We have investigated the base-induced long-range halogen dance reactions of 4,5-dibromo- or 4-bromo-5-iodothiazoles bearing sulfur-containing aromatic heterocycles at the C2-position. We have found that the reaction occurs in bithiazole regioisomers or (thiophenyl)thiazole derivatives, in which the C-5 halo group on the thiazole halogen donor regioselectively migrates to a halogen acceptor ring after treatment with lithium bis(trimethylsilyl)amide. The substrate with a thiophen-2-yl substituent required highly basic P4-t-Bu to induce the halogen dance reaction.

The main ingredients of Maobushisaishinto (MBST) are ephedrine (EP), methyl eugenol (ME), and aconitine (AC). The pharmacological effects are presumed to be due to the combined effects of these ingredients. In this study, we investigated the impact of the particles present in MBST suspensions on the absorption of the ingredients. Coarse, colloidal, and molecular dispersions were detected when MBST was dispersed in water at 25 and 70 °C. Regardless of temperature, the ratio of MBST in molecular dispersions was the highest, and the ratio of coarse dispersions was greater than that of colloidal dispersions. Particles ranging from 50 to 900 nm were observed in the colloidal dispersions prepared by treatment at 25 °C for 3 min. However, in 70 °C water, the mean particle size decreased, and the number of nanoparticles tended to increase. The levels of EP, ME, and AC in molecular dispersions were higher than those in coarse and colloidal dispersions, with no significant difference observed between the coarse and colloidal dispersions. On the other hand, in small intestinal penetration, the levels of EP, ME, and AC in colloidal dispersions were higher than those in the other two dispersions. Moreover, adding colloidal particles to the dissolved drug (molecular dispersions) increased the drug's permeability through the small intestinal membrane. In conclusion, colloidal particles are produced when MBST is suspended. Furthermore, we showed that these colloidal particles enhance the absorption of the main ingredients of MBST.

A co-amorphous state composed of probucol (PC) and fluvastatin sodium salt (FLU) was prepared by spray-drying (SD). We have previously reported that PC and atorvastatin calcium trihydrate salt (ATO) formed a co-amorphous state when prepared by a SD method and that the solubility of PC and the amorphous stability were improved by the preparation of the co-amorphous state. In the present study, the physicochemical properties, including the amorphous stability of the prepared co-amorphous state, were characterized. Powder X-ray diffraction measurement results suggested that PC and FLU formed a co-amorphous state and that a higher percentage of PC was dissolved from the PC-FLU co-amorphous state than from the PC-ATO co-amorphous state. The results are attributed to FLU exhibiting greater solubility and wettability than ATO, which is supported by the results of solubility tests and contact-angle measurements. The stability of the amorphous state of PC is higher in the co-amorphous state with ATO than in that with FLU. This difference is attributed to differences in the molecular interaction modes between PC-FLU and PC-ATO. Therefore, the selection of high-wettability molecules as a co-former for the co-amorphous state enhances its water solubility. The present study also indicates that molecular interactions enhance the stability of the co-amorphous state.

Enteric-coated microcapsules can protect roxithromycin (ROX) from acid hydrolysis enhancing efficacy, solubility, and dissolution rate, representing a promising oral formulation for children and patients with swallowing difficulties. ROX-layered core particles were obtained with polyvinylpyrrolidone (PVP) K30 as the binder and Eudragit L30 D-55 as the coating material using the Wurster process in a fluidized bed processor. The enteric-coated microcapsules were characterized using powder X-ray diffraction, differential scanning calorimetry, and polarized optical microscopy. Enteric microcapsules with appropriate coating levels and particle sizes underwent dissolution tests, acid resistance tests. The weight ratio of PVP K30 to ROX was 1/2, and the average particle size of ROX-layered core particles was 130 µm. ROX molecule crystallinity in the layered core particles was inhibited. ROX was dispersed in PVP K30 with small particle size and high wettability. The average particle size of ROX enteric microcapsules with 60% coating level was approximately 155 µm. The acid resistance test showed that enteric microcapsules with a coating level of >50% and plasticizer contents of 20-25% can effectively protect ROX stability in simulated gastric fluid within 2 h. The dissolution experiment showed that the enteric microcapsules could protect ROX under acidic conditions of pH 1.2 and released >75% of ROX in the simulated intestinal fluid at pH 6.8 in 45 min. The enteric microcapsule of ROX using Wurster fluidized bed method can protect ROX from acid hydrolysis to ensure the efficacy, and has potential application in pharmaceutical industries, owing to its favorable dissolution.

