweetener and 0, 2.5, 5, and 10% cocoa powder (Ch0-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs, respectively). Rebamipide ODTs without cocoa powder and sweetener were used as controls (Cont-ODTs). We performed a gustatory sensation test in 30 healthy adult volunteers. We used the 100-mm visual analog scale (VAS) to evaluate bitterness, sweetness, scent, and overall palatability of the ODTs. The acceptability of each ODT was evaluated on a 5-point scale. Compared to Cont-ODTs, Ch0-ODTs showed no significant improvement in the VAS score for bitterness, scent, and overall palatability during disintegration. However, compared to Cont-ODTs, Ch2.5-ODTs, Ch5-ODTs, and Ch10-ODTs showed an improvement in all items evaluated using the VAS. In particular, Ch2.5-ODTs showed a significant improvement compared to the Cont-ODTs in the VAS score of all items. Evaluation on a 5-point scale indicated that Ch2.5-ODTs and Ch10-ODTs had the highest acceptability. We prepared rebamipide chocolet with excellent palatability properties, which could not be achieved using a sweetener alone, by using the combination of a sweetener and cocoa powder as a new agent for masking bitterness. Our results indicate that cocoa powder may be used as a taste-masking agent in ODTs.

An alternative synthetic route toward a key intermediate in the total synthesis of isoschizogamine is described. The Claisen–Johnson rearrangement stereoselectively constructed a quaternary carbon. Trifluoroperacetic acid mediated the Baeyer–Villiger oxidation to form a bicyclic lactone. The Mukaiyama–Matsuo protocol converted the lactone into an α,β-unsaturated lactone, that was used as the substrate for the rhodium-mediated 1,4-addition of an arylboronic acid.

The present study proposes a method for the assessment of repeatability in supercritical fluid chromatography with electrochemical detection (SFC-ECD), based on the ISO 11843 part 7 (ISO 11843-7:2018) which can theoretically provide detection limits and standard deviation (S.D.) through the stochastic properties of baseline noise without repetitive measurements of real samples. On the baseline noise of SFC-ECD, large-amplitude and periodic noises with less than 0.05 Hz were observed, and the power spectrum of the baseline noise showed 1/f fluctuation (f = frequency). It was found that the present power spectrum analysis, according to the law of error propagation, can provide suitable noise parameters to calculate S.D. of baseline noise and a relative S.D. (RSD) of peak area by ISO 11843-7. The chromatographic determinations of α-, β-, γ- and δ-tocopherol have been taken as examples. In the present SFC-ECD, the RSDs of peak areas for α-, β-, γ- and δ-tocopherol obtained by ISO 11843-7 were within 95% confidence intervals of the RSD of them obtained by repetitive measurements (n = 6). Thus, we found that ISO 11843-7 is applicable to the assessment of repeatability in SFC-ECD for determining tocopherols without repetitive measurements.

A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.

Stroke is one of the leading causes of death and disability globally, while intravenous thrombolysis with recombinant tissue plasminogen activator remains the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. The attempts to develop new treatments for acute ischemic stroke meet costly and spectacularly disappointing results, which requires both long time and high costs, whereas repurposing of safe existing drugs to new indications provides a cost-effective and not time-consuming alternative. Vascular protection is a promising strategy for improving stroke outcome, as vascular function is critical to both cardiovascular diseases (CVD) and ischemic cerebrovascular disease (ICD). Vascular function related biological processes and pathways maybe the critical associations between CVD and ICD. In this study, a multi-database, in silico target identification, gene function enrichment, and network pharmacology analysis integration approach was proposed and applied to investigate the FDA-approved CVD drugs repurposing for ICD. A list of 119 candidate drugs can be obtained for further investigation of their potential in ICD treatment. As a pleiotropic drug with multi-target, carvedilol was set an example to investigate its promising potential for ICD therapy. Our results indicated that the mode of action of carvedilol for ICD treatment may tightly associated with vascular function regulation and the mechanism is multi-target and multi-signaling pathway related. The disease–disease association network-assisted prediction needs further investigations. In summary, the proposed methods herein may provide a promising alternative to inferring novel disease indications for known drugs.

