Showing papers in "Pharmaceutical Chemistry Journal in 2019"

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Emerging Lipid Based Drug Delivery Systems

Abstract: In the past decade, research in the area of nanodrug delivery has reached a new height with the advent of lipid based nanodrug delivery systems. Lipids being biocompatible and possessing diverse physicochemical properties have tremendous potential to enhance oral bioavailability of water insoluble drugs. Incorporation of a drug in lipid carriers is a smart approach to overcome problems related with conventional oral therapy. In recent years, two lipid based nanoparticles, namely solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are widely explored. SLN are spherical nanoparticles with a drug-containing solid lipid core stabilized with surfactants and formulated mainly to improve bioavailability of the drug molecules. Despite several advantages of SLNs, their major drawbacks include limited drug loading, drug leakage, and crystallization during storage. These drawbacks were avoided or reduced by the development of a new generation of lipid nanoparticles, the NLC, wherein a solid lipid is blended with liquid lipid. Modulation of drug release was added advantage with NLC formulations. The present review focuses on production techniques, characterization, release characteristics, stability, toxicity and potential applications of SLNs and NLCs.

Natural Deep Eutectic Solvents as Alternatives for Extracting Phlorotannins from Brown Algae

Abstract: Natural deep eutectic solvents (NADES) are promising green solvents for extracting biologically active compounds from plant raw material. This is the first study in which NADES were used to extract phlorotannins from brown algae Fucus vesiculosus L. and Ascophyllum nodosum (L.) Le Jolis. The extraction efficiency of polyphenols was evaluated using 10 NADES based on choline chloride, lactic acid, betaine, and glucose in various mole ratios. The effect of H2O in aqueous solutions of NADES on extraction of phlorotannins was studied. Algae were extracted by maceration for 120 min at 50°C with a 1:5 raw-material:extractant ratio. Phlorotannins were quantified by spectrophotometry using the Folin–Ciocalteu method. The maximum extraction of phlorotannins (60 – 72%) was achieved using aqueous NADES solutions (50 – 70%) based on choline chloride with added lactic or malic acid and also on malic acid and betaine. The NADES had efficiencies comparable to Me2CO and EtOH.

Recent Advances in Antiviral Benzimidazole Derivatives: A Mini Review

Abstract: Benzimidazole ring system is well known for its potential for various biological activities. Recent research works have indicated the excellent antiviral potential of various derivatives of this heterocycle. Depending upon the nature of substitution and side chain functionalities, benzimidazole derivatives exhibit anti-HCV, anti-HBV, anti-HIV, anti-HSV, anti-Coxsackie virus, anti-rotavirus, anti-mosquito larvae, anti-PRSV, anti-adenovirus, anti-tobacco mosaic, and anti-Sunn-hemp rosette viruses, etc. In this article, the recent literature available on antiviral benzimidazole derivatives is summarized. The article could be useful in designing new antiviral agents based on this ring system.

The Cytotoxic Effects of Thymol as the Major Component of Trachyspermum ammi on Breast Cancer (MCF-7) Cells

Abstract: Natural phenolic compounds have inhibition effects on various malignancies. Thymol is one of these compounds present in several plant sources such as ajowan (Trachyspermum ammi) fruits. In this study, thymol was evaluated for its potential cytotoxic activity as well as its effect on apoptotic gene expression in breast cancer cell line. We used the GC-MS technique to identify the essential oil constituents of ajowan. MCF-7 cells were treated by various concentrations of thymol and half maximum inhibitory concentration (IC50) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, morphological alterations and changes of P21, P53 and Mcl-1 gene expression in MCF-7 cells were investigated by microscopic examination and real-time RT-PCR assay. Data from MTT assay indicated that the IC50 values of thymol on MCF-7 cells for 48 h and 72 h were 54 and 62 μg/mL, respectively. Furthermore, this compound significantly affected gene expressions of P53 and P21, but not Mcl-1. Thymol can induce the apoptosis process in MCF-7, and hence it can be considered an anticancer agent in the future.

