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1.
Molecules ; 26(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34361587

RESUMO

A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro.


Assuntos
Antineoplásicos , Imidazolidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclização , Células HeLa , Humanos , Imidazolidinas/síntese química , Imidazolidinas/farmacologia
2.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439816

RESUMO

Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual axis leading to visual disability. This postsurgical complication, known as posterior capsular opacification (PCO), occurs in up to 30% of cataract patients and has no clinically proven pharmacological means of prevention. Despite the availability of many compounds capable of preventing early steps in PCO development, there is currently no effective means to deliver such therapies into the eye for a suitable duration. To model a solution to this unmet medical need, we fabricated acrylic substrates as intraocular lens (IOL) mimics scaled to place into the capsular bag of the mouse lens following a mock-cataract surgery. Substrates were coated with a hydrophilic crosslinked acrylate nanogel designed to elute Sorbinil, an aldose reductase inhibitor previously shown to suppress PCO. Insertion of the Sorbinil-eluting device into the lens capsule at the time of cataract surgery resulted in substantial prevention of cellular changes associated with PCO development. This model demonstrates that a cataract inhibitor can be delivered into the postsurgical lens capsule at therapeutic levels.


Assuntos
Opacificação da Cápsula/prevenção & controle , Extração de Catarata/efeitos adversos , Portadores de Fármacos , Inibidores Enzimáticos/farmacologia , Imidazolidinas/farmacologia , Lentes Intraoculares , Actinas/genética , Actinas/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Opacificação da Cápsula/etiologia , Opacificação da Cápsula/genética , Opacificação da Cápsula/patologia , Catarata/genética , Catarata/metabolismo , Catarata/patologia , Extração de Catarata/métodos , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Humanos , Cristalino/metabolismo , Cristalino/patologia , Cristalino/cirurgia , Camundongos , Nanogéis/administração & dosagem , Nanogéis/química , Transdução de Sinais , Vimentina/genética , Vimentina/metabolismo
3.
Acta Crystallogr C Struct Chem ; 77(Pt 8): 467-478, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34350844

RESUMO

5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3'-methyl-2',4'-dioxospiro[fluorene-9,5'-imidazolidin]-1'-yl)propyl]-4-phenylpiperazine-1,4-diium dichloride monohydrate, C29H32N4O22+·2Cl-·H2O (1), 3'-methyl-1'-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5'-imidazolidine]-2',4'-dione, C29H29N5O4·H2O (2), 3'-methyl-1'-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5'-imidazolidine]-2',4'-dione, C31H33N5O4 (3), and 1-benzyl-4-[5-(3'-methyl-2',4'-dioxospiro[fluorene-9,5'-imidazolidin]-1'-yl)pentyl]piperazine-1,4-diium dichloride 0.613-hydrate, C32H38N4O22+·2Cl-·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N-H...Cl and O-H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O-H...O and O-H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen-bond donors, it is C-H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Compostos Heterocíclicos/química , Imidazolidinas/química , Piperazinas/química , Animais , Cristalografia por Raios X , Fluorenos/química , Ligação de Hidrogênio , Camundongos , Estrutura Molecular
4.
Org Lett ; 23(16): 6348-6351, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34346221

RESUMO

A variety of enantioenriched gem-disubstituted 4-imidazolidinones were prepared in up to >99% yield and 95% ee by the Pd-catalyzed decarboxylative asymmetric allylic alkylation of imidazolidinone-derived ß-amidoesters. In the process of preparing these substrates, a rapid synthetic route to 4-imidazolidinone derivatives was developed, beginning from 2-thiohydantoin. The orthogonality of the benzoyl imide and tert-butyl carbamate groups used to protect these nitrogen-rich products was demonstrated, enabling potential applications in drug design.


