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1.
Arch Pharm (Weinheim) ; 357(2): e2300426, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37991233

RESUMO

Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a-c), 2-quinoline (2a-c), and 8-hydroxy-2-quinolyl moiety (3a-c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition.


Assuntos
Antineoplásicos , Neoplasias , Quinolinas , Humanos , Hidrazonas , Relação Estrutura-Atividade , Células HEK293 , Ensaios de Seleção de Medicamentos Antitumorais , Quinolinas/farmacologia , Quinolinas/química , Tiazóis , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células
2.
Drug Resist Updat ; 50: 100682, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32087558

RESUMO

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/tratamento farmacológico , Tecnologia Farmacêutica/métodos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glicoconjugados/química , Humanos , Nanopartículas , Óxido Nítrico/metabolismo , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Polímeros/química
3.
Bioorg Chem ; 98: 103746, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199306

RESUMO

The voltage-gated potassium channel Kv1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which Kv1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the Kv1.3 channel. The screening resulted in two compounds inhibiting the Kv1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for Kv1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the Kv1.3 channel and three Kv1.3 mutants, designed to resemble the pore region of Kv1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the Kv1.3 channel, resulting in a 20-fold higher potency for TVS-12.


Assuntos
Desenho de Fármacos , Canal de Potássio Kv1.3/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Canal de Potássio Kv1.3/metabolismo , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Relação Estrutura-Atividade , Xenopus laevis
4.
Arch Pharm (Weinheim) ; 351(5): e1700371, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29660818

RESUMO

The biological activity of three previously synthesized 17ß-carboxamide glucocorticoids (BG, BEG, and MPEA) was tested in vitro on mitogen stimulated and non-stimulated peripheral blood mononuclear cells (MNCs) and granulocytes from human healthy donors, and the results were compared to the conventional glucocorticoid dexamethasone. The tested 17ß-carboxamide glucocorticoids did not induce decreases in MNC viability and proliferation, while modulation of reactive oxygen species (ROS) synthesis in granulocytes was dependent on the cell donor. The obtained results indicate the possibility of avoidance of strong lymphocyte suppression, which is generally recognized during administration of conventional glucocorticoids. Furthermore, the metabolism of the tested derivatives was predicted in silico. The predicted metabolites were synthesized and the in silico results were confirmed by in vitro evaluation of the metabolism of BG, BEG, and MPEA in human serum and in cultures of peripheral blood MNCs. The results of the biological activity and metabolism evaluation and of previous in vivo evaluations of biological activity indicate the soft drug nature of BG, BEG, and MPEA. In order to be fully considered as soft glucocorticoids, further investigations on the toxicity and activity of the formed metabolites are required.


Assuntos
Glucocorticoides/farmacologia , Granulócitos/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Simulação por Computador , Dexametasona/farmacologia , Glucocorticoides/química , Granulócitos/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo
5.
Arch Pharm (Weinheim) ; 350(5)2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28418199

RESUMO

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17ß-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.


Assuntos
Anti-Inflamatórios/farmacologia , Desenho Assistido por Computador , Otopatias/tratamento farmacológico , Edema/tratamento farmacológico , Glucocorticoides/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/química , Óleo de Cróton , Relação Dose-Resposta a Droga , Desenho de Fármacos , Otopatias/induzido quimicamente , Edema/induzido quimicamente , Glucocorticoides/efeitos adversos , Glucocorticoides/química , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar
6.
Molecules ; 20(8): 14684-98, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26287134

RESUMO

The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD), solid self-microemulsifying drug delivery systems (S-SMEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS) were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin(®) UFL2) was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin(®) UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6) were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine.


Assuntos
Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Água/química , Varredura Diferencial de Calorimetria , Carbamazepina/química , Emulsões/química , Membranas Artificiais , Tamanho da Partícula , Permeabilidade , Pós , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Comprimidos , Difração de Raios X
7.
Arch Pharm (Weinheim) ; 347(11): 786-97, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25159891

RESUMO

Molecular docking studies were performed on 18 17ß-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17ß-carboxamide steroids with potentially better biological profile than dexamethasone.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Edema/prevenção & controle , Glucocorticoides/síntese química , Glucocorticoides/farmacologia , Inflamação/prevenção & controle , Animais , Anti-Inflamatórios/metabolismo , Biotransformação , Óleo de Cróton , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Glucocorticoides/metabolismo , Hidrocortisona/análogos & derivados , Hidrocortisona/síntese química , Hidrocortisona/metabolismo , Hidrocortisona/farmacologia , Inflamação/induzido quimicamente , Ligantes , Metilprednisolona/análogos & derivados , Metilprednisolona/síntese química , Metilprednisolona/metabolismo , Metilprednisolona/farmacologia , Modelos Biológicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Prednisolona/análogos & derivados , Prednisolona/síntese química , Prednisolona/metabolismo , Prednisolona/farmacologia , Ratos , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
8.
Pharmaceutics ; 16(6)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38931946

RESUMO

Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1-13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC50 values were in the range of 22.99-51.66 µM (HCT 116 cell line), 8.63-41.20 µM (BxPC-3 cell line) and 24.78-81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses.