Subvisible Particulate Matter in Therapeutic Protein Injections

Abstract: Strategies for determining particulate matter in therapeutic protein injections, including extrinsic and intrinsic particles, are reviewed. Special attention is devoted to the advantages and limitations of various methods used for these purposes, each of which enables different particle characteristics to be determined. The source of particles (extrinsic, intrinsic, or inherent) can be understood better and particle-size distribution and other characteristics can be studied and used to differentiate them if methods based on different measurement principles are used. Protein aggregates in drugs have broad particle-size distributions, from oligomers to particles reaching hundreds of microns. The particle properties can be used to assess the risk associated with protein aggregates in the drug and to study their possible formation mechanisms. Such information could be useful during drug development and manufacturing to reduce the particulate matter content.

Design of Experiments in Pharmaceutical Development

Abstract: In order to develop high-quality pharmaceutical products, a traditional approach based the univariate or trial and error method was used in the past that led to several problems like non-reproducible, high-cost, and time consuming methods. To overcome these drawbacks, a new concept of the Design of Experiment (DoE) was introduced. DoE is a statistical element of the Quality by Design (QbD) approach introduced by British statistician Sir Ronald Fisher in 1925. The basic objectives of DoE are screening, optimization, and robustness. It involves the execution of experimental design on the basis of suitable variables along with statistical evaluation of obtained responses and exploration of the design space using mathematical or graphical approach. The statistical evaluation empowers to build up the quality of finished products and helps to meet the increasing demands for product of superior quality and standards. This article mainly focuses on the applications of DoE in pharmaceutical product development along with its objectives, design, and selection criteria.

Synergistic Effect of Quercetin in Combination with Sulfamethoxazole as New Antibacterial Agent: In Vitro and In Vivo Study

Abstract: The present study was aimed at creating a combination between lower dose of sulfamethoxazole (S) as a broad-spectrum synthetic antibiotic and quercetin (Q), a natural polyphenol to decrease the antibiotic side effects and increase its antioxidant activity. Staphylococcus aureus infected animal model was studied both in vitro and in vivo in comparison to doxycycline (Dox) as standard antibiotic. The in vitro test results indicated that Q exhibited activity alone and in combination with S against tested bacterial strains, while S in low concentration was inactive. The in vivo results revealed that the S+Q combination in mice showed significant improvements in the liver and kidney functions as compared to those in the infected group or S- and Dox-treated groups. Moreover, malondialdehyde level was significantly decreased, while superoxide dismutase and catalase activities were significantly increased in the sera of (S+Q)-treated group in comparison to other treated groups. The spleen recovery in the (S+Q)-treated group was observed with the disappearance of S. aureus colonies as compared to the infected mice. In conclusion, the in vivo treatment of S. aureus infection with S+Q combination decreased the sulfamethoxazole side effects while increasing its antibacterial activity, which supported the therapeutic use of this combination in humans.

Design and Antitumor Activity of Platinum Complexes

Abstract: This review presents the main advances in the design of antitumor platinum complexes over the last five years. Particular attention is paid to unconventional antitumor platinum compounds (complexes in the trans configuration, Pt(IV) complexes with S and P donor ligands, multinuclear complexes).

Bismuth Oxide Nanoparticles in Drug Delivery Systems

Abstract: The paper presents the overlook on bismuth oxide nanoparticles as a potential material applied in medicine-related fields of science. First, the types of drug delivery systems are described. General properties of bismuth oxide are considered as well. The main part of article is devoted to bismuth oxide-based systems intended for drug delivery and medical imaging purposes. It has been confirmed by many scientists that bismuth oxide nanoparticles are a promising material for drug delivery systems and for enhancing the properties of other products in medical applications.

Synthesis, Antimicrobial Properties, and Toxicity of a Nanobiocomposite Based on Ag(0) Particles and Poly(1-Vinyl-1,2,4-Triazole)

Abstract: The synthesis of a water-soluble polymer nanocomposite with Ag(0) particles encapsulated in a poly(1-vinyl-1,2,4-triazole) matrix is reported. The nanocomposite contains isolated spherical Ag(0) particles sized from 2 to 8 nm that are uniformly distributed in the polymer matrix and have a characteristic plasmonic absorption maximum at 412 nm. The new nanocomposite belongs to marginally hazardous category 4. The structural morphology of animal brain tissue is not disturbed after subacute intragastric injection. The bacteriostatic concentration of the nanocomposite varies in the range 0.5 – 32 μg/mL; bactericidal, 1 – 64 μg/mL.