Assuntos
Imidazolidinas/síntese química , Paládio/química , Alquilação , Catálise , Imidazolidinas/química , Estrutura Molecular , Estereoisomerismo
5.
Future Med Chem ; 13(14): 1185-1201, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34148377

RESUMO

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a-q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42-20.7 and 1.02-19.1 µM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Indóis/química , Tiossemicarbazonas/química , Aldeído Redutase/metabolismo , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Humanos , Imidazolidinas/química , Imidazolidinas/metabolismo , Simulação de Acoplamento Molecular , NADP/química , NADP/metabolismo , Relação Estrutura-Atividade , Tiossemicarbazonas/metabolismo
6.
J Alzheimers Dis ; 81(4): 1453-1468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935097

RESUMO

BACKGROUND: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-ß (Aß) plaque burden. OBJECTIVE: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aß accumulation. METHODS: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aß plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. RESULTS: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aß plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. CONCLUSION: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer's disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Centella , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Imidazolidinas/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Triterpenos/farmacologia
7.
Eur J Med Chem ; 221: 113526, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992929

RESUMO

HDAC6 isoform selective inhibitors can be pursued as an alternative to pan-HDACs inhibitors due to their therapeutic effect and low toxicity. Efforts of the structure optimization of our previous compound 10c (IC50 = 4.4 nM) resulted in a new series of 3, 4-disubstituted-imidazolidine-2, 5-dione based HDAC6 inhibitors with better HDAC6 inhibitory activities and improved selectivities. The most potent compound 71 exhibited a low nanomolar HDAC6 inhibitory activity (IC50 = 2.1 nM) and showed 5545-fold, 5864-fold as well as 1638-fold selectivity relative to HDAC1, HDAC2 and HDAC8, respectively. Western blot analysis further confirmed that compound 71 selectively increased the acetylation level of α-tubulin without affecting histone H3. Moreover, compound 71 also possesses good properties in term of caspase-3 activation, apoptosis induction, anti-proliferative activity, cytotoxicity and plasma stability. Therefore, compound 71 can be applied in cancer therapy or used as a lead compound to develop more potent HDAC6 selective inhibitor.


Assuntos
Desenho de Fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Imidazolidinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Estrutura Molecular , Relação Estrutura-Atividade
8.
Phys Chem Chem Phys ; 23(16): 9695-9708, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908506

RESUMO

Attempts to obtain new cocrystals of nonsteroidal antiandrogenic drug nilutamide produced alternative polymorphic forms of the compound (Form II and Form III) and their crystal structures were elucidated by single-crystal X-ray diffraction. Apart from the cocrystallization technique, lyophilization was found to be an effective strategy for achieving polymorph control of nilutamide, which was difficult to obtain by other methods. The physicochemical properties and relative stability of the commercial Form I and newly obtained Form II were comprehensively investigated by a variety of analytical methods (thermal analysis, solution calorimetry, solubility, and sublimation), whereas for Form III, only a handful of experimental parameters were obtained due to the elusive nature of the polymorph. Form I and Form II were found to be monotropically related, with Form I being confirmed as the thermodynamically most stable solid phase. In addition, the performance of different DFT-D and semi-empirical schemes for lattice energy calculation and polymorph energy ranking was compared and analysed. Lattice energy calculations using periodic DFT at B3LYP-D3/6-31(F+)G(d,p) and PBEh-3c/def2-mSVP levels of theory were found to provide the most accurate lattice energy values for Form I against experimental data, while PIXEL and PBEh-3c/def2-mSVP were the only methods that predicted the correct order of stability of Forms I and II.


Assuntos
Antagonistas de Androgênios/química , Imidazolidinas/química , Cristalização , Teoria da Densidade Funcional , Modelos Químicos , Termodinâmica
9.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808213

RESUMO

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. OBJECTIVES: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats". METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. CONCLUSIONS: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.