This review reports on the development of new synthetic methods using oxiranyl anions and their application to the synthesis of polycyclic ether marine natural products. Novel iterative and convergent methods for large, complex polycyclic ether structures have been devised. In these, the reactions of sulfonyl-stabilized oxiranyl anions were employed to construct trans-fused polyether ring systems, along with 6-endo cyclization and ring expansion reactions. Total syntheses of polycyclic ether marine toxins, viz. hemibrevetoxin B, gambierol, and gymnocin-A, were achieved based on the oxiranyl anion strategy developed.

Herein we describe a short total synthesis of (+)-spinoxazine B, which inhibits nitric oxide (NO) production in BV-2 microgrial cells. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus, and it is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.

Polygala Root (the root of Polygala tenuifolia WILLDENOW; Japanese name “Onji”), a well-known crude drug, traditionally used as an expectorant and sedative, has been attracting increased interest in recent years owing to its newly found pharmacological effect related to neuroprotection. However, there is no specific method for identifying and estimating the quality of this crude drug in the Japanese Pharmacopoeia, 17th edition. Therefore, in order to develop a TLC-based simple and convenient identification method using characteristic chemical marker(s) for the drug and its extract products, UV-sensitive constituents of Polygala Root were first investigated. A total of 23 aromatic compounds were isolated and characterized. Two new compounds, namely, polygalaonjisides A (1) and B (2), were characterized as syringic acid 4-O-(2′-O-β-D-apiosyl)-β-D-glucoside and 2-O-(β-D-glucosyl)-3′-O-benzoylsucrose, respectively. Based on these phytochemical results, a TLC method focusing on three marker spots with Rf value of approximately 0.4–0.5 due to tenuifolisides A and B and 3,6′-di-O-sinapoylsucrose was proposed as a simple and convenient test to identify Polygala Root or its single-extract products on the market. The data presented in this paper could be useful in stipulating a confirmation test to identify Polygala Root.

Fluorinated aromatic compounds are found in a variety of biologically active compounds, including clinical drugs and agrochemicals. Therefore, the synthesis of aryl fluorides is particularly important in the medicinal and process chemistry fields. In this paper, we report a method for the synthesis of aryl fluorides by benzyne fluorination under microflow conditions using the efficient Comet X-01 micromixer. In comparison to our previously reported method under ordinary batch conditions, this approach facilitates a significant reduction in reaction times, to ca. 10 s, as well as increases in the yields of fluoroarenes (by up to 51%).

A series of organotin(IV) complexes was herein prepared and characterized. A one-pot synthetic strategy afforded reasonable to high yields, depending on the nature of the ligand. All new complexes were fully characterized by spectroscopic techniques, consisting of IR, MS and NMR (¹H, ¹³C and ¹¹⁹Sn). The in vitro cytotoxicity tests demonstrated that the organotin complexes produced a greater inhibition, versus cisplatin (the positive control), of the growth of six human cancer cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous leukemia), HCT-15 (colorectal), MCF-7 (breast), MDA-MB-231 (breast) and SKLU-1 (non-small cell lung). The potency of this cytotoxic activity depended on the nature of the substituent bonded to the aromatic ring. All complexes exhibited excellent IC₅₀ values. The test compounds were also screened in vitro for their antifungal effect against Candida glabrata and Candida albicans, showing minimum inhibitory concentration (MIC) values lower than those obtained for fluconazole. A brine shrimp bioassay was performed to examine the toxic properties. Molecular docking studies demonstrated that the organotin(IV) complexes bind at the active site of topoisomerase I in a similar manner to topotecan, sharing affinity for certain amino acid side chains (Ile535, Arg364 and Asp533), as well as for similar DNA regions (DA113, DC112 and DT10).

The i-motif is a high-order DNA structure formed by hemiprotonated cytosine–cytosine base pairs under acidic conditions. It is less well studied than other high-order DNA structures, such as G-quadruplexes. However, increasing numbers of i-motif-binding ligands are being reported, and they are being used as tools to investigate the i-motif’s structure and biological functions. It has become clear that the i-motif has a functional role in the regulation of gene expression. In this review, we provide an overview of i-motif ligands so far reported, and we summarize their effects on the structure and their use as tools to investigate its biological functions.