Modern Preservatives of Microbiological Stability (Review)

Abstract: Modern antimicrobial preservatives authorized for use in dosage form technology are reviewed. The nomenclature and various classifications of preservatives according to chemical nature, mechanism and spectrum of antimicrobial action, optimum effective concentrations for antimicrobial activity, and separate factors affecting the activity of antimicrobial preservatives in various dosage forms, e.g., optimum solution pH values and specific adsorbents reducing preservative activity, are presented. Antimicrobial preservatives used widely in pharmaceutical technology, i.e., parabens, sorbic acid and its salts, benzoic acid and its salts, and benzalkonium chloride, are discussed in detail. Ascience-based approach to selecting antimicrobial preservatives is shown to produce the most stable and safest medicines.

Phenolic Compounds of Endemic Buxus Plants in Caspian Hyrcanian Forest (Buxus Hyrcana Pojark) and Their Biological Activities

Abstract: The present paper describes the bioactive constituents and the antioxidant, antibacterial, and antiproliferative properties of extracts from fruits, stems and leaves of Buxus hyrcana Pojark, flowering plant species of the genus Buxus. The obtained data of HPLC and GC-MS analyses show that gallic acid, resorcinol, epicatechin, and ferulic acid are the major phenolic constituents, and quercetin and genistein are the major flavonoid and isoflavonoid compounds present in all parts of B. hyrcana. In addition, GC-MS measurements showed that main constituents in B. hyrcana extracts were glycerin 1,2,3-propanetriol (52%), 2,3-butanediol (49.56%), and 2-hexyl-1-octanol (9.64%). The leaf extract exhibited maximum antioxidant activity as compared to the stem and fruit extracts. The leaf extract also showed higher activity against Gram-negative bacteria, while the stem extract exhibited higher activity against Gram-positive species. In addition, all extracts demonstrated moderate to strong cytotoxic activity against human hepatocytes (Chang liver cells) and breast cancer cell line. This is the first report on bioactive compound profiles and their biological potential in extracts of various aerials part of B. hyrcana. Present studies will open ways to a large spectrum of natural bioactive compounds and their use in pharmaceutical and food industries as antioxidant, antibacterial, and nutraceutical constituents.

Polyene Macrolide Antibotic Derivatives: Preparation, Overcoming Drug Resistance, and Prospects for Use in Medical Practice (Review)

Abstract: Series of semi-synthetic polyene macrolide antibiotics (PMAs) that were prepared by chemical modification in original research by the authors are reviewed. Chemical modification, in particular phosphorylation, was shown to produce highly efficacious PMAs with low toxicities and extended spectra of biological activity. The prospects of using liposomal and nano-derivatives of these antifungal antibiotics are discussed. Crucial issues related to the resistance of pathogenic fungi and the expanding distribution of invasive mycoses are identified. Semi-synthetic PMAs are shown to be highly effective at preventing and treating invasive mycoses and opportunistic fungal infections occurring in AIDS patients. Special attention is paid to structure—activity relationships for the semi-synthetic PMAs. Possible mechanisms of action of these compounds on pathogenic fungi are discussed. An automated intellectual information system was developed for selecting the optimal conditions for development, synthesis, and application in medical practice of new PMAs.