Assuntos
Imidazolidinas/farmacologia , MicroRNAs/genética , Fosfocreatina/análogos & derivados , Angina Instável/genética , Animais , Biomarcadores Farmacológicos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Imidazolidinas/metabolismo , Isoproterenol/uso terapêutico , Masculino , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fosfocreatina/genética , Fosfocreatina/metabolismo , Fosfocreatina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
10.
Life Sci ; 277: 119531, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33887348

RESUMO

AIMS: EGFR and VEGFR-2 have emerged as promising targets for cancer management as they play a crucial role in tumor growth, angiogenesis and metastasis. A novel series of 2-thioxoimidazolidin-4-one derivatives were synthesized and evaluated as apoptotic inducers and EGFR/VEGFR-2 dual inhibitors. MAIN METHODS: The cytotoxic activities of all synthesized compounds were tested against MCF-7, HepG2 and A549 cell lines. The molecular mechanism of the most promising cytotoxic compounds was investigated via a series of assays including in vitro EGFR and VEGFR-2 inhibitory activity in MCF-7 cell line. Additionally, levels of p53, Bax, Bcl-2, caspase 7, 9 as well as cell cycle analysis were assessed in MCF-7 cell line to gain better understanding of their apoptotic activity. Molecular docking study was carried out to predict binding pattern of these compounds with EGFR and VEGFR-2 active sites. Finally, in silico ADME and drug-likeness profiling were calculated. KEY FINDINGS: Compounds 6 and 8a exhibited superior cytotoxic activity compared to sorafenib and erlotinib, against the three tested cell lines. In the same context, 6 and 8a showed better EGFR and VEGFR-2 inhibitory activity compared to the reference compounds. The later effect was further supported by the docking study. Furthermore, these compounds displayed potent apoptotic activity as evident by cell accumulation at pre-G1 phase and cell cycle arrest at G2/M phase together with increased p53, caspae-7 and caspase-9 levels and Bax/Bcl-2 ratio. Finally, synthesized compounds have acceptable drug likeness. SIGNIFICANCE: Compounds 6 and 8a act as potent dual EGFR/VEGFR-2 inhibitors with evident apoptotic activity.


Assuntos
Imidazolidinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Imidazolidinas/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
J Org Chem ; 86(8): 5744-5756, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33775093

RESUMO

A novel protocol for the synthesis of pyrido[2,3-b]indoles (α-carbolines, 3) from (E)-3-(2-oxo-2-phenylethylidene) indolin-2-one derivatives 1 and 1,1-enediamine (EDAM) 2a via an unexpected cascade reaction in ethanol was developed. Pyrido[2,3-b]indole derivatives 4 were obtained by the same reaction, albeit by stirring the mixture for a longer period of time (about 48 h). As a result, two kinds of functionalized α-carbolines 3 and 4 were synthesized by the facile reaction of the (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one derivatives and 2-(nitromethylene)imidazolidine under basic conditions (Cs2CO3) in ethanol. In addition, a diverse array of EDAM substrates (2b-2k) were tested in this reaction to afford the expected target compounds 5. This protocol is suitable for the combinatorial and parallel syntheses of natural-like products, including highly functionalized α-carbolines and pyrroles, especially 2-oxoindolin-3-yl pyrroles. This approach features several advantages, such as being a simple and practical operation (requiring only filtration and washing without column chromatography), furnishing excellent yields (72-98%), and producing diverse libraries of target compounds with potential biological activities.


Assuntos
Imidazolidinas , Pirróis , Indóis
12.
Pest Manag Sci ; 77(7): 3224-3232, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33723881

RESUMO

BACKGROUND: The diamondback moth (Plutella xylostella) is one of the most destructive lepidopteran pests on cruciferous vegetables. However, resistance has emerged to current chemical and biological insecticides used for P. xylostella control, indicating the necessity of screening new targets on P. xylostella, and finding new insecticides against P. xylostella. In particular, octopamine receptors are representative G protein-coupled receptors found only in invertebrates and are potential targets for identifying novel insecticides. RESULTS: A ß-adrenergic-like octopamine receptor gene (PxOA2B1) was cloned, and its pharmacological characteristics in P. xylostella were studied. The results demonstrated that octopamine could activate the PxOA2B1 receptor, with a half-maximal effective concentration (EC50 ) of 49.5 nm. Amitraz, an insecticide and acaricide, and its metabolite (N-2,4-dimethylphenyl-N'-methylformamidine; DPMF) were also found to act as PxOAB1R agonists. We synthesized phenyl imidazolidin-2-one derivatives 3a-h using DPMF as the lead compound, and compounds 3a-h showed similar antagonist activities as phentolamine, mianserin and chlorpromazine. In particular, 3d, with an EC50 of 25.2 nm, showed very similar antagonist activity to mianserin. CONCLUSION: This research found that PxOAB1R might be a potential target for P. xylostella control. Phenyl imidazolidin-2-ones could be novel potential antagonists targeted at octopamine receptors and would be useful tools for the design and development of novel insecticides. © 2021 Society of Chemical Industry.


