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A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases ( Ee AChE, Eq BChE) with IC 50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC 50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1–42 aggregation (80.6% and 91.3% at 50 μM and 100 μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD. [ABSTRACT FROM AUTHOR]

A sensitive and fast HPLC method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS) was developed for the determination of tebipenem pivoxyl and in the presence of degradation products formed during thermolysis. The chromatographic separations were performed on stationary phases produced in core–shell technology with particle diameter of 5.0 µm. The mobile phases consisted of formic acid (0.1%) and acetonitrile at different ratios. The flow rate was 0.8 mL/min while the wavelength was set at 331 nm. The stability characteristics of tebipenem pivoxyl were studied by performing stress tests in the solid state in dry air (RH=0%) and at an increased relative air humidity (RH=90%). The validation parameters such as selectivity, accuracy, precision and sensitivity were found to be satisfying. The satisfied selectivity and precision of determination were obtained for the separation of tebipenem pivoxyl from its degradation products using a stationary phase with 5.0 µm particles. The evaluation of the chemical structure of the 9 degradation products of tebipenem pivoxyl was conducted following separation based on the stationary phase with a 5.0 µm particle size by applying a Q-TOF-MS/MS detector. The main degradation products of tebipenem pivoxyl were identified: a product resulting from the condensation of the substituents of 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl and acid and ester forms of tebipenem with an open β-lactam ring in dry air at an increased temperature (RH=0%, T =393 K) as well as acid and ester forms of tebipenem with an open β-lactam ring at an increased relative air humidity and an elevated temperature (RH=90%, T =333 K). Retention times of tebipenem pivoxyl and its degradation products were used as training data set for predictive model of quantitative structure–retention relationship. An artificial neural network with adaptation protocol and extensive feature selection process was created. Input parameters for model were calculated from molecular geometries optimized with application of Density Functional Theory. The model was prepared and optimized especially for small data sets such as degradation products of specific compound. Validation of the model with statistical test against requirements for QSAR showed its ability for prediction of retention times within given data set. Mean error of 24.75% (0.8 min) was achieved with utilization of topological, geometrical and electronic descriptors. [ABSTRACT FROM AUTHOR]

Electrochemical degradation of the antiretroviral drug raltegravir was investigated using different electrode materials (platinum, glassy carbon and boron-doped diamond). After preliminary studies with the use of multivariate chemometric method, electrochemical degradation was conducted with a boron-doped diamond electrode and phosphate buffer at pH 9. To assess the role of different variable in degradation kinetics, final experiments were conducted with varying applied current densities, chloride and humic acid concentrations, and using a natural river water sample. The results showed that raltegravir degradation generally followed pseudo-first-order kinetics. The degradation rate was inhibited by the presence of humic acid, while increasing the applied current density or chloride concentration enhanced the removal of raltegravir. Degradation process performed in the river water sample followed second-order kinetics and led to almost complete degradation of raltegravir within 30 min, highlighting the impact of natural matrices on reaction kinetics. Total organic carbon analysis was utilized, showing that even rapid degradation of the parent compound did not ensure total mineralization. Additionally, the energy consumption analysis revealed that the presence of chloride ions significantly improves efficiency of the organic carbon elimination. With the use of high-resolution mass spectrometry fourteen transformation products were elucidated, and their aquatic toxicity was predicted using in silico approach. Half of the identified transformation products were found to possess higher aquatic toxic potential than the parent compound, emphasizing the necessity of the mineralization assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The main objective of this study was to investigate the metabolism of miconazole, an azole antifungal drug. Miconazole was subjected to incubation with human liver microsomes (HLM) to mimic phase I metabolism reactions for the first time. Employing a combination of an HLM assay and UHPLC-HRMS analysis enabled the identification of seven metabolites of miconazole, undescribed so far. Throughout the incubation with HLM, miconazole underwent biotransformation reactions including hydroxylation of the benzene ring and oxidation of the imidazole moiety, along with its subsequent degradation. Additionally, based on the obtained results, screen-printed electrodes (SPEs) were optimized to simulate the same biotransformation reactions, by the use of a simple, fast, and cheap electrochemical method. The potential toxicity of the identified metabolites was assessed using various in silico models.

