Recently, the focus has been on the importance of assessing the oral disintegrative properties of orally disintegrating tablets (ODTs). In particular, in the development stages and the quality control field of ODT products, a physical assessment method which easily measures oral disintegrative properties is desired. For this reason, we developed a new disintegration test method (Kyoto-model disintegration method or KYO method), which is useful to predict the oral disintegrative properties of an ODT easily, and examined the availability of the method. In the KYO method, ODT samples were classified in terms of their water permeability, and a moderate water volume was decided. Subsequently, the disintegrative properties were assessed with the newly proposed method. For 25 commercial prescription ODTs used as samples, a good correlation was shown between the results of a human sensory test by five healthy male volunteers and the results using the KYO method. Furthermore, the KYO method could evaluate time-dependent changes in ODT samples. On the other hand, no correlation was observed between the Japanese Pharmacopeia disintegration test and the human sensory test. These results suggested that the KYO method reflected the disintegration nature of the ODTs in the oral cavity, and could easily be applied to development stages and the quality control field of ODT products.
Chitosan, as a natural biopolymer, has potential applications in controlling the release of drugs due to its unique natural and physiochemical properties. Conventionally, an emulsion crosslinking method was used to prepare chitosan microspheres. In this study, a novel method of preparing 5-fluorouracil-loaded chitosan microspheres was established by combining the emulsification technique and a two-step solidification method using both glutaraldehyde (GTA) and tripolyphosphate (TPP) as crosslinking agents. The microspheres were characterized by surface morphology, encapsulation efficiency, yield of microspheres and drug release profile in vitro. The optimal chitosan microspheres were achieved by crosslinking chitosan with both TPP (0.1%, pH 4.0) and GTA (1.0%, v/v) with span-80 additive under a crosslinking time of 1 h with TPP and GTA, respectively.
A one-pot, three-component and catalyst-free method for the efficient and simple synthesis of dialkyl 3-(dicyanomethyl)-2-oxoindolin-3-ylphosphonates at 50 °C under solvent-free conditions is reported. The features of this procedure are mild reaction conditions, high yields of products, and operational simplicity.
A series of novel water-soluble β-carbolines bearing a flexible amino side chain was designed, synthesized and evaluated as potent cytotoxic and DNA intercatalating agents. The N9-arylated alkyl substituted β-carbolines represented the most interesting cytotoxic activities. The results suggested that (1) the N9-arylated alkyl substituents of β-carboline nucleus played a very important role in the modulation of the cytotoxic potencies; (2) the length of the alkylamino side chain significantly affected their cytotoxic potency, and N,N-dimethylaminopropylamino substituent were more favorable. In addition, these compounds were found to exhibit significant DNA intercalating potencies.
In the present study, some selected, previously reported 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) and 3-hydroxy-quinazoline-2,4-diones (QZs), were evaluated for their affinity at the (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA) receptor in the [3H]-6-cyano-7-nitroquinoxaline-2,3-dione ([3H]-CNQX) binding assay. Electrophysiological experiments were performed in oocytes expressing rat homomeric GluR3 subunits in order to assess the pharmacological profile of the tested compounds. The binding data, together with those regarding the functional activity, confirmed that most of the TQXs and QZs reported herein are potent AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these derivatives showed anticonvulsant properties.
Cefpodoxime proxetil (CP) is a prodrug, the third generation cephem-type broad-spectrum antibiotic administered orally. However, CP was found to be a poorly water-soluble drug with low bioavailability when orally administered. In the present investigation, the spray-dried cefpodoxime proxetil nanosuspension (SDN) was prepared. The physicochemical properties were characterized by rheological evaluation, particle size measurement and its distribution, dynamics of reconstitution, in-vitro dissolution testing, surface morphology, surface area and pore size measurements. The pharmacokinetic study of SDN, in comparison to a marketed cefpodoxime proxetil for oral suspension (MS), was also performed in rabbits after a single oral dose. It was found that SDN exhibited a significant decrease in tmax, a 1.60-fold higher area under curve (AUC) and 2.33-fold higher maximum plasma concentration (Cmax) than MS.