Assuntos
Inseticidas , Mariposas , Receptores de Amina Biogênica , Adrenérgicos , Animais , Imidazolidinas , Resistência a Inseticidas , Inseticidas/farmacologia , Larva , Mariposas/genética , Receptores de Amina Biogênica/genética
13.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525514

RESUMO

Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at a-, b-, or g-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9'(10H,10H')-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.


Assuntos
Disciplinas das Ciências Naturais/métodos , Óxidos de Nitrogênio/química , Imidazóis/química , Imidazolidinas/química , Morfolinas/química , Oxazóis/química , Piperidinas/química , Pirrolidinas/química , Substâncias Redutoras/química
14.
Bioorg Chem ; 109: 104735, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33640632

RESUMO

A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6-22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6-16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6-16), occurred the most potent P-gp inhibitors in the MDR T-lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action.


Assuntos
Antineoplásicos/farmacologia , Imidazolidinas/farmacologia , Linfoma de Células T/tratamento farmacológico , Compostos de Espiro/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
15.
Nat Protoc ; 16(3): 1476-1493, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33504989

RESUMO

N-heterocyclic carbene gold(I) chloride and hydroxide complexes are regularly used as synthons to access various oxygen-, nitrogen- or carbon-bound gold complexes. They are also widely employed as efficient catalysts in addition reactions of hydroelements to unsaturated bonds and in several rearrangement and decarboxylation protocols. Here we describe the multigram synthesis of the most common mononuclear N-heterocyclic carbene gold(I) chloride complexes bearing the N,N'-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and N,N'-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene (IPr*) ligands. Their synthesis is achieved through the straightforward and practical weak base approach in a total time of 4-5 h. This straightforward methodology is conducted under air and possesses considerable advantages over alternative routes, such as the use of a sustainable reaction solvent, minimal amounts of a mild base and commercially available or easily obtained starting materials. Additionally, we describe the synthesis of the mononuclear gold(I) hydroxide complex bearing the IPr ligand, using the state-of-the-art method requiring 24 h. Finally, the improved synthesis of the dinuclear gold(I) hydroxide complex [{Au(IPr)}2(µ-OH)][BF4] is described (~3 h). All procedures can be performed by researchers with standard training and lead to high yields (76-99%) of microanalytically pure bench-stable materials.


Assuntos
Ouro/química , Compostos Heterocíclicos/síntese química , Metano/análogos & derivados , Catálise , Compostos Heterocíclicos/química , Imidazóis , Imidazolidinas , Ligantes , Metano/síntese química , Modelos Moleculares
16.
Eur J Pharmacol ; 895: 173884, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33482179

