Search Results (10)

In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, and sertraline, from various biological fluids. In this regard, poly(3,4-ethylenedioxythiophene)–graphene oxide (PEDOT-GO) was electrodeposited on an SPME fiber as a conductive coating, then the fiber played the acceptor-electrode role during the extraction. Thus, the immigration of the analytes under the influence of an electric field and their absorption onto the fiber coating were accomplished simultaneously. Under the optimized conditions, the limits of detection for the target analytes were acquired in the range of 0.005–0.025 µg L⁻¹ using gas chromatography–mass spectrometry. The linearity of the method was 0.010–500 µg L⁻¹ for the imipramine and sertraline, 0.025–500 µg L⁻¹ for the amitriptyline, nortriptyline, and desipramine, and 1.000–250 µg L⁻¹ for the maprotiline (R² ≥ 0.9984). Moreover, this method provided suitable precision and fiber-to-fiber reproducibility, with RSDs ≤ 8.4%. The applicability of the proposed setup was eventually investigated for extraction of the drugs from human bone marrow aspirate, urine, plasma, and well water samples, in which satisfactory relative recoveries, from 93–105%, were obtained. Full article

Potentiometry with membrane selective electrodes is preferable for measuring the various constituents of pharmaceuticals. In this work, carbon paste electrodes (CPE) were prepared, modified, and tested for the determination of maprotiline hydrochloride, which acts as an antidepressant. The proposed CPE was based on an ionic association complex of maprotiline-tetraphenylborate, 2-nitrophenyloctyl as a binder, and sodium tetraphenylborate as an ionic lipophilic additive. The optimized composition improved potentiometric properties up to theoretical Nernst response values of −59.5 ± 0.8 mV dec⁻¹, in the concentration range of maprotiline from 1.6 × 10⁻⁷ to 1.0 × 10⁻² mol L⁻¹, and a detection limit of 1.1 × 10⁻⁷ mol L⁻¹. The CPE provides excellent reversibility and reproducibility, exhibits a fast response time, and is applicable over a wide pH range. No significant effect was observed in several interfering species tested. The proposed electrode was used for the precise determination of maprotiline in pure solutions, urine samples, and a real sample—the drug Ludiomil. Full article

The increasing use of pharmaceuticals, their presence in the aquatic environment, and the associated toxic effects, have raised concerns in recent years. In this work, a new multi-residue analytical method was developed and validated for the determination of 10 pharmaceuticals in wastewaters using online solid-phase extraction (online SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The compounds included in the method were antineoplastics (cabazitaxel, docetaxel, doxorubicin, etoposide, irinotecan, methotrexate, paclitaxel, and topotecan), renin inhibitors (aliskiren), and antidepressants (maprotiline). The method was developed through several experiments on four online SPE cartridges, three reversed phase chromatography columns, and four combinations of mobile phase components. Under optimal conditions, very low limits of detection (LODs) of 1.30 to 10.6 ng L⁻¹ were obtained. The method was repeatable, with relative standard deviations (RSD, %) for intraday and interday precisions ranged from 1.6 to 7.8 and from 3.3 to 13.2, respectively. Recovery values ranged from 78.4 to 111.4%, indicating the reproducibility of the method. Matrix effects were mainly presented as signal suppression, with topotecan and doxorubicin being the two most affected compounds (31.0% signal suppression). The proposed method was successfully applied to hospital effluents, detecting methotrexate (4.7–9.3 ng L⁻¹) and maprotiline (11.2–23.1 ng L⁻¹). Due to the shorter overall run time of 15 min, including sample preparation, and reduced sample volume (0.9 mL), this on-line SPE-LC-MS/MS method was extremely convenient and efficient in comparison to the classical off-line SPE method. The proposed method was also highly sensitive and can be used for ultratrace quantification of the studied pharmaceuticals in wastewaters, providing useful data for effective environmental monitoring. Full article

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (K_as) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH₂–CH₂- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔE_stbs), although the complex stability orders based on K_as and ΔE_stbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery. Full article