Fungal infections pose a significant global health burden, resulting in millions of severe cases and deaths annually. The escalating demand for effective antifungal treatments has led to a rise in the wholesale distribution of antifungal drugs, which consequently has led to their release into the environment, posing a threat to ecosystems and human health. This article aims to provide a comprehensive review of the presence and distribution of antifungal drugs in the environment, evaluate their potential ecological and health risks, and assess current methods for their removal. Reviewed studies from 2010 to 2023 period have revealed the widespread occurrence of 19 various antifungals in natural waters and other matrices at alarmingly high concentrations. Due to the inefficiency of conventional water treatment in removing these compounds, advanced oxidation processes, membrane filtration, and adsorption techniques have been developed as promising decontamination methods.In conclusion, this review emphasizes the urgent need for a comprehensive understanding of the presence, fate, and removal of antifungal drugs in the environment. By addressing the current knowledge gaps and exploring future prospects, this study contributes to the development of strategies for mitigating the environmental impact of antifungal drugs and protecting ecosystems and human health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound.

Photolytic transformation of aspartame - a widely used artificial sweetener - under the simulated sunlight was studied for the first time. The experiments were conducted in pH range of 2.5 - 7.0 and in eight soft drinks available in the market. The highest degradation rate in the tested buffered solutions was observed under the neutral pH conditions. Irradiation of the soft drinks resulted in significantly (up to tenfold) faster degradation of aspartame, regardless of its initial concentration in the beverage. Such considerable acceleration of decomposition, not reported for aspartame so far, was ascribed to influence of the co-occurring ingredients, which can act as the photosensitizers. These findings indicate that some formulations may be particularly unfavorable in the context of aspartame photostability. Qualitative analysis of the studied processes revealed formation of six phototransformation products including three previously not described. In silico estimation of toxicity showed that some of the identified photoproducts, including the novel phenolic derivatives, may be more harmful than the parent compound. Taking into account relatively extensive formation of those products in the soft drinks, such finding may be particularly important from the food safety point of view., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The influence of ionizing radiation on the physicochemical properties of quercetin and rutin in the solid state was studied. Quercetin and rutin were irradiated with the standard recommended radiation dose (25 kGy) according to EN 522 standard. The samples were irradiated by electron beam radiation. EPR studies indicate the formation of a small number of free radicals due to irradiation. Moreover, some radicals recombined with the mean lifetime of 1200 and 93 h, and a stable radical concentration reached only 0.29 and 0.90 ppm for quercetin and rutin, respectively. The performed spectroscopic study (FT-IR) confirmed the radiostability of the flavonoids tested. Chromatographic tests (HPLC, HPLC-MS) showed that irradiation of quercetin and rutin with a 25 kGy dose did not change the physicochemical properties of the tested compounds. Degradation products were not observed. The antioxidant activities were determined by the 2,2-diphenyl-1-pycrylhydrazyl (DPPH) free radical scavenging activity assay, ABTS Radical Scavenging Assay (ABTS), Ferric Reducing Antioxidant Power Assay (FRAP), Cupric Ion Reducing Antioxidant Capacity Assay (CUPRAC). The conducted research confirmed that exposure to ionizing radiation does not change the chemical structure of tested flavonoids and their antioxidant properties.

The purpose of this study was to determine the effect of electron beam irradiation (EBI) at a dose of 25 kGy on the stability and antioxidant properties of resveratrol (RSV), a nutraceutical with clinically proven activity. The electron paramagnetic resonance (EPR) method was used to evaluate the concentration of free radicals after irradiation. Minor changes in chemical structure due to free radicals induced by EBI were confirmed by FTIR spectroscopy. HPLC and HPLC-MS analysis ruled out the appearance of degradation products after irradiation. In addition, HPLC analysis confirmed the absence of trans- to cis-resveratrol conversion. Changes in the antioxidant potential of RSV after irradiation were studied using DPPH, ABTS, CUPRAC, and FRAP techniques. It was confirmed that EBI favorably affected the antioxidant properties of tests based on the HAT mechanism (increase in DPPH and CUPRAC tests).