In order to determine the optimum size of heterocycle of lead compound 1 (6-methyl-3-phenethyl-3,4-dihydro-1H-quinoline-2-thione; IC50=0.8 μM) for inhibition of melanogenesis, we have synthesized and evaluated some benzimdazole-2(3H)-thiones 5a—e. The preliminary bioassay has shown that the benzimdazole-2(3H)-thione motif of 5 is essential structural unit for their inhibitory activity. Among all thiones 5a—e, the compound 5d strongly inhibited the formation of melanin with IC50 value of 1.3 μM.
Tautomerization of methyl-substituted dihydropyrazine (DHP) derivatives to their latent enamine form was investigated theoretically and empirically. Among two types of hydrogen transfer model simulated by means of density functional theory calculation, a simple intramolecular hydrogen shift mechanism for 5,6-dimethyl-2,3-dihydropyrazine (1) and 5-methyl-6-phenyl-2,3-dihydropyrazine (3) required high activation energies for tautomerism, while a water-assisted intermolecular hydrogen transfer mechanism gave smaller activation energies (about 160 kJ/mol). Examination of the deuterium exchange reaction of 3 in 50% (v/v) D2O/dimethyl sulfoxide-d6 solution revealed temperature-dependent and stepwise deuterium exchange of the 5-methyl group. Reaction of compound 3 with phenyl isocyanate in acetonitrile afforded a mono adduct (7) at the 5-methyl group, and a cyclic adduct (8). These results represent evidence of tautomerism of 5-methyl-2,3-dihydropyrazines (imine forms) to the latent enamine tautomers, and suggest that DHPs may behave as enamines to a significant degree under physiological conditions.
A new chlorinated briarane, fragilide J (1), has been isolated from the sea whip gorgonian coral Junceella fragilis. In addition, the sea whip gorgonian coral Ellisella robusta yielded two chlorinated briaranes, including a new compound, robustolide L (2), and a known metabolite, robustolide H (3). The structures of these compounds were determined using spectroscopic methods. The structure, including the absolute configuration of 3, was further confirmed by X-ray data analysis for the first time.
The production of sesquiterpene-type phytoalexins with a vetispyradiene skeleton by Hyoscyamus albus hairy roots induced by methyl jasmonate (MeJA) was reported in a previous paper. The production pattern on co-treatment with cupper sulfate and MeJA (CuSO4–MeJA) showed a TLC profile differing from that on treatment with MeJA. Thus, we studied the production of phytoalexins on hairy root culture involving co-treatment with CuSO4–MeJA. In the experiment, many sesquiterpene-type phytoalexins with a vetispyradiene skeleton were isolated, most of which were different from the products reported in the previous paper. Here, we isolated four new phytoalexins (1—4) along with known compounds 5—10 from the culture medium of H. albus hairy roots co-treated with MeJA–CuSO4. The structures of the new compounds (1—4) were determined as: (3R,4S,5R,7S,9R)-3-acetoxy-9-(2-methylpropionyloxy)solavetivone (1), (3R,4S,5R,7S,9R)-3-hydroxy-9-(3-methylbutanoyloxy)solavetivone (2), (3R,4S,5R,7S,9R)-3-acetoxy-9-(3-methyl-butanoyloxy)solavetivone (3), and (3R,4S,5R,7S,9R)-3-acetoxy-9-(3-methyl-2-butenoyloxy)-solavetivone (4) based on MS and NMR including 2D-NMR data. These findings indicated that the production of phytoalexins in H. albus hairy roots yielded different products based on treatment with different chemicals (CuSO4, MeJA, and MeJA–CuSO4).
Eighteen compounds, including three new triterpenoids, camellisins A—C (1—3), were isolated from the roots of Camellia sinensis. Their structures were determined on the basis of detailed spectroscopic analysis.