Evaluation of the Antioxidant, Hepatoprotective, and Anti-Inflammatory Activities of Bisresorcinol Isolated from the Trunk of Heliciopsis Terminalis

Abstract: A bisresorcinol, (8′Z)-3,5-dihydroxy-1-[16′-(3″,5″-dihydroxyphenyl)-8′-hexadecen-1′-yl]benzene (I), was isolated as an abundant constituent from the Vietnamese medicinal plant Heliciopsis terminalis (Kurz) Sleumer (Proteaceae). The antioxidant, hepatoprotective, and anti-inflammatory activities of compound I were tested in correlation with the use of H. terminalis as a hepatoprotective drug by ethnic people in Vietnam. Bisresorcinol I showed weak scavenging activity against DPPH radical at an EC50 value of 156.9 mg/mL. At a concentration of 100 mg/mL, compound I inhibited 19,78% of MDAproduction as one of the biomarkers for lipid peroxidation. Bisresorcinol I protected HepG2 cells against harmful CCl4. The hepatoprotective ability was observed at a concentration of 100 mg/mL with up to 44.42% cells alive, which was significantly higher than that in the control treated with CCl4 (29.93 %). The NO scavenging activity of I was determined in RAW 264.7 cells with an IC50 value of 71.15 mg/mL. Bisresorcinol I exhibited its anti-inflammatory activity through modulation of proinflammatory cytokines IL-6 and TNF-α as well as anti-inflammatory IL-10 in RAW264.7 cells.

Assessment of the Acute Toxicity and Analgesic Activity of Ethyl-6-Amino-4-Aryl-5-Cyano-2,4-Dihydropyrano-2,3-C]-Pyrazole-3-Carboxylates

Abstract: The acute toxicity and analgesic activity of compounds of the ethyl-6-amino-4-aryl-5-cyano-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate series were investigated. Study compounds were found to be essentially nontoxic and to have analgesic activity.

Synthesis and Analgesic and Anti-Inflammatory Activities of (3,3-Dipropyl-6,7-Dimethoxy-3,4-Dihydroisoquinolin-1(2H)-Ylidene)-Acetamide Hydrochlorides

Abstract: Cyclocondensation of 4-(3,4-dimethoxybenzyl)heptan-4-ol with N-substituted cyanoacetamide was used to synthesize (3,3-dipropyl-6,7-dimethoxy-3,4-dihydroisoquinolin-2(2H)-ylidene)acetamides. The hydrochlorides of the resulting enaminoamides exist in the imino form. All hydrochlorides displayed analgesic effects in the hotplate test at the level of sodium metamizole, and the most active were the amide with the N-substituted 2-(3,4-dimethyoxyphenyl)ethyl radical, which had greater levels of analgesic activity than metamizole and nimesulide. Many of the resulting amides displayed anti-inflammatory effects in a carragheenan model which were comparable in magnitude to those of sodium metamizole.

Design, Synthesis, Drug-Likeness Studies and Bio-Evaluation of Some New Chalconeimines

Abstract: Newly designed chalconeimines were synthesized, characterized and evaluated for their in vitro antioxidant and antibacterial effectiveness. Results of antioxidant activity assay reveal that all the tested compounds possess good to moderate antioxidant activity which is lower in comparison to that of a standard drug (gallic acid). On the other hand, all the synthesized compounds were found to exhibit a considerably wider spectrum of antibacterial activity, but it was also narrower in comparison to that of a standard drug (ciprofloxacin). Elucidation of structure—activity relationships revealed that electron donating groups (-OH, -OCH3) contribute more to antioxidant potency, whereas electron withdrawing groups (-Cl) impart better antibacterial effectiveness. Moreover, results of drug-likeness studies indicate that a reasonable correlation exists between the drug-like properties and antioxidant activity of the synthesized chalconeimines.

Synthesis, Structure Elucidation and Antimicrobial Properties of New Bis-1,3,4-Oxadiazole Derivatives

Abstract: Four new 1,3,4-bis-oxadiazole derivatives were synthesized, two of them bearing quaternary ammonium salts. The newly synthesized bis-1,3,4-oxadiazoles were investigated for their antibacterial activity against various Gram-positive and Gram-negative strains of bacteria. The target products were prepared from 2-(dimethylamino)ethyl methacrylate (DMAEMA) or 2-(diethylamino)ethyl methacrylate (DEAEMA) via reactions with hexanedioic acid. The structures of all synthesized compounds were confirmed by IR, 1H-NMR, and 13C-NMR spectroscopy. The results of biological activity testing showed that two compounds exhibited the best antibacterial activity against Citrobacterfreundii (ATCC 8090) and Methicillin-resistant Staphylococcus aureus (ATCC 43300) strains.

