Showing papers by "Josef Jampilek published in 2017"

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Abstract: Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].

Characterization of Essential Oil Composition in Different Basil Species and Pot Cultures by a GC-MS Method

Abstract: Basil (Ocimum L.) species are used as medicinal plants due to their essential oils exhibiting specific biological activity. The present work demonstrated that both the variety and season/conditions of cultivation had a significant effect on (i) the produced amount (extraction yield), (ii) qualitative, as well as (iii) quantitative profile of basil essential oil. Among studied basil varieties, a new variety, ‘Manes’, was characterized for the first time. Based on our quantitative evaluation of GC-MS profiles, the following chemotypes and average concentrations of a main component were detected in the studied basil varieties: ‘Ohře’, ‘Lettuce Leaf’, ‘Purple Opaal’, ‘Dark Green’ (linalool, 5.99, 2.49, 2.34, 2.01 mg/mL, respectively), and ‘Mammolo Genovese’, ‘Manes’, ‘Red Rubin’ (eucalyptol, 1.34, 0.96, 0.76 mg/mL, respectively). At the same time, when considering other compounds identified in GC-MS profiles, all the studied varieties, except from ‘Lettuce Leaf’, were methyl eugenol-rich with a strong dependence of the eugenol:methyl eugenol ratio on the seasonal changes (mainly solar irradiation, but also temperature and relative humidity). More complex and/or variable (depending on the season and cultivation) chemotypes were observed with ‘Lettuce Leaf’ (plus estragole, 2.27 mg/mL), ‘Dark Green’ (plus eucalyptol, 1.36 mg/mL), ‘Mammolo Genovese’ (plus eugenol, 1.19 mg/mL), ‘Red Rubin’ (plus linalool and eugenol, 0.46 and 0.56 mg/mL, respectively), and ‘Manes’ (plus linalool and eugenol, 0.58 and 0.40 mg/mL, respectively). When considering superior extraction yield (ca. 17 mL·kg−1, i.e., two to five times higher than other examined varieties) and consistent amounts (yields) of essential oil when comparing inter-seasonal or inter-year data (RSD and inter-year difference in mean yield values ˂2.5%), this new basil variety is very promising for use in the pharmaceutical, food, and cosmetic industries.

Nanomaterials for Delivery of Nutrients and Growth-Promoting Compounds to Plants

Abstract: Nanotechnology is a rapidly expanding field that affords the development of materials in nanoscale dimensions that have unique properties and a wide spectrum of applications. Nanomaterials can be found more frequently in agriculture and the food sector. The application of nanomaterials for delivery of nutrients and growth-promoting compounds to plants has become more and more popular, and their utilization at the proper place, at the proper time, in the proper amount and of the proper composition emends the efficacy of fertilizers. This contribution reviews the potential application of various nanocarriers used for delivery of N, P and K macronutrients and plant growth-stimulating nanoscale essential metals nutrients (Fe, Zn, Cu, Mn, Co) as well as carbon-based (single- and multiwalled carbon nanotubes) and non-essential metal (Ti, Ag, Au, Ce, Al)- and metalloid (Si, Se)-based nanomaterials showing beneficial effects on plant growth that could be used in agricultural practice.

Nanopesticides: preparation, targeting, and controlled release

Abstract: Nanoformulations applied in biomedicine and agriculture are designed to decrease dose-dependent toxicity by the reduced amount of an applied compound, which is realized by increasing the solubility of poorly water soluble active ingredients, enhancing their bioavailability, targeted delivery, controlled release, and/or protection against degradation. The toxicity of pesticides is influenced by their chemical stability, solubility, bioavailability, photodecomposition, and soil sorption; therefore one of possible solutions designed to minimize the dose-dependent toxicity of active ingredients includes the development of nanocarriers able to modify the properties of active ingredients and allow their controlled delivery and release. However, the causal link between nanoengineered pesticide properties and their biological effects is not well known and represents an important challenge of nanoecotoxicology. This paper is focused on methods of preparation of nanoengineered active ingredients, their formulation to nanocarriers for targeted biodistribution/controlled release and their biological effectiveness. Benefits and environmental risks of nanopesticides are discussed as well.

