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.

Seven anthraquinones including two new compounds namely capillasterquinones A and B (1 and 2) and one new butenolide namely capillasterolide (8) were isolated and structurally elucidated from the crinoid Capillaster multiradiatus. The inhibitory effect of compounds 1–8 on lipopolysaccharide (LPS)-induced nitric oxide (NO) production as well as inhibition of 1 on expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) proteins in RAW264.7 cells were also evaluated. As the obtained results, capillasterquinone A (1) showed strong NO production inhibitory activity with an IC₅₀ of 5.89±0.11 µM. In addition, compound 1 reduced the LPS-induced iNOS and COX-2 expressions in a dose-dependent manner.

The current study examined the mechanism of wet granulation with a high-speed mixer using porous calcium silicate (PCS) as the excipient and low-molecular-weight sugar alcohols (erythritol, mannitol, maltitol, or xylitol) as the binder. Granules did not form when erythritol or mannitol was used as the binder. No major changes in X-ray powder diffraction data and near-infrared (NIR) spectroscopy spectra were noted when erythritol was used in granulation. Meanwhile, granules formed when xylitol was used as the binder. The NIR spectra of the obtained granules had a widened band near 5100 cm⁻¹ due to hydroxyl groups. From the peak fitting near 4800 cm⁻¹ using the Gaussian–Lorentzian product function, the contribution of hydrogen bonds in water species increased during granulation. The NIR spectra of these potential binders revealed a band of hydroxyl groups for intramolecular hydrogen bonds near 6900 cm⁻¹ when maltitol or xylitol was used as the binder, whereas no band was observed for erythritol and mannitol. Changes in the NIR spectra assigned to water were useful in evaluating the progression of granulation as a process analytical technology. Moreover, X-ray powder diffraction illustrated that the peak due to xylitol crystals disappeared. Xylitol existed in an amorphous state in the granules, suggesting molecular interactions. Thus, hydroxyl groups in sugar alcohols facilitate hydrogen bonding between PCS (silanol groups) and molecules via water, and this is considered to be the mechanism by which granules are formed.

We investigated the salt cocrystals formed by tofogliflozin with sodium acetate and potassium acetate by determining the crystal structures of the salt cocrystals and characterizing the solid states. The salt cocrystal screening using the slurry method and the liquid-assisted grinding method resulted in the formation of tofogliflozin–sodium acetate 1 : 1 and tofogliflozin–potassium acetate 1 : 1 salt cocrystals. Single-crystal X-ray diffraction revealed that, although each salt cocrystal belongs to a different space group, both of the salt cocrystals have almost similar structural features, including the conformation of tofogliflozin molecules, the coordination to Na⁺/K⁺ ions, and hydrogen bonds. The salt cocrystals exhibited extreme hygroscopicity with deliquescence, which is also a property of sodium acetate and potassium acetate. In addition, tofogliflozin–potassium acetate salt cocrystal had two polymorphs, which were enantiotropically related.

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.

From the leaves of Diospyros maritima, collected from Okinawa Island, eight new glycosides based on ent-kaurane-type diterpenoids, entitled diosmariosides A–H, were isolated. The absolute structure of diosmarioside E (5) was determined by X-ray crystallographic analysis. The structure of diosmarioside H was elucidated to be a dimeric compound between diosmarioside A and a sugeroside through a ketal bond. An assay of cytotoxicity towards the lung adenocarcinoma (A549) cell line was performed. Among the compounds isolated, only diosmarioside D (4) and sugeroside 9 showed strong activity. The anti-microbial activity toward multi-drug resistant strains was also determined, but no activity was observed.

Molecules bearing pyrazole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated with DNA interactions. This study aimed to the synthesis of new pyrazol derivatives and evaluated their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized, and their structures were elucidated by ¹H-NMR and high resolution (HR)-MS (electrospray ionization positive mode (ESI⁺)). Antiproliferative inhibition assays, UV titration assays, fluorescence titration assays, circular dichroism (CD) assays, KI quenching studies, topoisomerase inhibitory activity assays and molecular docking were evaluated for these compounds. Especially, compounds 5e and 5q showed higher antitumor activity with IC₅₀ values <13 µM for the tested cell lines. However, compounds 5e and 5q did not inhibit the topoisomerase activity evaluated by relaxation assay. These results show that the pyrazole nucleus contributes to the incorporation of molecules into the DNA. Moreover, it was highlighted that positive charges are relevant for the design of promising antitumor and DNA binding compounds.

The reaction of lauroyl isothiocyanate 1 with enaminonitrile derivative 2 furnished N-(6-cyano-3, 4-diphenylthieno[2,3-c]pyridazin-5-yl-carbamothioyl)dodecanamide 3, which was used as precursor for the synthesis of novel heterocyclic systems. Polyfunctional pyrimidine and fused pyrimidine derivatives were obtained by the cyclization of compound 3 under different basic conditions as well as its reactions with thiourea, o-aminothiophenol, hydrazine hydrate, phenyl hydrazine, ethyl phenyl acetate or ethyl benzoyl acetate. The structures of the new compounds were confirmed by microanalytical and spectral properties. The synthesised compounds were tested in-vitro for their antimicrobial activity and showed congruent results against most of the tested microorganisms compared to the standard drugs Gentamycin and Ketoconazol.

The admixture of a steroid ointment and a moisturizing cream is frequently prescribed to patients suffering from atopic dermatitis. For the mixing operation, a revolution/rotation-type hybrid mixer is widely used in pharmacy. The purpose of this study was to monitor the mixed state of the admixtures during the mixing process of the hybrid mixer. The key technology used in this study was magnetic resonance imaging (MRI). Two different commercial mometasone furoate-containing ointments were used as a test steroid ointment. After layering the moisturizing cream and the steroid ointment in an ointment bottle, the sample was mixed for a predetermined period using the hybrid mixer. According to MRI transverse relaxation time (T₂) mapping for nondestructive monitoring, it was confirmed that the Flumeta^® ointment-containing admixture became homogeneous by mixing for 60 s or more. As for the mometasone furoate ointment 0.1%-containing admixture, the mixed state, after becoming homogeneous, was separated into two layers again by the prolonged mixing process. From the ¹H-NMR spectra of the phase-separated layers, re-separation was caused by removing aqueous components from the bottom of the samples. MRI is a powerful tool for monitoring the mixed state of the admixture during the mixing process. We believe that our findings offer profound insights into the clinical practice of the mixing operation using a hybrid mixer.

The epidermal growth factor receptor (EGFR) is a receptor in the ErbB family, and is overexpressed in some cancer cells. Recent research has shown that, since clustering of the EGFR increases the possibility of its dimerization and activation, the dimerization state of the EGFR on the cell surface is important for the recognition of the EGFR. In case a bivalent inhibitor has an optimized linker length, the clusters of the EGFR could be recognized with high affinity and kinase activation, which depends on EGF, could be suppressed. Peptide 1, which is derived from the dimerization arm of the EGFR, has been found previously to inhibit autophosphorylation of the EGFR. In this study, bivalent ligands based on peptide 1 with linkers of poly(L-proline) or poly-[(glycine)₄(L-serine)] have been designed and synthesized. Bivalent ligands with polyproline linkers could maintain the distance between the ligand moieties. The inhibitory activity of these bivalent ligands against EGFR autophosphorylation was measured and was found to increase as the linker enlarges up to a 15-mer proline linker. The inhibitory activity of a bivalent ligand 7b is significantly higher compared to the corresponding monomeric peptide 2a. This suggests that bivalent EGFR ligands with optimal and rigid linkers could recognize the clusters of the EGFR with higher affinity and suppress kinase activation involving EGF.