WHO declared the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as a global pandemic (coronavirus disease 2019 (COVID-19)) in March 2020. Molnupiravir (MPV) is an oral antiviral drug that received use authorization for mild to moderate COVID-19 treatment in adults. However, the global and national drug testing and research of MPV is still difficult due to lack of standards and validated procedures. Therefore, this work aims to synthesize the standard substance of two main molnupiravir impurities, N-hydroxycytidine (NHC) and dimethyl dioxol (DMDO), followed by development of a HPLC-photo diode array (PDA) for their simultaneous analysis. The procedure was validated in compliance with the international pharmaceutical analysis guideline (ICH), and employed to test these compounds in molnupiravir on the market. As a result, NHC and DMDO were successfully synthesized by a hydrolysis in an alkaline environment, and acetalization in an acid environment with very high yields of 83.76 and 73.51%, respectively, along with the purities of over 99%. NHC was detected below the allowable threshold whereas DMDO could not be detected in our samples. The findings show the high applicability of our synthesis and determination procedures in the large-scale production and quality control of impurities of commercial molnupiravir medicines.

Density functional theory calculations on the cyclization of di-t-butyl 2-(2-aminophenyl)-2-methyl malonate (1) to t-butyl 3-methyloxindole-3-carboxylate (2) reveal that acetic acid-assisted protonation of the carbonyl oxygen atom reduces the activation Gibbs free energy significantly lower than methanol-assisted pathways. Experimental data confirm that reaction concentration plays a pivotal role in oxindole formation. Experimental results also indicate distinct reaction mechanisms at low and high concentrations. Achieving high enantioselectivity for chiral compound 2 in high-concentration reactions requires discovering a novel chiral acid.

2α-Functionalization of 1α,25-dihydroxyvitamin D (active vitamin D) A-ring enhances binding affinity for the vitamin D receptor (VDR) and prolongs the half-life in target cells due to gaining resistance to CYP24A1-dependant metabolism. The wide variety of modified A-ring precursor enynes for Trost coupling with CD-ring bromoolefin were synthesized from d-glucose. The A-ring modification provided potent, selective biological activities without calcemic side-effects in vivo; for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D (MART-10) exhibits potent antitumor activity (0.3µg/kg/d, twice/week for 3 weeks) in nude mice inoculated with BxpC-3 cancer cells, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D (AH-1) shows better bone-forming effects (0.02µg/kg/d, 5d/week for 4 weeks) in ovariectomized (OVX) rats as an osteoporosis model than natural active vitamin D, and NS-74c exhibits potent VDR-antagonistic activity (IC 7.4pM) in HL-60 culture cells. The A-ring modification was also applicable to the synthesis of stable 14-epi-19-nortachysterols, and their novel VDR binding mode was confirmed by X-ray co-crystallographic analysis. 25-Hydroxyvitamin D has two independent target molecules: VDR and a sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein (SCAP) complex, and 25-hydroxyvitamin D shows SREBP/SCAP inhibitory activity. The VDR-silent vitamin D analog KK-052 with selective SREBP/SCAP inhibitory activity in vivo was developed. A chemical library of side-chain fluorinated vitamin D analogs is currently under construction, and some analogs have shown potent anti-inflammatory activity and therapeutic effects on psoriasis model mice.