RESUMO

We have recently demonstrated that aldose reductase (AR) inhibitor; fidarestat prevents doxorubicin (Dox)-induced cardiotoxic side effects and inflammation in vitro and in vivo. However, the effect of fidarestat and its combination with Dox on immune cell activation and the immunomodulatory effects are not known. In this study, we examined the immunomodulatory effects of fidarestat in combination with Dox in vivo and in vitro. We observed that fidarestat decreased Dox-induced upregulation of CD11b in THP-1 monocytes. Fidarestat further attenuated Dox-induced upregulation of IL-6, IL-1ß, and Nos2 in murine BMDM. Fidarestat also attenuated Dox-induced activation and infiltration of multiple subsets of inflammatory immune cells identified by expression of markers CD11b+, CD11b+F4/80+, Ly6C+CCR2high, and Ly6C+CD11b+ in the mouse spleen and liver. Furthermore, significant upregulation of markers of mitochondrial biogenesis PGC-1α, COX IV, TFAM, and phosphorylation of AMPKα1 (Ser485) was observed in THP-1 cells and livers of mice treated with Dox in combination with fidarestat. Our results suggest that fidarestat by up-regulating mitochondrial biogenesis exerts protection against Dox-induced immune and inflammatory responses in vitro and in vivo, providing further evidence for developing fidarestat as a combination agent with anthracycline drugs to prevent chemotherapy-induced inflammation and toxicity.


Assuntos
Aldeído Redutase/metabolismo , Doxorrubicina/toxicidade , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Biogênese de Organelas , Aldeído Redutase/antagonistas & inibidores , Animais , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Imidazolidinas/farmacologia , Inflamação/enzimologia , Inflamação/imunologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Macrófagos/enzimologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/imunologia , Mitocôndrias Hepáticas/patologia , Monócitos/enzimologia , Monócitos/imunologia , Monócitos/patologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Células THP-1
17.
J Mass Spectrom ; 56(2): e4694, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33410180

RESUMO

The progression of diabetic complications can be prevented by inhibition of aldose reductase and fidarestat considered to be highly potent. To date, metabolites of the fidarestat, toxicity, and efficacy are unknown. Therefore, the present study on characterization of hitherto unknown in vitro and in vivo metabolites of fidarestat using liquid chromatography-electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) is undertaken. In vitro and in vivo metabolites of fidarestat have been identified and characterized by using LC/ESI/MS/MS and accurate mass measurements. To identify in vivo metabolites, plasma, urine, and feces samples were collected after oral administration of fidarestat to Sprague-Dawley rats, whereas for in vitro metabolites, fidarestat was incubated in human S9 fraction, human liver microsomes, and rat liver microsomes. Furthermore, in silico toxicity and efficacy of the identified metabolites were evaluated. Eighteen metabolites have been identified. The main in vitro phase I metabolites of fidarestat are oxidative deamination, oxidative deamination and hydroxylation, reductive defluroniation, and trihydroxylation. Phase II metabolites are methylation, acetylation, glycosylation, cysteamination, and glucuronidation. Docking studies suggest that oxidative deaminated metabolite has better docking energy and conformation that keeps consensus with fidarestat whereas the rest of the metabolites do not give satisfactory results. Aldose reductase activity has been determined for oxidative deaminated metabolite (F-1), and it shows an IC50 value of 0.44 µM. The major metabolite, oxidative deaminated, did not show any cytotoxicity in H9C2, HEK, HEPG2, and Panc1 cell lines. However, in silico toxicity, the predication result showed toxicity in skin irritation and ocular irritancy SEV/MOD versus MLD/NON (v5.1) model for fidarestat and its all metabolites. In drug discovery and development research, it is distinctly the case that the potential for pharmacologically active metabolites must be considered. Thus, the active metabolites of fidarestat may have an advantage as drug candidates as many drugs were initially observed as metabolites.


Assuntos
Imidazolidinas/metabolismo , Imidazolidinas/farmacocinética , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Imidazolidinas/análise , Imidazolidinas/toxicidade , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
18.
Bioorg Med Chem Lett ; 31: 127670, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161124