Solid State Fermentation Optimization of Pleurotus Ostreatus for Lovastatin Production

Abstract: The present study was aimed at optimization of the solid state fermentation of lovastatin (HMG-CoA reductase inhibitor) using the Plackett – Burman (PB) design and response surface methodology (RSM) for edible and medicinal mushroom Pleurotus ostreatus so as to improve Pleurotus-fermented products (like red yeast rice) with health promoting properties. According to the results of PB design, the barley, yeast extract, and particle size of the solid substrate were found to have significant effect on lovastatin production. The concentrations of barley and yeast extract and the particle size of the solid substrate were further optimized by RSM. As a result, high lovastatin production (34.97 mg/g) was achieved at the optimized conditions of barley (8 g), yeast extract (1% w/w), and particle size of the solid substrate (0.5 - 1 mm) at 28°C for 6 days.

Sorption Properties of Sunflower Husk Melanins

Abstract: The sorption properties of sunflower husk melanins were studied according to pharmacopoeial monograph GPM123002115 using marker compounds methylene blue, methyl orange, gelatin, and iodine The sorption capacities of the studied samples were found to be 1909 ± 42 mg/g for methylene blue; 3021 ± 18, methyl orange; 1147 ± 28, gelatin; and 384 ± 24%, I2 The sorption capacities of the samples were greater than those of the sorbents Polifepan and Polysorb and comparable with that of activated charcoal for medium-molecular-mass toxicants The melanins showed high affinity for anionic substances The protein-binding capacities of the melanins were inferior only to that of Polysorb and significantly greater than those of Polifepan and activated charcoal The sorption capacity for I2 matched that of Polifepan and was >15 times less than that of activated charcoal The results showed that enterosorbents based on melanins could be developed

Dissolution of Ketoprofen from Poly(Ethylene Glycol) Solid Dispersions

Abstract: The effect of solid dispersions (SDs) on the solubility of the nonsteroidal anti-inflammatory drug ketoprofen was determined. Ketoprofen and its SDs with poly(ethylene glycol) PEG-400, -1000, -1500, -2000, and -3000 were studied. Dissolution of ketoprofen from the SDs increased by 1.2 – 1.8 times; the dissolution rate, by 1.7 – 2.4 times. The improved release of ketoprofen from the SDs was proposed to be due to several factors such as solubilization and amorphization of the compound and formation of intermolecular H-bonds. The results could be used to develop rapidly dissolving ketoprofen solid dosage forms.

UHPLC Method Development for Determining Sitagliptin and Dapagliflozin in Lipid-Based Self-Nanoemulsifying Systems as Combined Dose in Commercial Products and its Application to Pharmacokinetic Study of Dapagliflozin in Rats

Abstract: Anew simple, precise, selective and reproducible reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) method has been developed and validated for the first time in simultaneous determination of two anti-diabetic drugs, sitagliptin (SN) and dapagliflozin (DN), in lipid-based self-nanoemulsifying formulations as a new combined preparation dose. The chromatographic separation was carried out on a reversed-phase Acquity® BEH C18 column using methanol–acetonitrile–water mixture at 24/18/58 (%v/v/v) ratio as the mobile phase. The isocratic flow rate was 0.4 mL/min with a run time of 6 min. The UV detection of both SN and DN was performed at 210 nm. The method was validated over a concentration range of 100 – 10000 ng/mL (r2 = 0.9997 and 0.9999 for SN and DN, respectively). The selectivity, specificity, recovery, accuracy and precision for determining SN and DN in lipid-based formulation were validated. The lower limits of detection and quantitation of the method were 27 and 89 ng mL–1 for SN and 19 and 61 ng mL–1 for DN, respectively. The intra- and inter-day coefficients of variation were less than 4%. The validated method has been successfully applied to quantify both SN and DN in self-nanoemulsifying formulation of combined dosage form. In addition, the proposed method was also applied for in vivo pharmacokinetic study using an animal model (rat) to further illustrate the scope and application of the proposed method.