9.
Artigo em Inglês | MEDLINE | ID: mdl-38776787

RESUMO

DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests - parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.


Assuntos
Absorção Gastrointestinal , Relação Quantitativa Estrutura-Atividade , Inibidores da Topoisomerase II , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacocinética , Micelas , Modelos Lineares , Membranas Artificiais , DNA Girase/metabolismo , DNA Girase/química , Humanos , DNA Topoisomerase IV/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química
10.
Chem Biol Interact ; 399: 111138, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38992768

RESUMO

Oxidative stress status, as a disruption of redox homeostasis, in the blood sera of Wistar rats caused by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Throughout this study, each oxime in a dose of 0.1 of LD50/kg im was given 2x/week for 4 weeks. Then, seven days after the last oximes' application, markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, reduced glutathione, GSH, and oxidized glutathione, GSSG), were determined. Oxidative stress parameters, MDA and AOPP were significantly highest in the K048-, K074- and K075-treated groups (p < 0.001). The activity of CAT was significantly elevated in the obidoxime-treated group (p < 0.05), while treatment with K027, K048, and K074 induced high elevation in SOD levels (p < 0.01, p < 0.001). Interestingly, the activity of GSH in each oxime-treated group was significantly elevated. Unlike, treatment with obidoxime caused elevation in GSSG levels (p < 0.01). As a continuation of our previously published data, these results assure that applied oximes following subacute treatment ameliorated the oxidative status and further adverse systemic toxic effects in rats.

11.
Int J Pharm ; 655: 124033, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38522490

RESUMO

The incorporation of polymers into drug delivery vehicles has been shown to be a useful approach to prolong the residence time of drugs in the precorneal tear film and to improve penetration into biological membranes. The main objective of this research was to formulate novel viscous eye drops with ketotifen as the active ingredient, containing the polysaccharides: chitosan (MCH), hydroxypropyl guar gum (HPG) and hyaluronic acid (SH) alone and in combination as functional polymers. DSC and FT-IR techniques showed the compatibility between ketotifen and polymers. Physicochemical and rheological analysis at ambient and simulated physiological conditions, as well as the evaluation of mucoadhesive properties showed that vehicles containing combinations of polymers have suitable physicochemical and functional properties with demonstrated synergism between combined polymers (MCH and HPG i.e. SH and HPG). The drug permeability was successfully estimated in vitro using HCE-T cell-based models. MTT cytotoxicity assay demonstrates that the tested formulations were non-toxic and well tolerated. In vivo preclinical study on mice revealed that both vehicles containing mixed polymers enhanced and prolonged the antipruritic/analgesic-like effect of ophthalmic ketotifen. Based on these results, both combinations of polysaccharide polymers, especially SH-HPG, could be considered as potential new carriers for ketotifen for ophthalmic use.


Assuntos
Cetotifeno , Polímeros , Animais , Camundongos , Cetotifeno/efeitos adversos , Soluções Oftálmicas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Polissacarídeos/química , Antagonistas dos Receptores Histamínicos
12.
Bioelectrochemistry ; 149: 108323, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36403341

RESUMO

Electrochemical oxidation of newly synthesized acridine derivatives (ADs): PG, PA, EG and EA was studied using square wave voltammetry at a glassy carbon electrode. Oxidation occurs as an irreversible process for all ADs. The ADs interaction with DNA was investigated using multi-layer DNA electrochemical biosensor. The shift of dA peak in positive direction indicated that the type of interaction is most likely an intercalation. PG showed the widest range of concentration capable to interact with DNA (1 × 10-7 M - 2.5 × 10-4 M). Analysing logIcomplexIDNA-IcomplexvslogcAD plots, the binding constants were determined. For the lowest PG concentrations, obtained K value close to 106 M-1 refers to strong binding. The values of K for PA may be classified as medium strength, while EG and EA showed low K values. Our results unequivocally showed that the characteristics of association complexes may vary depending on the concentration of the interacting substance. The negative ΔG value for all ADs, (- 21 to - 34 kJ mol-1), confirms the process spontaneity. The best result, indicating the most stable formed complex with DNA adsorbed at the electrode surface, showed PG when present in low concentration, order of 10-7 M. The intercalation of ADs into DNA was supported by molecular docking analysis.