The impact of different oxidation processes on the maprotiline degradation pathways was investigated by liquid chromatography-high resolution mass spectrometry (LC/HRMS) experiments. The in-house SPIX software was used to process HRMS data allowing to ensure the potential singular species formed. Semiconductors photocatalysts, namely Fe-ZnO, Ce-ZnO and TiO₂, proved to be more efficient than heterogeneous photo-Fenton processes in the presence of hydrogen peroxide and persulfate. No significant differences were observed in the degradation pathways in the presence of photocatalysis, while the SO₄⁻ mediated process promote the formation of different transformation products (TPs). Species resulting from ring-openings were observed with higher persistence in the presence of SO₄⁻. In-silico tests on mutagenicity, developmental/reproductive toxicity, Fathead minnow LC₅₀, D. magna LC₅₀, fish acute LC₅₀ were carried out to estimate the toxicity of the identified transformation products. Low toxicant properties were estimated for TPs resulting from hydroxylation onto bridge rather than onto aromatic rings, as well as those resulting from the ring-opening. Full article

Ethanoanthracene cycloadducts (5–7) anti, (5–7) syn, and (5–7) dec have been synthesized from the Diels–Alder (DA) reaction of diene 1,8-dichloroanthracene 2, with the dienophiles; acrylonitrile 3, 1-cynavinyl acetate 4, and phenyl vinyl sulfone 5, individually. The steric effect of dienophile substituents were more favorable toward the anti-isomer formation as deduced from ¹H-NMR spectrum. The cheminformatics prediction for (5–7) anti and (5–7) syn was investigated. The in silico anticipated anti-depression activity of the (5–7) anti and (5–7) syn compounds were investigated and compared to maprotiline 9 as reference anti-depressant drug. The study showed that steric interactions play a crucial role in the binding affinity of these compounds to the representative models; 4xnx, 2QJU, and 3GWU. The pharmacokinetic and drug-like properties of (5–7) anti and (5–7) syn exhibited that these compounds could be represented as potential candidates for further development into antidepressant-like agents. Full article

High genetic and phenotypic variability between Leishmania species and strains within species make the development of broad-spectrum antileishmanial drugs challenging. Thus, screening panels consisting of several diverse Leishmania species can be useful in enabling compound prioritization based on their spectrum of activity. In this study, a robust and reproducible high content assay was developed, and 1280 small molecules were simultaneously screened against clinically relevant cutaneous and visceral species: L. amazonensis, L. braziliensis, and L. donovani. The assay is based on THP-1 macrophages infected with stationary phase promastigotes and posterior evaluation of both compound antileishmanial activity and host cell toxicity. The profile of compound activity was species-specific, and out of 51 active compounds, only 14 presented broad-spectrum activity against the three species, with activities ranging from 52% to 100%. Notably, the compounds CB1954, Clomipramine, Maprotiline, Protriptyline, and ML-9 presented pan-leishmanial activity, with efficacy greater than 70%. The results highlight the reduced number of compound classes with pan-leishmanial activity that might be available from diversity libraries, emphasizing the need to screen active compounds against a panel of species and strains. The assay reported here can be adapted to virtually any Leishmania species without the need for genetic modification of parasites, providing the basis for the discovery of broad spectrum anti-leishmanial agents. Full article

Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt’s lymphoma (BL) is a rare form of non-Hodgkin’s lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity of a library of 9,10-dihydro-9,10-ethanoanthracene based compounds structurally related to the antidepressant drug maprotiline against BL cell lines MUTU-1 and DG-75. Structural modifications were achieved by Diels-Alder reaction of the core 9-(2-nitrovinyl)anthracene with number of dienophiles including maleic anhydride, maleimides, acrylonitrile and benzyne. The antiproliferative activity of these compounds was evaluated in BL cell lines EBV⁻ MUTU-1 and EBV⁺ DG-75 (chemoresistant). The most potent compounds 13j, 15, 16a, 16b, 16c, 16d and 19a displayed IC₅₀ values in the range 0.17–0.38 μM against the BL cell line EBV⁻ MUTU-1 and IC₅₀ values in the range 0.45–0.78 μM against the chemoresistant BL cell line EBV⁺ DG-75. Compounds 15, 16b and 16c demonstrated potent ROS dependent apoptotic effects on the BL cell lines which were superior to the control drug taxol and showed minimal cytotoxicity to peripheral blood mononuclear cells (PBMCs). The results suggest that this class of compounds merits further investigation as antiproliferative agents for BL. Full article

The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively. Full article

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington’s disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin). In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine. Full article