Nanoantimicrobials: Activity, Benefits, and Weaknesses

Abstract: Bacterial, mycobacterial, and fungal infections represent an increasing worldwide threat. The increase in the number of infections is caused by general immunosuppression (primarily by tumor treatment and administration of immunosuppressive agents), an increase in the number of HIV-positive patients, and development of resistance not only to commonly used drugs, but also to second- or third-choice drugs. The development of cross-resistant or multidrug-resistant strains constitutes a serious problem as well. This situation can be solved by the discovery of new molecular scaffolds, reengineering/repositioning of some old drug classes, or application of nanotechnology, which may reduce the costs of design and discovery processes. Antimicrobial chemotherapeutics encapsulated in nanoformulations created from biodegradable polymers have great potential to replace the bulk form of these chemotherapeutics. Controlled-release and targeted-delivery nanoformulations protect chemotherapeutics against decomposition or deactivation, enhance bioavailability, decrease toxicity for nontarget tissues, and decrease the “pill burden.” In many cases, nanoencapsulated drugs have restored antibacterial activity against resistant strains. This contribution is focused on methods of incorporation of active ingredients into different types of nanocarriers for targeted biodistribution/controlled release and on the antimicrobial effectiveness of these formulations. In addition, weaknesses in the application of nanoantimicrobials in clinical practice and potential health risks related to the application of nanoformulations are discussed.

Silver Nanoparticles Stabilised by Cationic Gemini Surfactants with Variable Spacer Length

Abstract: The present study is focused on the synthesis and investigation of the physicochemical and biological properties of silver nanoparticles stabilized with a series of cationic gemini surfactants having a polymethylene spacer of variable length. UV-VIS spectroscopy, dynamic light scattering, scanning electron microscopy and zeta potential measurements were applied to provide physicochemical characterization of the silver nanoparticles. The mean size values of the nanoparticles were found to be in the 50 to 115 nm range. From the nanoparticle size distributions and scanning electron microscopy images it results that a population of small nanoparticles with the size of several nanometers was confirmed if the nanoparticles were stabilized with gemini molecules with either a short methylene spacer (two or four −CH2− groups) or a long spacer (12 −CH2− groups). The average zeta potential value for silver nanoparticles stabilized with gemini molecules is roughly independent of gemini surfactant spacer length and is approx. +58 mV. An interaction model between silver nanoparticles and gemini molecules which reflects the gained experimental data, is suggested. Microbicidal activity determinations revealed that the silver nanoparticles stabilized with gemini surfactants are more efficient against Gram-negative bacteria and yeasts, which has a direct relation to the interaction mechanism of nanoparticles with the bacterial cell membrane and its structural composition.

Proline-Based Carbamates as Cholinesterase Inhibitors.

Abstract: Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure-inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3'-/4'-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

Halogenated 1-Hydroxynaphthalene-2-Carboxanilides Affecting Photosynthetic Electron Transport in Photosystem II

Abstract: Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 1-Hydroxy-N-phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC50 = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P680 and plastoquinone QB in the PET chain occurring on the acceptor side of PS II can be suggested as the site of action of the compounds. The structure-activity relationships are discussed.

In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters.

Abstract: Finding a balance between a desired drug's potency and its physicochemical properties that are important for its molecule pharmacokinetic or pharmacodynamics profile is still a challenging issue in rational drug discovery. Quantitative assessment of the lipophilic characteristics of potential drug molecules is indispensable for efficient development of Absorption, Distribution, Metabolism, Excretion, Toxicity-tailored structure-activity models; therefore reliable procedures for deriving log P from molecular structure are desirable. In the current work a range of various software log P predictors for estimation of the numerical lipophilic values for a set of cholic acid derivatives were employed and subsequently cross-compared with the experimental parameters. Thus, the empirical lipophilicity (RM) was compared with the corresponding log P characteristics calculated using alternative methods for deducing the lipophilic features. The mean values of the selected molecular descriptors that were averaged over the chosen calculation methods (consensus clog P) were subsequently correlated with the RM parameter. As an additional experiment, the iterative variable elimination partial least squares (IVE-PLS) methodology for an ensemble of descriptors retrieved from Dragon 6.0 software was applied for a set of drug transporters. To investigate the variations within the ensemble of cholic acid derivatives principal component analysis (PCA) and self-organizing neural network (SOM) procedures were used to visualize the major differences in the performance of drug promoters with respect to their lipophilic profile.