Assuntos
Técnicas Biossensoriais , DNA , Simulação de Acoplamento Molecular , DNA/química , Técnicas Biossensoriais/métodos , Eletrodos , Aminoácidos
13.
Pharmaceuticals (Basel) ; 16(4)2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37111306

RESUMO

Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (1-13) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as N-hydroxyurea derivatives (1, 2 and 3), 3,5-di-tert-butylphenol derivatives (4, 5, 6, 7 and 13), urea derivatives (8, 9 and 10) and "type B hydroxamic acids" (11 and 12). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (1, 2, 3, 5, 6, 11 and 12) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors 1, 3, 5, 11 and 12 showed good antioxidant properties.

14.
Pharmaceuticals (Basel) ; 16(5)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37242450

RESUMO

The aim of the study was a synthesis and investigation of the dose-dependent anti-inflammatory effect of new thiourea derivatives of naproxen with selected aromatic amines and esters of aromatic amino acids. The results of the in vivo study indicate that derivatives of m-anisidine (4) and N-methyl tryptophan methyl ester (7) showed the most potent anti-inflammatory activity four hours after injection of carrageenan, with the percentage of inhibition of 54.01% and 54.12%, respectively. In vitro assays of COX-2 inhibition demonstrated that none of the tested compounds achieved 50% inhibition at concentrations lower than 100 µM. On the other hand, the aromatic amine derivatives (1-5) accomplished significant inhibition of 5-LOX, and the lowest IC50 value was observed for compound 4 (0.30 µM). High anti-edematous activity of compound 4 in the rat paw edema model, together with potent inhibition of 5-LOX, highlight this compound as a promising anti-inflammatory agent.

15.
Pharmaceutics ; 15(5)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37242684

RESUMO

Cancer is the disease with the highest mortality. Drug studies contribute to promising treatments; however there is an urgent need for selective drug candidates. Pancreatic cancer is difficult to treat and the cancer progresses rapidly. Unfortunately, current treatments are ineffective. In this study, ten new diarylthiophene-2-carbohydrazide derivatives were synthesized and evaluated for their pharmacological activity. The 2D and 3D anticancer activity studies suggested the compounds 7a, 7d, and 7f were promising. Among these, 7f (4.86 µM) showed the best 2D inhibitory activity against PaCa-2 cells. Compounds 7a, 7d and 7f were also tested for their cytotoxic effects on healthy cell line but only compound 7d showed selectivity. Compounds 7a, 7d, and 7f showed the best 3D cell line inhibitory effect according to spheroid diameters. The compounds were screened for their COX-2 and 5-LOX inhibitory activity. For COX-2, the best IC50 value was observed for 7c (10.13 µM) and all compounds showed significantly lower inhibition compared to standard. In the 5-LOX inhibition study, compounds 7a (3.78 µM), 7c (2.60 µM), 7e (3.3 µM), and 7f (2.94 µM) demonstrated influential activity compared to standard. Regarding molecular docking studies, binding mode of compounds 7c, 7e, and 7f to the 5-LOX enzyme were non-redox or redox types, but not the iron-binding type. As dual inhibitors of 5-LOX and pancreatic cancer cell line, 7a and 7f were identified as the most promising compounds.

16.
J Funct Biomater ; 14(3)2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36976097

RESUMO

Acridine and its derivatives (9-chloroacridine and 9-aminoacridine) are investigated here, supported on FAU type zeolite Y, as a delivery system of anticancer agents. FTIR/Raman spectroscopy and electron microscopy revealed successful drug loading on the zeolite surface, while spectrofluorimetry was employed for drug quantification. The effects of the tested compounds on cell viability were evaluated using in vitro methylthiazol-tetrazolium (MTT) colorimetric technique against human colorectal carcinoma (cell line HCT-116) and MRC-5 fibroblasts. Zeolite structure remained unchanged during homogeneous drug impregnation with achieved drug loadings in the 18-21 mg/g range. The highest drug release, in the µM concentration range, with favourable kinetics was established for zeolite-supported 9-aminoacridine. The acridine delivery via zeolite carrier is viewed in terms of solvation energy and zeolite adsorption sites. The cytotoxic effect of supported acridines on HCT-116 cells reveals that the zeolite carrier improves toxicity, while the highest efficiency is displayed by zeolite-impregnated 9-aminoacridine. The 9-aminoacridine delivery via zeolite carrier favours healthy tissue preservation while accompanying increased toxicity toward cancer cells. Cytotoxicity results are well correlated with theoretical modelling and release study, providing promising results for applicative purposes.