Upon single treatment against Staphylococus aureus, quercetin–pivaloxymethyl conjugate (Q-POM) had antibacterial activities with minimum inhibitory concentrations (MICs) of 16–32 mg/L. Q-POM showed MIC of 32 mg/L against vancomycin-resistant Enterococcus faceium (VRE), which is remarkably lower than other antibiotics investigated (≥256 mg/L). Under sub-MIC concentrations, Q-POM potentiated the activity of ampicillin, cefepime, and vancomycin against S. aureus and Enterococcus (including highly resistant strains such as hetero-resistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and VRE), by decreasing the MICs of these antibiotics by 4–128 folds. Q-POM was found to be partially synergistic with ampicillin and cefepime against S. aureus and Enterococcus, while it was strongly synergistic with vancomycin. Q-POM at 5 mg/L inhibited the formation of biofilms of S. aureus by 24–83% and VRE by 70%. Additionally, Q-POM inhibited the hemolytic activity of S. aureus in a dose-dependent manner. Cytotoxic activity was evaluated in human liver epithelial cells (HepG2), and the 50% cytotoxicity concentration (CC₅₀) value of Q-POM was higher than 50 mg/L. These results indicate the potential use of Q-POM in treatment of methicillin-resistant Staphylococcus aureus (MRSA) and VRE infections.

We developed the first carbenoid insertion reaction into the urea C−N bond. The urea insertion reaction proceeded smoothly using Rh₂(NHPiv)₄, a rhodium catalyst previously designed by our group, to construct a diazabicyclic system. Highly functionalized bridged molecules with three adjacent stereocenters were diastereoselectively synthesized via the urea insertion reaction followed by hydride reduction or nucleophilic addition sequences in one-pot.

The objective of this study is to design primary drying conditions in a production lyophilizer based on a pilot lyophilizer. Although the shelf temperature and the chamber pressure need to be designed to maintain the sublimation interface temperature of the formulation below the collapse temperature, it is difficult to utilize a production lyophilizer to optimize cycle parameters for manufacturing. In this report, we assumed that the water vapor transfer resistance (R_p) in the pilot lyophilizer can be used in the commercial lyophilizer without any correction, under the condition where both lyophilizers were operated in the high efficiency particulate air (HEPA)-filtrated airflow condition. The shelf temperature and the drying time for the commercial manufacturing were designed based on the maximum R_p value calculated from the pilot lyophilizer (1008 vials) under HEPA-filtrated airflow condition and from the vial heat transfer coefficient of the production lyophilizer (6000 vials). And, the cycle parameters were verified using the production lyophilizer of 60000 vials. It was therefore concluded that the operation of lab- or pilot-scale lyophilizer under HEPA-filtrated airflow condition was one of important factors for the scale-up.

To conduct organic synthesis in the field of pharmaceutical science, methodologies that can easily and quickly supply compounds with high drug-likeness are highly desirable. Based on the original catalyst design concept “Radical-Conjugated Redox Catalysis (RCRC)” established during my research, various C(sp³)–H functionalizations and protein modifications have been developed, taking advantage of the high reactivity and chemoselectivity of the single-electron transfer process. This review focuses on the eight-year research efforts by my collaborators and me, from conception to results.

Asymmetric fluorination of cyclic tetrasubstituted alkenes with a pendant amide group was investigated under dianionic phase-transfer catalysis. Fluorination proceeded with high face selectivity, affording the corresponding allylic fluorides with a chiral tetrasubstituted carbon center with up to 97% enantiomeric excess (ee). It should be noted that deprotonative fluorination occurred mainly in preference to intramolecular nucleophilic attack of the amide group.

We examined the amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity. Additionally, 5 different in vitro short dissolution test methods (Tricorptester, magnetic stirrer, rotating injection syringe, paddle apparatus, shaking) were used to evaluate dissolution and the results were compared to those obtained with the human volunteers. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured using the RACTAB^® technique. Quantitative findings showed that amlodipine dissolution from ODT was dependent on time in the oral cavity and the amount of coating applied for physical masking. We also found that dissolution in the oral cavity was best correlated to that in in vitro short dissolution tests with a time period of 30 s. For more detailed evaluations, mean prediction error, mean absolute error, and root mean square error values were calculated, each of which was lowest with the Tricorptester method among all of the investigated test methods. Our results indicate that mimicking of the inside of the human oral cavity is accurate with a testing time of 30 s, while the Tricorptester method was the most preferable of all in vitro tests investigated in this study.