RESUMO

Searching for new alternatives to antibiotic treatments is crucial to surmount the multidrug-resistant bacteria. In this work, the antimicrobial activity of synthetic imidazolidines was evaluated as well as their modulating effect on the resistance to fluoroquinolones in a S. aureus strain (SA-1199B), which overexpresses the norA gene that encodes the NorA efflux pump. Results showed weak antimicrobial activity (512 µg mL-1) for two fluorobenzylidene derivatives against this bacterial strain, while the other benzylidene derivatives were inactive. Despite this fact, both fluorinated compounds were able to enhance the activity of norfloxacin and ciprofloxacin against SA-1199B up to 6.4- and 3.2-fold, respectively. In addition, both derivatives potentiated the action of ethidium bromide against this strain, suggesting that the modulating effect probably involves the inhibition of the NorA efflux pump, which is in concordance with the fluorimetic assays and molecular docking analyses performed in this work.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Imidazolidinas/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Imidazolidinas/síntese química , Imidazolidinas/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
19.
J Hazard Mater ; 410: 124659, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33279323

RESUMO

Copper vanadate nanoparticles (Cu2V2O7) are synthesized by using a simple hydrothermal method and later anchored with sulfur-doped reduced graphene oxide (S-rGO) by using ultrasonication to form a hybrid nanocomposite. The synthesized composite underwent characterizations like X-ray diffraction analysis (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR), Dynamic ray scattering-Ultra violet-visible spectroscopy (DRS-UV-visible) and X-ray photoelectron spectroscopically revealed the triclinic pattern of the P 1̅ space group of α-Cu2V2O7 and the reduced oxygen deficiency state of metal centers (Cu+ or V4+) resulting with oxides of mixed-valence oxidative states and forming of Cu-O bond. Morphological analysis was carried out by using transmission electron microscopy (TEM) and Field emission scanning electron microscopy (FE-SEM) with elemental mapping and EDX analysis. Furthermore, a novel electrochemical sensor is prepared by using the hybrid sCu2V2O7/S-rGO nanocomposite on to a disposable screen-printed carbon paste electrode (SPCE) for electrochemical sensing of antiandrogen drug nilutamide (NLT). This report reveals excellent activity in determining NLT with a low detection limit of 0.00459 nM for the linear range of 0.001-15 µM with high sensitivity of 26.2605 µA µM-1 cm-2. Further, electrode performance showed appreciable performance in real-time monitoring of biological samples like human blood serum, urine samples.


Assuntos
Grafite , Nanocompostos , Preparações Farmacêuticas , Antagonistas de Androgênios , Cobre , Técnicas Eletroquímicas , Eletrodos , Humanos , Imidazolidinas , Limite de Detecção , Espectroscopia de Infravermelho com Transformada de Fourier , Enxofre , Vanadatos
20.
J Agric Food Chem ; 69(1): 45-54, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33372787

RESUMO

Herbicide safeners enhance herbicide detoxification in crops without reducing their herbicidal efficacy against target weeds. To alleviate maize injury caused by the sulfonylurea herbicide nicosulfuron, a series of 1,3-disubstituted imidazolidine or hexahydropyrimidine derivatives were rationally designed via bioisosterism and active subunit combinations. Thirty novel compounds were synthesized using an efficient one-pot method and low-cost raw materials and characterized by IR, 1H NMR, 13C NMR, and high-resolution mass spectrometer (HRMS). Bioactivity and structure-activity relationship (SAR) were evaluated for herbicide safeners tested against nicosulfuron injury. Most of the compounds effectively protected sensitive maize against nicosulfuron damage. The parent skeletons and substituents of the target compounds both substantially influenced their safener activity. Compound I-3 exhibited superior bioactivity compared to the safener isoxadifen-ethyl. Molecular docking simulations disclosed that compound I-3 competed with nicosulfuron for the acetolactate synthase active site and demonstrated that this is the protective mechanism of safeners. The target compound I-3 presented with strong herbicide safener activity in maize and is, therefore, a potential candidate for the development of a novel herbicide safener.


Assuntos
Herbicidas/toxicidade , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , Acetolactato Sintase/química , Acetolactato Sintase/metabolismo , Desenho de Fármacos , Herbicidas/química , Imidazolidinas/química , Simulação de Acoplamento Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Substâncias Protetoras/química , Piridinas/química , Piridinas/toxicidade , Pirimidinas/química , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/toxicidade , Zea mays/química , Zea mays/efeitos dos fármacos , Zea mays/enzimologia
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