In the present study the photochemical fate of organoiodine compound - amiodarone was performed. The drug turned out to be highly susceptible to UV-Vis irradiation, especially in the presence of humic substances and organic matrix. Qualitative LC-MS analysis revealed formation of twelve - mainly previously unreported - transformation products (TPs). Four major TPs were submitted to the toxicity analysis with the use of D. magna. All of the tested TPs presented higher toxic potential than the parent compound. The phenolic TPs were approximately 100 times more toxic than amiodarone. Toxic properties of the major TPs resulted in steadily increasing toxic potential of the photo-generated mixture over the time of irradiation. Moreover, the experimental toxicity data, concerning the TPs, were compared with results estimated by 6 in silico models with the use of a multivariate chemometric analysis. The results showed that the applied computational methods were able neither to correctly predict toxic properties of the studied compounds, nor the trends in change of their toxic parameters. Additional validation of in silico models ability to predict toxicity of iodinated organic compounds showed that the studied computational methods do not present sufficient prediction ability. Therefore their estimations concerning organoiodines should be verified using experimental tests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Basal cell carcinoma (BCC) is the most common malignant neoplasm of the skin. Management of patients with recurrent BCC remains a current clinical issue. Data concerning BCC recurrence rates as well as characteristics of this group of patients in the Polish population are scarce., Aim: Identification and analysis of clinical, epidemiological and histopathological factors influencing BCC recurrence., Material and Methods: Histopathological diagnoses of BCC patients treated by surgical methods at the Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, between 2013 and 2018, were retrospectively analysed. The analysis included 1097 tumours diagnosed in 802 patients, of which 1061 were primary BCC (pBCC) and 36 - recurring BCC (rBCC)., Results: In the analysed cohort, rBCCs constituted 3.3% of cases. 49.8% of pBCCs occurred in women; while in the rBCC group - 47.2%. The most common histopathological type was infiltrative BCC, however, it was significantly more prevalent in rBCCs (36.9% and 52.8%, respectively). The average maximum size of pBCC was 12.3 ±8.8 mm, while of rBCC 18.4 ±15.1 mm ( p = 0.036). The most common location of both pBCC and rBCC was the nose (tumours in this localization constituted 23.2% and 25.0%, respectively)., Conclusions: In the analysed cohort a relatively low percentage of rBCC was found. Among analysed risk factors, the most important ones were the infiltrative histopathological type of BCC and the non-radical treatment of the primary tumour., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)

A new series of tetrahydroacridine derivatives with the fluorobenzoyl moiety was synthesized and evaluated for cytotoxic activity against lung cancer cell lines A549 and colorectal cancer HT29. The cytotoxic activity of the compounds was compared on the somatic cell line-EAhy926. Compounds showed high cytotoxic activity on A549 cells (IC 50  183.26-68.07 μM) and HT29 cells (IC 50 68.41-19.70 μM), higher than controls-etoposide (IC 50 451.47 μM) toward A549 and 5-fluorouracil (IC 50 1626.85 μM) against HT29. Derivative 4 was the most cytotoxic to A549, whereas for the cell lines HT29 compound 6. Selected compounds showed similar cytotoxicity to the EAhy926 cell line (IC 50 about 50 μM). In the hyaluronidase inhibition assay, all compounds exhibited anti-inflammatory activity, including 4 exhibiting the best inhibitory activity-IC 50 of 52.27 μM when the IC 50 heparin was 56.41 μM. Mathematical modeling was performed to determine LD 50 after intraperitoneal, oral, intravenous and subcutaneous administration and to predict potential mutagenicity and carcinogenicity of the compounds analyzed. Obtained results showed that tested derivatives are slightly toxic compounds, and LD 50 values (mg/kg) ranged from 680 to 1200 (oral rat model), the analyzed compounds have low mutagenic potential, and differences between derivatives are insignificant and very low probability of carcinogenicity. To confirm mathematical calculations, an in vivo test was carried out on a laboratory mouse model for two selected compounds. It allowed to qualify compounds: 6 to category 4 of the GHS scale, and 4 to category 3 of the GHS scale.

The photolytic and photocatalytic transformation of loxapine with the use of H 2 O 2 , TiO 2 and SrTiO 3 under the simulated solar radiation was studied. A micro-scale method for simultaneous irradiation of multiple samples in photostability chamber was applied. RP-UHPLC-DAD coupled with ESI-Q-TOF mass spectrometer was used for the quantitative and qualitative analysis of the processes. Influence of catalysts concentration on kinetic parameters of loxapine photodecomposition was evaluated, and TiO 2 at medium concentration (100 mg L -1 ) turned out to be the most effective. Sixteen transformation products were detected and their structures were elucidated. On the basis of the elucidated structures, computational evaluation of toxicity, bioconcentration and bioaccumulation factors as well as biodegradability of transformation products were conducted. The multivariate chemometric method (principal component analysis) was used to compare the calculated properties as well as the applied methods. Most of the transformation products were generally less toxic and more biodegradable than the parent compound., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC 50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC 50  = 31.2 nm), and it was more active than reference drug, tacrine (IC 50  = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC 50  = 8.0 nm), also higher than tacrine (IC 50  = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25 μm-72%, 50 μm-78.44%, and 100 μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease., (© 2017 John Wiley & Sons A/S.)