17.
Chem Biol Interact ; 383: 110658, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37572873

RESUMO

Oxidative stress status and morphological injuries in the brain of Wistar rats induced by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Each oxime in a dose of 0.1 of LD50/kg im was given 2x/week for 4 weeks. Markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, glutathione reductase, GR, and glutathione peroxidase, GPx), were estimated in the brain tissue homogenates on day 35 of the study. Brain alterations were carefully quantified by semiquantitative grading scales - brain damage score (BDS). Oxidative stress parameters, MDA and AOPP were significantly highest in the asoxime-, obidoxime- and K075-treated groups (p < 0.001). The activity of SOD and CAT was significantly elevated in the obidoxime-, K048-, and K075-treated groups (p < 0.001). Besides, GR was markedly decreased in the obidoxime- and K074-treated groups (p < 0.01), while treatment with K048, K074 and K075 induced extremely high elevation in GPx levels (p < 0.001). In the same groups of rats, brain alterations associated with polymorphonuclear cell infiltrate were significantly more severe than those observed in animals receiving only asoxime or K027 (p < 0.001). The presented results confirmed that treatment with different oximes significantly improved the oxidative status and attenuated signs of inflammation in rats' brains. Presented results, together with our previously published data can help to predict likely adverse systemic toxic effects, and target organ systems, which are crucial for establishing risk categories, as well as in dose selection of K-oximes as drug candidates.


Assuntos
Cloreto de Obidoxima , Oximas , Ratos , Animais , Oximas/farmacologia , Cloreto de Obidoxima/farmacologia , Ratos Wistar , Acetilcolinesterase/metabolismo , Produtos da Oxidação Avançada de Proteínas/metabolismo , Produtos da Oxidação Avançada de Proteínas/farmacologia , Estresse Oxidativo , Encéfalo , Superóxido Dismutase/metabolismo
18.
Int J Pharm ; 633: 122613, 2023 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-36657554

RESUMO

Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3-2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nanoparticles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.


Assuntos
Lecitinas , Nanopartículas , Ratos , Animais , Lecitinas/química , Ligantes , Nanopartículas/química , Lipossomos , Tamanho da Partícula , Disponibilidade Biológica , Administração Oral , Solubilidade , Portadores de Fármacos/farmacocinética
19.
Pharmaceutics ; 16(1)2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38276479

RESUMO

The objective of this study was to synthesize seven novel thiourea derivatives of naproxen (8-14), examine the anti-inflammatory activity of the newly synthesized compounds, investigate the cytotoxic potential of both sets of synthesized compounds (1-7 and 8-14), and select the most promising anti-inflammatory and antitumor drug candidates. The results of the in vivo anti-inflammatory study clearly showed that compounds 8 and 9 were capable of decreasing paw edema, as evident from a high percentage of inhibition (44.83% and 49.29%, respectively). In addition, the results of in vitro enzyme inhibition assays demonstrated that neither of the newly synthesized compounds reached 50% inhibition of 5-LOX at concentrations lower than 100 µM. In terms of antitumor potential, derivatives 3 and 8 exhibited strong cytotoxic effects on the HeLa cell line, suggesting the involvement of the extrinsic pathway of apoptosis. According to the overall results obtained for both sets of synthesized molecules, derivatives 4 and 8 can be underlined as molecules with the strongest anti-inflammatory activity, while derivatives 3 and 8 are the most promising cytotoxic agents.

20.
Int J Biol Macromol ; 221: 48-60, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36058395

RESUMO

Escin is an amphiphilic and weakly acidic drug that oral administration may lead to the irritation of gastric mucosa. The entrapment of escin into chitosan (CH)/xanthan gum (XG)-based polyelectrolyte complexes (PECs) can facilitate controlled drug release which may be beneficial for the reduction of its side effects. This study aimed to investigate the influence of escin content and drying method on the formation, physicochemical, and controlled, pH-dependent drug release properties of CH/XG-based PECs. Measurements of transmittance, conductivity, and rheological characterization confirmed the formation of CH/XG-based PECs with escin entrapped at escin-to-polymers mass ratios 1:1, 1:2, and 1:4. Ambient-dried PECs had higher yield, entrapment efficiency, and escin content in comparison with spray-dried ones. FT-IR spectra confirmed the interactions between CH, XG, and escin, which were stronger in ambient-dried PECs. PXRD and DSC analyses showed the amorphous escin character in all dry PECs, regardless of the drying method. The most promising controlled and pH-dependent in vitro escin release was from the ambient-dried PEC at the escin-to-polymers mass ratio of 1:1. For that reason and due to the highest yield and entrapment efficiency, this carrier has the potential to prevent the irritation of gastric mucosa after oral administration of escin.


Assuntos
Quitosana , Polieletrólitos/química , Quitosana/química , Escina , Sistemas de Liberação de Medicamentos , Espectroscopia de Infravermelho com Transformada de Fourier , Concentração de Íons de Hidrogênio
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