A phytochemical investigation on the flesh fruits of atemoya led to the isolation of seven new kaurane type diterpenoids, (4S*,5S*,8S*,9R*,10S*,13R*,16R*)-16-hydro-18-nor-kauran-4,17-diol (1), (4S*,5S*,8S*,9R*,10S*,13R*,16S*)-18-nor-kauran-4,16,17-triol (2), (4S*,5S*,8S*,9R*,10S*,13R*,16S*)-17-acetoxy-18-nor-kauran-4,16-diol (3), (4S*,5S*,8S*,9R*,10S*,13R*,16R*)-18-nor-kauran-4,16,17-triol (4), (4S*,5S*,8S*,9R*,10S*,13R*,16S*)-17-acetoxy-16-hydro-18-nor-kauran-4-ol (5), (4R*,5S*,8S*,9R*,10S*,13R*,16S*)-16,17-dihydroxy-19-nor-kauran-4-hydroperoxide (6), and (4R*,5S*,8S*,9R*,10S*,13R*,16S*)-kauran-16,19-diol (7) along with 26 known ent-kaurane compounds. Their structures are determined on the basis of spectroscopic data and optical rotation. Compounds 1-5 were new 18-nor-kauran-4-ol type diterpenoids, which are very rarely obtained from natural sources.

Osteoporosis is caused by an imbalance between bone resorption and formation, which decreases bone mass and strength and increases the risk of fracture. Therefore, osteoporosis is treated with oral resorption inhibitors, such as bisphosphonates, and parenteral osteogenic drugs, including parathyroid hormone and antisclerostin antibodies. However, orally active osteogenic drugs have not yet been developed. In the present study, to find novel candidates for oral osteogenic drugs, various benzofuran derivatives were synthesized and their effects on osteoblast differentiation were examined in mouse mesenchymal stem cells (ST2 cells). Among the compounds tested, 3-{4-[2-(2-isopropoxyethoxy)ethoxy]phenyl}benzofuran-5-carboxamide (23d) exhibited potent osteoblast differentiation-promoting activity, estimated as EC for increasing alkaline phosphatase activity, and good oral absorption in female rats, resulting in high C/EC. Dual-energy X-ray absorptiometry scanning revealed that 23d at 10 mg/kg/d for 8 weeks increased femoral bone mineral density in ovariectomized rats with an elevation in plasma bone-type alkaline phosphatase activity, and micro-computed tomography showed that it increased bone volume, mineral contents, and strength in femoral diaphysis cortical, but not trabecular bone during the experiment period. 23d potently inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that its osteoblastogenic activity is mediated by the suppression of CDK8, as previously reported for diphenylether derivatives. In conclusion, the structure-activity relationships of novel benzofuran derivatives were clarified and 3,5-disubstituted benzofuran was identified as a useful scaffold for orally active osteogenic compounds. Compound 23d exhibited potent osteoblastogenic activity through CDK8 inhibition and osteogenic effects in ovariectomized rats, indicating its potential as an orally active anti-osteoporotic drug.

This study investigates the influence of needleless versus needle-based electrospinning methods on the fiber diameter of polyamide 6 (PA6) nanofibers under comparable conditions, with an emphasis on potential pharmaceutical applications. Additionally, it examines how varying solvent systems impact fiber diameter specifically in needleless electrospinning. In this study, it was found that fibers produced by the needleless method were thicker compared to those produced by the needle-based method, a trend attributable to the specific solution characteristics and parameter settings unique to this study. Notably, a 2 : 1 acetic acid : formic acid solvent mixture yielded the largest fiber diameters among the solvent systems assessed for needleless electrospinning. These results underscore the potential of PA6 nanofibers in pharmaceutical applications, suggesting that further optimization of electrospinning conditions could enhance their suitability. The study also discusses the implications of scale-up production using needleless technology, highlighting its viability for industrial applications over single-needle electrospinning.

In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.

A method for preparing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton has been developed using domino intermolecular and intramolecular S2 cyclization. Using this method, the formation of pyrrolidine proceeded smoothly with good yield without the E2 elimination product. This reaction condition is effective for synthesizing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton.