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain.

Abstract: Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a–h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (compound 8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a–h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a–h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a–h were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 μM indicated. The structure–antimycobacterial activity relationships of the analyzed 8a–h series are also discussed.

Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2-Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates

Abstract: Eight 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates and eight 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The PET-inhibiting activity of the compounds was relatively low; the corresponding IC50 values ranged from 0.05 to 0.664 mmol/L; and the highest activity within the series of compounds was observed for 1-[(2-chlorophenyl)-carbamoyl]naphthalen-2-yl propylcarbamate. It has been proven that the compounds are PET-inhibitors in photosystem II. Despite rather low PET-inhibiting activities, primary structure-activity trends can be discussed.

A Rapid and Simple TLC-Densitometric Method for Assay of Clobetasol Propionate in Topical Solution.

Abstract: A rapid, simple to use and low-cost thin-layer chromatographic procedure in normal phase system with densitometric detection at 246 nm was carefully validated according to the International Conference on Harmonisation (ICH) guidelines for assay of clobetasol propionate in topical solution containing clobetasol propionate in quantity 0.50 mg/mL. The adopted thin-layer chromatographic (TLC)-densitometric procedure could effectively separate clobetasol propionate from its related compound, namely clobetasol. It is linear for clobetasol propionate in the range of 0.188 ÷ 5 µg/spot. The limit of detection (LOD) and limit of quantification (LOQ) value is 0.061 and 0.186 µg/spot, respectively. Accuracy of proposed procedure was evaluated by recovery test. The mean recovery of studied clobetasol propionate ranges from 98.7 to 101.0%. The coefficient of variation (CV, %) obtained during intra-day and inter-day studies, which was less than 2% (0.40 ÷ 1.17%), confirms the precision of described method. The assay value of clobetasol propionate is consistent with the pharmacopoeial requirements. In conclusion, it can be suitable as a simple and economic procedure for routine quality control laboratories of clobetasol propionate in topical solution.

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot †

Abstract: The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5–8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, “Drug Synthesis and Analysis,” meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.

Chromatographic and Computational Study of Hydro-lipophilic Properties of N-Alkoxyphenylhydroxy-naphthalenecarboxamides

Abstract: N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently reported as series of compounds with antimycobacterial, antibacterial and herbicidal activity. As it was found that the lipophilicity of these significantly biologically effective agents determined their activity, in this study hydro-lipophilic properties of all three series are investigated. All fifty-seven anilides were analysed using the reversed-phase high performance liquid chromatography method for lipophilicity measurement. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, the correlation between the logarithm of capacity factor k and log P/Clog P values calculated in various ways is discussed as well as the relationships between the lipophilicity and the chemical structure of the studied compounds.

Investigation of permeation of acyclovir through skin using alaptide

Abstract: The investigation deals with the affection of the permeation of acyclovir through full-thickness pig ear skin using a Franz diffusion cell from the donor vehicles of phosphate buffer (pH 7.4) and propylene glycol–water (1:1) using synthesised (S)-8-methyl-6,9-diazaspiro[4.5]decane-7,10-dione, alaptide as a transdermal permeation enhancer. Alaptide was applied in ratio 1:10 (w/w) relative to the amount of acyclovir. At the first hour after application, the permeated amount of acyclovir from propylene glycol—water system, simulating semisolid dosage forms, was ca. four-fold higher than from the formulation without alaptide. Despite that the enhancement ratio of alaptide in a steady state was 1.7, the pseudo-enhancement ratio of alaptide in the time range of first to third hour was 2.3. Both enhancement ratios indicate that alaptide modifies skin structure, while the short-term application of the alaptide formulation seems to be more advantageous.