Two new polychlorolipids, namely, (2R,3S,4R,5S,6S,7R)-2,3,5,6,7-pentachloropentadec-14-en-4-yl hydrogen sulfate (2) and (2R,3S,4R,5S,6S,7R)-2,3,5,6,7-pentachloropentadec-14-en-4-ol (4), along with a known chlorosulfolipid (1), were isolated from the octocoral Dendronephthya griffini. (2R,3S,4R,5S,6S,7R,E)-2,3,5,6,7,15-Hexachloropentadec-14-en-4-ol (3) was isolated for the first time from a natural source. The structures of these compounds were elucidated by extensive spectroscopic analysis and by comparison of the NMR data with those of known compound 1. This type of compound was isolated for the first time from the soft corals.
The purpose of the study was to screen the effects of formulation factors on the in vitro release profile of diclofenac sodium from matrix tablets using design of experiment (DOE). Formulations of diclofenac sodium tablets, with Carbopol® 71G as matrix substance, were optimized by artificial neural network. According to Central Composite Design, 10 formulations of diclofenac sodium matrix tablets were prepared. As network inputs, concentration of Carbopol® 71G and the Kollidon® K-25 were selected. In vitro dissolution time profiles at 5 different sampling times were chosen as responses. The independent variables and the release parameters were processed by multilayer perceptrons neural network (MLP). Results of drug release studies indicate that drug release rates vary between different formulations, with a range of 1 h to more than 8 h to complete dissolution. For two tested formulations there was no difference between experimental and MLP predicted in vitro profiles. The MLP model was optimized. The root mean square value for the trained network was 0.07%, which indicated that the optimal MLP model was reached. The optimal tablet formulation predicted by MLP was with 23% of Carbopol® 71G and 0.8% of Kollidon® K-25. Calculated difference factor (f1 7.37) and similarity factor (f2 70.79) indicate that there is no difference between predicted and experimentally observed drug release profiles for the optimal formulation. The satisfactory prediction of drug release for optimal formulation by the MLP in this study has shown the applicability of this optimization method in modeling extended release tablet formulation.
We previously reported that safflower (Carthamus tinctorius L.) ethyl acetate extract (HE) possessed an inhibitory action on serotonin (5HT) uptake in Chinese hamster ovary (CHO) cells expressing 5HT transporter (SERT) (S6 cells). Here, HE was adopted to go through an activity-guided isolation, and then an ingredient with potent SERT inhibitory action was obtained, which was elucidated as N1,N5-(Z)-N10-(E)-tri-p-coumaroylspermidine (CX), a new coumaroylspermidine analog, by using spectroscopic methods including extensive 1D- and 2D-NMR analyses. Preliminary pharmacological study demonstrated that CX was a potent SERT inhibitor.
A new series of novel 4-(1H-benz[d]imidazol-2yl)-1,3-thiazol-2-amines 5a—d and 4-(1H-benz[d]imidazol-2yl)-3-alkyl-2,3-dihydro-1,3-thiazol-2-amine 8a—d has been synthesized by the cyclocondensation of 2-acetyl benzimidiazoles 4a—d and 2-bromo-1-(1-alkyl-1H-benzo[d]imidazol-2-yl)-1-ethanone 7a—d with thiourea respectively, and evaluated for their antibacterial and antifungal activity against clinical isolates of Gram-positive and Gram-negative bacteria. Some of these hybrids in these series exhibited antibacterial activity comparable to standard Streptomycin and Benzyl penicillin and antifungal activity against Fluconazole. All the newly synthesized compounds were characterized by their spectral data and further used to estimate their ability towards antimicrobial activity.