Optimization of the manufacturing process based on scientific evidence is essential for quality control of active pharmaceutical ingredients. Real-time monitoring can ensure the production of stable quality crystals in the crystallization process. Raman spectroscopy is an attractive tool for pharmaceutical quality evaluation and process analytical technology because of its ability to analyze samples non-destructively and rapidly. In this study, we attempted to monitor the crystal polymorphs of carbamazepine (CBZ I and CBZ III) during the dissolution and crystallization processes using low-frequency Raman spectroscopy, which can reflect differences in lattice vibrations originating from polymorphs in the scattering peaks. Furthermore, using multivariate analysis of the obtained spectra, we attempted to develop a model that enables the quantification of each polymorph. A partial least squares was performed to build the prediction model. The prediction model was built using a set of 33 calibration samples, and an external set of 12 validation samples was used to evaluate the model. The model presents a good prediction capacity. The quantitative results for the solid amount of carbamazepine in suspension calculated using the model during the dissolution and crystallization process showed results that correlated very well with the particle view results. It is suggested that low-frequency Raman spectroscopy can be used as a useful process analytical technology tool.

Pharmaceutical packaging is essential for enhancing the storage stability of medicine and can improve medication adherence and usability. Despite their widespread use, blister packs can be challenging to use, especially when pushing out the medication. This study investigates how specific cavity characteristics of blister packs can enhance usability for spherical capsules, which are harder to push out than tablets. The findings of this study show that reducing the thickness of the unformed sheet, or the thickness at the top and corners of the cavities, reduces the effort required to push out the capsules. Similarly, for cavities with different shapes, reducing the thickness at the top and increasing the corner radius also eases the push-out process. These insights emphasize the importance of systematic design in pharmaceutical packaging to improve patient medication adherence.

In the present study, an algae-containing octocoral, Junceella fragilis, was subjected to chemical screening. The analysis resulted in the extraction of six polyacetoxybriaranes: a new compound, identified as fragilide Z (1), alongside previously identified analogs, which included 12-epi-fragilide G (2), fragilide P (3), junceellolide D (4), junceellonoid A (5), and juncin ZI (6). The structures of compounds 2-6 were investigated through single-crystal X-ray diffraction analysis, whereas that of 1 was examined through two-dimensional nuclear magnetic resonance analysis. Compounds 1-6 proved active in enhancing the growth of MG-63 human mesenchymal stem cells.

A total synthesis of javaberine A was achieved through a lithium amide-mediated intramolecular hydroamination of an N-allyl aminoalkene. The desired hydroamination was accomplished using an excess of i-PrNH with a substoichiometric amount of n-BuLi. Using an excess of both n-BuLi and i-PrNH led to tandem cyclization, however, resulting in the construction of a tricyclic structure through the formation of one C-N and two C-C bonds in a single operation. Additionally, epimerization of the H8-H14 cis-benzyl tetrahydroisoquinoline to the trans isomer was achieved via β-elimination followed by intramolecular hydroamination.

Sesame (Sesamum indicum L.) is an important oilseed crop, and its seeds are a source of edible oil and widely used as a nutritious food that is beneficial to health in oriental countries. Phytochemical and biological investigations of the seeds have been well reported; however, those of the leaves have been limited. To explore the potential value of sesame leaves, we focused on their antihypertensive potency. Oral administration of sesame leaf extract significantly reduced blood pressure in spontaneously hypertensive rats. Next, we examined the angiotensin I-converting enzyme (ACE)-inhibitory activity of sesame leaves, stems, and seeds and observed that the inhibitory potencies of leaves and seeds were stronger than those of stems. Acteoside and pedaliin, the major compounds in the leaves, as well as exhibited ACE inhibitory activity. Furthermore, we determined the content of these compounds in the leaves, stems, and seeds using LC/MS. The contents of both compounds in the leaves were higher than those in the stems and seeds. These results suggest that sesame leaf extract can mitigate hypertension, at least in part, via the inhibition of ACE activity by acteoside and pedaliin, suggesting that sesame leaves may have the potential to be used for treating hypertension.