Quantitative Determination of Total Flavonoids in Blood-Red Hawthorn Leaves

Abstract: A quantitative determination method for total flavonoids in blood-red hawthorn leaves recalculated as vitexin 2″-O-rhamnoside using difference spectrophotometry at 392 nm was developed. The error of a single determination of total flavonoids in blood-red hawthorn leaves was ± 1.57% with confidence probability 95%. The contents of total flavonoids in blood-red hawthorn leaves varied from 2.65 ± 0.05 to 3.53 ± 0.06%.

Synthesis and In Vivo Evaluation of New Coumarin Conjugates as Potential Indirect-Action Anticoagulants

Abstract: A synthetic method for a series of new coumarin conjugates was developed. Their structures and physicochemical properties were determined by modern spectral methods (IR, NMR, ESI-MS). The anticoagulant activity was studied in vivo by determining the prothrombin time (PT). Compounds 4a (PT = 10.88 ± 0.56 sec) and 4b (13.10 ± 3.56 sec) were the most active and comparable to the reference drug warfarin (7.97 ± 1.93 sec).

Synthesis and Neurotropic Activity of New Condensed Pyrano[4,3- b ]-Pyridines Derivatives

Abstract: Methods for synthesizing new condensed pyrano[4, 3-b]pyridine derivatives from 2-methyl-2-ethyltetrahydropyran-4-one were developed. The neurotropic activities of the compounds were studied.

Synthesis, Antimicrobial Activity, and Behavioral Response Effects of N-Substituted 4-Aryl-2-Hydroxy-4-Oxobut-2-Enoic Acid Hydrazides and Their Metal Complexes

Abstract: N-Substituted 4-aryl-2-hydroxy-4-oxobut-2-enoic acid hydrazides and their complexes with Ni(II), Mn(II), Co(II), Cu(II), and Zn(II) were prepared. Their antimicrobial activity and behavioral response effects in mice were studied. Compounds with low acute toxicities and activities comparable to or exceeding those of the reference drugs were discovered.

Synthesis and Anticonvulsant Activity of 4-Amino-3-Nitro-1-Thiocoumarins and 4-Amino-3-Nitroquinolin-2-Ones

Abstract: Novel thiocoumarins and quinolin-2-ones were synthesized and screened for anticonvulsant activity. The structure–activity relationship of a series of synthesized compounds and previously prepared coumarin derivatives was analyzed. The methyl ester of N-(3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)-4-aminobutyric acid (3a) at a dose of 12.5 mg/kg (i.p.) had the greatest anticonvulsant activity in mouse tests.

Modern Extraction Methods for Medicinal Plant Raw Material (Review)

Abstract: Various extraction methods are reviewed. Their advantages and disadvantages are discussed. Traditional and modern extraction methods are compared.

Synthesis and Antimicrobial Activity of 3-Phenyl-1-Methylquinolin-2-One Derivatives

Abstract: A series of quaternary salts were obtained by reacting 3-(4-bromoacetylphenyl)-1-methylquinolin-2(1H)-one with Py, 4-methylpyridine, quinoline, benzo[f]quinoline, and triphenylphosphine. Derivatives of thiazole, imidazo[1,2-a]pyridine, and imidazo[1,2-a]pyrimidine were produced using dinucleophilic reagents. Several of the synthesized compounds possessed high antimicrobial activity, indicating that further research on this series of compounds was promising.

Synthesis and Anticonvulsant Activity of N-Substituted 4-Amino-3-Nitrocoumarins

Abstract: The synthesis and anticonvulsant activity of new coumarin derivatives are reported. N-(3-Nitrocoumarin-4-yl)-4-aminobutyric acid (1a) at doses of 60 and 80 mg/kg (in the MES test) and methyl N-(3,6-dinitrocoumarin-4-yl)-4-aminobutyrate (1e) at doses of 20 and 40 mg/kg (in the corazole antagonism test) possessed the greatest anticonvulsant activity of the synthesized compounds. The results indicated that the coumarin derivatives were promising for further development as potential anticonvulsant agents.