Selenite (H2SeO3) reacts with thiol compounds (RSH) under acidic conditions to form selenotrisulfides (RSSeSR, i.e. monoselenodithiols). The stoichiometry of the reaction is proposed as 4RSH+H2SeO3→RSSeSR+RSSR+3H2O. Surprisingly, we found novel polynuclear selenium-containing compounds, i.e. polyselenodipenicillamines (PenSSe2–4SPen), in the reaction of D-penicillamine (PenSH) with H2SeO3. The selenium-centered features of PenSSe2–4SPen were determined by 1H-NMR and LC-MS/MS analyses, showing that the selenium isotope abundance patterns of the compounds were in good agreement with the theoretically-calculated ones. In order to better understand the mechanisms for PenSSe2–4SPen production, various molar ratio of H2SeO3 (1/8 to 4 times of PenSH) was reacted with PenSH, and the concentration of the products was calculated from integral values of dimethyl proton signals for PenSSe1–2SPen as compared with methyl proton signals for acetic acid (an internal standard). Total PenSSe1–2SPen concentration was increased with increasing of H2SeO3, in which concomitant decrease of PenSSPen (disulfide form of PenSH) was observed. Based on these results, we proposed the PenSSe2–4SPen production mechanisms being involved in penicillamine selenopersulfides (PenSSe1–2H).
Two new indole alkaloids, kopsiyunnanines G (1) and H (2), possessing the Aspidosperma skeleton were isolated from the aerial part of Yunnan Kopsia arborea BLUME (Apocynaceae). Their structures and stereochemistry were elucidated by means of MS and 2D NMR analyses.
A series of 4-aminomethylpyridazines and -pyridazin-3(2H)-ones (“diaza-benzylamines”), bearing alkylamino side chains in ortho position relative to the CH2NH2 unit, was synthesized by catalytic hydrogenation of the corresponding nitriles in strongly acidic medium. N-Benzyl protecting groups either at the pyridazinone ring nitrogen or at an exocyclic nitrogen were selectively removed hydrogenolytically or by treatment with a Lewis acid. The new compounds were tested in vitro for semicarbazide-sensitive amine oxidase (SSAO) inhibitory activity and 4-(aminomethyl)-N,N′-diethylpyridazine-3,5-diamine (22) was found to be the most active representative.
A total of 36 compounds (1—36) were obtained from the stem bark of Poncirus trifoliata including three new prenylated flavonoids, (−)-5,4′-dihydroxy-7,8-[(3″,4″-cis-dihydroxy-3″,4″-dihydro)-2″,2″-dimethylpyrano]-flavone (1), (−)-5,4′-dihydroxy-7,8-[(3″-hydroxy-4″-one)-2″,2″-dimethylpyrano]-flavone (2), and (−)-5,4′-dihydroxy-7,8-[(cis-3″-hydroxy-4″-ethoxy-3″,4″-dihydro)-2″,2″-dimethylpyrano]-flavone (3). The new structures were elucidated by means of spectroscopic methods. Compounds 1—20 were evaluated for their anti-human immunodeficiency virus-1 (HIV-1) activity, in which 2 showed significant anti-HIV-1 activity with high therapeutic index (TI) of 143.65.
To search for compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, ten 5,5′-(p-phenylenebisazo)-8-hydroxyquinoline sulfonates (4a—j) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro for the first time. Some compounds demonstrated anti-HIV-1 activity, especially 5,5′-(p-phenylenebisazo)-8-hydroxyquinoline p-ethylbenzenesulfonate (4g) and 5,5′-(p-phenylenebisazo)-8-hydroxyquinoline p-chlorobenzenesulfonate (4i) showed the more potent anti-HIV-1 activity with 50% effective concentration (EC50) values of 2.59 and 4.01 μg/ml, and therapeutic index (TI) values of 31.77 and 24.51, respectively.