The photolytic and photocatalytic transformation of tiapride with the use of TiO 2 and H 2 O 2 was investigated. A novel micro-scale method for simultaneous irradiation with simulated full solar spectrum of multiple samples in photostability chamber was proposed. RP-UHPLC-DAD coupled with ESI-Q-TOF mass spectrometer was used for the quantitative and qualitative analysis of the processes. Quantitative method was fully validated, and kinetic parameters of tiapride photodegradation were compared. Structures of twenty-one photoproducts as well as phototransformation pathways were proposed. Based on the elucidated structures, computational toxicity assessment with the use of various software was performed and some of transformation products were found as a potentially highly mutagenic and carcinogenic compounds. The multivariate statistical method (principal component analysis) was used to compare toxicity of phototransformation products as well as toxicity assessment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Forced degradation of clozapine in solutions under acidic, basic, neutral, photo UV-vis, photo UVC and oxidative stress conditions was investigated and structural elucidation of its degradation products was performed with the use of the UHPLC-DAD system coupled with accurate hybrid ESI-Q-TOF mass spectrometer. The developed method allows to collect all essential data for the determination of degradation kinetics and for the structural elucidation of the formed products. Six degradation products were found and their masses and formulas were obtained with high accuracy (0.61-3.75ppm). For all the analyzed compounds MS/MS fragmentation spectra were also obtained allowing structural elucidation of the unknown degradation products. It was found that the decomposition of clozapine yields the first-order kinetic reaction in all stress conditions and it is fragile towards acidic hydrolysis and oxidative conditions. Additionally, PCA analysis of registered TOF (MS) forced degradation profiles of clozapine shows no differences between the samples obtained from pharmaceutical formulation and bulk substance., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The possibility of applying radiation sterilization to cefpirome sulfate was investigated. The lack of changes in the chemical structure of cefpirome sulfate irradiated with a dose of 25 kGy, required to attain sterility, was confirmed by UV, FT-IR, Raman, DSC and chromatographic methods. Some radical defects with concentration no more than over a several dozen ppm were created by radiation. The antibacterial activity of cefpirome sulfate for two Gram-positive and three Gram-negative strains was changed. The radiation sterilised cefpirome sulfate was not in vitro cytotoxic against fibroblast cells., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The stability-indicating LC assay method was developed and validated for quantitative determination of cefpirome sulfate (CPS) in the presence of degradation products formed during the forced degradation studies. An isocratic HPLC method was developed with Lichrospher RP-18 column, 5 μm particle size, 125 mm x 4 mm column and 12 mM ammonium acetate-acetonitrile (90 : 10 v/v) as a mobile phase. The flow rate of the mobile phase was 1.0 mL/min. Detection wavelength was 270 nm and temperature was 30 degrees C. Cefpirome sulfate as other cephalosporins was subjected to stress conditions of degradation in aqueous solutions including hydrolysis, oxidation, photolysis and thermal degradation. The developed method was validated with regard to linearity, accuracy, precision, selectivity and robustness. The method was applied successfully for identification and determination of cefpirome sulfate in pharmaceuticals and during kinetic studies.

Three rapid, simple and accurate analytical methods for the determination of citalopram in tablets were developed. The capillary zone electrophoresis (CZE) method was carried out using fused silica capillary with 67 mM phosphate buffer pH 7.0 as the background electrolyte, 30 kV of separation voltage and UV detection at 239 nm. The direct spectrophotometric method was performed by measuring the absorbance at the wavelength of 239 nm and derivative spectrophotometric assay was carried out by measuring the value of the second derivative of the spectrum at 210 nm. The linearity range for CZE method was 5-50 microg/mL and for both spectrophotometric methods was 2-12 microg/mL. The recovery in CZE was between 98.6 and 102.4%, in the direct spectrophotometry between 95.0 and 98.0% and in derivative spectrophotometry between 97.6 and 103.3%. The RSD values were between 1.36 and 2.30%, 1.80 and 2.70%, 1.52 and 2.68%, respectively.

An isocratic high-performance liquid chromatographic method for the quantitation of felbamate in serum is presented. The method is based on protein precipitation with acetonitrile and reversed-phase chromatography with spectrophotometric detection at 210 nm. The separation was performed on a Nova-Pak C18 column and the mobile phase consisted of acetonitrile-water (1:4, v/v). Phenobarbital was applied as an internal standard. The assay was linear over the concentration range 0.5-200.0 microg/ml (r = 0.9999). Intra-day and inter-day precision expressed by relative standard deviation is less than 3%. The percentage of recovery was 98.63 +/- 2.47. The method is suitable for drug level monitoring and for pharmacokinetic studies.