This study introduces a novel method for ring-closing chlorosulfenylation of alkenoic thioesters using N-chlorosuccinimide in hexafluoroisopropanol under mild conditions. This reaction efficiently forms five-membered cyclic sulfur compounds with high selectivity, representing a significant advancement in the synthesis of chlorinated S-heterocycles. Computational analysis using density functional theory demonstrates the superiority of thioester nucleophiles over traditional benzyl sulfides in this reaction, highlighting the energetic preference for thioesters.

Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. However, orally active small-molecule osteogenic drugs are not clinically available. Natural coumarin derivatives, such as osthole, exert osteoblastogenic effects. In the present study, novel 4,6-substituted coumarin derivatives were synthesized, and their osteoblastogenic effects were assessed in a bone mesenchymal stem cell line (ST2 cell), and structure-activity relationships were discussed. Among the derivatives tested, the osteoblastogenic effects of 2-oxo-4-[4-(tetrahydro-2H-pyran-4-yloxymethyl)phenyl]-2H-chromene-6-carboxamide (11m) and 2-oxo-4-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2H-chromene-6-carboxamide (29v) were potent: EC for increasing alkaline phosphatase (ALP) activity were 34 and 24 nM, respectively. The maximal plasma concentrations (C) of 11m and 29v (10 mg/kg, per os (p.o.)) in female rats were 3637 and 975 nM, respectively, resulting in high C/EC ratios of 105.9 and 40.8, respectively, indicating possible osteoblastogenic effects in vivo. Compound 11m (10 mg/kg, p.o., 8 weeks) was previously reported to increase plasma bone-type ALP activity as well as femoral metaphyseal and diaphyseal cortical bone volumes and mineral contents in micro-computed tomography analyses of ovariectomized female rats (OVX rats). Compound 29v at the same dose also exerted osteoblastogenic and osteogenic effects in OVX rats; however, these effects were weaker than those of 11m. Furthermore, 11m and 29v inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that their osteoblastogenic effects involved the suppression of CDK8. In conclusion, a synthetic 4,6-substituted coumarin structure is a useful scaffold for osteoblastogenic and osteogenic compounds via the inhibition of CDK8, and 11m and 29v have potential as anti-osteoporotic drugs that exert osteogenic effects on cortical bone.

Powders used in pharmaceuticals require good flowability. The angle of repose and compressibility index are often used to measure the flowability of pharmaceutical powders. However, confirming the relationship between external forces and flowability for smooth powder handling is necessary. Therefore, we measured pharmaceutical excipient powder using a lower cell direct movable constant-volume shear tester and evaluated the powder's physical properties. In this study, we utilized microcrystalline cellulose, widely used as a pharmaceutical excipient and developed in many grades with different physical properties such as particle shape. We measured the shear parameters that describe the characteristic friction and cohesion properties of each microcrystalline cellulose grade. We found that the relative compression ratio (RCR) correlated with the angle of repose. Differences in the shape of the powder yield locus were observed among the grades, and the ratio of the upward convex area of the powder yield locus curve (APC) was defined as the value that quantified these differences. Furthermore, to clarify the relationship between the particle shape parameters (e.g., particle size distribution and shape) and shear parameters, we analyzed these factors using partial least squares regression. RCR was correlated with linearity and was significantly influenced by particle shape. Accurate prediction formulas were also calculated for the stress transmission and relaxation ratios. There was no correlation with the individual shape parameters, and these are considered that is involved in a complex combination. In APC, in addition to the shape parameters used in this study, bulk density had a significant effect.

Despite the great strides in biopharmaceuticals and monoclonal antibodies today, natural products remain highly attractive as drug candidates. Therefore, building a library of natural products through total synthesis is critically important for drug discovery. This perspective article details the collective total synthesis of polycyclic natural products using "bioinspired reactions" that mimic natural product biosynthesis. It discusses the total syntheses of 20 natural products, including dimeric diketopiperazine alkaloids, monoterpenoid indole alkaloids, and iridoid glycosides, each achieved in fewer than 14 steps starting from commercially available materials.