4′-O-[β-D-Apiosyl(1→2)]-β-D-glucosyl]-5-hydroxyl-7-O-sinapylflavanone (1), 3-(4-acetoxy-3,5-dimethoxy)-phenyl-2E-propenyl-β-D-glucopyranoside (2), 3-(4-hydroxy-3,5-dimethoxy)-phenyl-2E-propenyl-β-D-glucopyranoside (3), 5,7-dimethoxy-4′-O-β-D-glucopyranoside flavanone (4), 4′,5-dimethoxy-7-hydroxy flavanone (5), and 5,7-dimethoxy-4′-hydroxy flavanone (6), were isolated from the organic extracts of Viscum album L. (European Mistletoe). These compounds were studied for their anti-glycation and antioxidant properties. The structures of new compounds 1 and 2 were deduced on the basis of spectroscopic evidence.
Pollenopyrroside A and pollenopyrroside B, novel pyrrole ketohexoside derivatives, were isolated from the extract of Bee-collected Brassica campestris pollen. Their structures were elucidated by spectroscopic analysis (UV, IR, MS, NMR and X-ray) and chemical evidence. Pollenopyrrosides A and B represent a novel carbon skeleton with a six–six and five–six member dioxaspirocycle bearing nitrogen atom, respectively.
Two new curine-type bisbenzylisoquinoline alkaloids, wattisines A (1) and B (2) along with three known alkaloids were isolated from the roots of Cyclea wattii. Their structures were established by interpretation of NMR and high-resolution electrospray ionization (ESI)-MS data. Absolute configuration of wattisines A and B were determined by single-crystal X-ray diffraction and circular dichroism (CD) spectra, respectively. In vitro, wattisine A (1) showed significant cytotoxic activities with IC50 value of 1.74 μM against HCT-8, and 7.29 μM against Bel-7402.
The combination of Zn(OAc)2 and N,N-dimethylformamide was found to effectively hydrosilylate various ketones at room temperature. Furthermore, our protocol allows the chemoselective reduction of a formyl group in the presence of a ketone group.
Three new sesquiterpenoids, isodauc-7(14)-en-6α,10β-diol (1), 10β-hydroxyisodauc-6-en-14-al (2), and (7S*)-opposit-4(15)-en-1β,7-diol (4), along with ten known compounds have been isolated from the aerial parts of Senecio argunensis. Their structures were established by means of detailed spectroscopic analysis including IR, HR-MS, and 1D NMR and 2D NMR data. The sesquiterpenoids were assayed against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Compounds 4 exhibited weak antibacterial activity against Escherichia coli and Bacillus subtilis.
Microporous coated matrix tablet consists of a microporous membrane which is produced directly from a nonporous polymer coating during transit in the gastro-intestinal tract. In the present study, efforts have been made to develop and evaluate the in-vitro performance of a matrix embedded microporous controlled release system to deliver a drug with high aqueous solubility (≥3 g/ml), high pKa (≥9.0) and low molecular weight (<500 Da). The matrix embedded core tablets were prepared and coated using film former (2% w/w) and different pore formers (1—20% w/w of film former) such as plasticizer (PEG 4000), surfactant (Tween 80) and polysaccharide (Dextran) in a conventional coating pan. The tablets were evaluated for various physical parameters, coat tensile strength and in-vitro drug release characteristics. The ethyl cellulose films suppressed the initial burst effect in drug release more than cellulose acetate and polymethacrylates films. PEG 4000 was found to be most effective plasticizer and pore former in controlling drug release, followed by Tween 80 and dextran. The prepared formulations provided prolonged and zero-order drug release.
Seven-membered heterocyclic [1,2,5]triazepane and [1,2,5]oxadiazepane derivatives were synthesized as candidate structures for application in drug discovery in place of conventional piperazine or morpholine moieties, offering multiple sites for modification with functional groups. We first synthesized the N-protected heterocycles, and then confirmed their utility by synthesizing analogues of the oxazolidinone antibacterial agent linezolid. The analogues exhibited potent in vitro and in vivo antibacterial activity. In particular, compound 10a exhibited good in vivo efficacy when administered intravenously in a murine model of systemic infection with methicillin-resistant Staphylococcus aureus SR3637. These seven-membered heterocycles are expected to be versatile structural units for drug discovery.