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1.
Eur J Med Chem ; 180: 171-190, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306905

RESUMO

p300 is an important histone acetyltransferase in epigenetics, and its overexpression is closely related to various diseases such as cancers. C646 is one of the most representative p300 inhibitors and used in various studies of p300. However, its intrinsic drawbacks such as containing potentially toxic groups prevent it from further development. In order to find potent p300 inhibitors with good drug-like properties, C646 was chosen as the lead compound and a series of new p300 inhibitors were designed based on the principle of bioisosterism and reasonable scaffold hopping, and the structure-activity relationship was systematically explored. Ten of them were found to show comparable inhibitory activity as C646. The most potent compound, 1r (IC50 = 0.16 µM), showed better p300 inhibitory activity than C646 with improved drug-like properties. Western blotting experiment confirmed that 1r could reduce the level of H3K27 acetylation more significantly than C646. Further cellular assay indicated that it could inhibit the proliferation of human breast ductal carcinoma cell T47D and human breast cancer cell MCF7 with the IC50 values of 5.08 µM and 22.54 µM, respectively. Docking study of 1r with p300 protein showed the possible reasons for its higher inhibition activity. Thus, compound 1r might be with potential for development as a novel epigenetic agent targeting p300.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazolonas/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade , Fatores de Transcrição de p300-CBP/metabolismo
2.
Med Chem ; 15(6): 624-633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113352

RESUMO

BACKGROUND: The development of new classes of blood glucose-lowering medications has increased the number of treatment opportunities available for type 2 diabetes. Nevertheless, long term complicated treatments and side effects of available antidiabetic therapies have urged huge demands for effective affordable anti-diabetic agents that can lessen negative health consequences. In this sense, the exploration of alternative medicinal remedies associated with new significant antidiabetic efficiencies with minimized adverse effects is an active domain of research. OBJECTIVE: The aim of this study was to synthesize a series of benzothiazole-pyrazolidinedione hybrids and evaluate their antidiabetic activity along with molecular docking and in silico analysis. METHODS: The hybrids were synthesized by a multi-step synthesis and were further subjected for in vivo anti-hyperglycemic assessment on rat models of type II diabetes. Molecular modelling study was undertaken against peroxisome proliferator-activated receptor γ (PPARγ) to highlight possible key interactions. RESULTS: Docking studies revealed that appropriate substituents on benzothiazole ring interacted favorably with the hydrophobic Ω-pocket of PPARγ binding site resulting in improving their antihyperglycemic activity. All the synthesized hybrids manifested promising anti-hyperglycemic potency. Excitingly, 5a, 5b and 5c were even more potent than the standard drug. CONCLUSION: The newly synthesized hybrids can be considered as a new class of antidiabetic agents and this study provided useful information on further optimization.


Assuntos
Benzotiazóis/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pirazolonas/uso terapêutico , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/metabolismo , Domínio Catalítico , Desenho de Drogas , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Simulação de Acoplamento Molecular , PPAR gama/química , PPAR gama/metabolismo , Ligação Proteica , Pirazolonas/síntese química , Pirazolonas/química , Pirazolonas/metabolismo , Ratos
3.
Molecules ; 24(3)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30754632

RESUMO

Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 µg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pirazolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Células MCF-7 , Micelas , Nanotecnologia , Poliésteres/química , Polietilenoglicóis/química , Pirazolonas/síntese química , Pirazolonas/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Org Biomol Chem ; 17(2): 388-396, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30601507

RESUMO

Chemoselective, biocompatible ligation reactions are the key components for efficient and modular access to biomolecular scaffolds. Tetrazine ligation leads to the formation of a mixture of isomers, which makes reaction monitoring, purification and characterization of conjugates difficult. We report herein a modified tetrazine ligation strategy based on the use of a pyrazolone coupling partner, which provides a single molecule conjugate.


Assuntos
Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/química , Pirazolonas/química , Técnicas de Química Sintética/métodos , Corantes Fluorescentes/síntese química , Compostos Heterocíclicos com 1 Anel/síntese química , Humanos , Isomerismo , Muramidase/química , Pirazolonas/síntese química
5.
Bioorg Chem ; 84: 41-50, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30481645

RESUMO

In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H NMR, 13C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC50 = 0.114 µM), 3h (IC50 = 0.049 µM), and 3i (IC50 = 0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds.


Assuntos
Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Pirazolonas/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Pirazolonas/síntese química , Pirazolonas/química , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade
6.
Org Biomol Chem ; 16(48): 9461-9471, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30516790

RESUMO

A bisphosphine-catalyzed sequential [3 + 2] cycloaddition and Michael addition reaction of ynones with benzylidenepyrazolones has been developed. Under the catalysis of DPPB [1,4-bis(diphenylphosphino)butane], the reaction proceeded smoothly to give spiro-[cyclopentanone] pyrazolone derivatives in moderate to good yields with good diastereoselectivities via sequential dual α',α'-C(sp3)-H bifunctionalization annulation. This strategy provides a novel route toward the synthesis of spiro-[cyclopentanone] pyrazolones containing three contiguous stereocenters which possess potential pharmaceutical activities.


Assuntos
Ciclopentanos/síntese química , Pirazolonas/síntese química , Compostos de Espiro/síntese química , Catálise , Cristalografia por Raios X , Reação de Cicloadição/métodos , Ciclopentanos/química , Modelos Moleculares , Fosfinas/síntese química , Fosfinas/química , Pirazolonas/química , Compostos de Espiro/química , Estereoisomerismo
7.
Inorg Chem ; 57(22): 14123-14133, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30362721

RESUMO

Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(2,4-nitrophenyl)hydrazine, HL2 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl) (phenyl)methylene)-1-(4-nitrophenyl)hydrazine, and HL3 = 2-((5-hydroxo-3-methyl-1-phenyl-1 H-pyrazol-4-yl)(phenyl)methylene)-1-(pyridin-2-yl)hydrazine) have been prepared starting from 4-benzoyl-3-methyl-1-phenyl-1 H-pyrazol-5(4 H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance 1H-15N coupling in {1H-15N}-HSQC and {1H-15N}-HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, 1H, and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C═N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Desenho de Drogas , Hidrazonas/farmacologia , Pirazolonas/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Ligantes , Modelos Químicos , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Teoria Quântica
8.
Eur J Med Chem ; 159: 47-58, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30268823

RESUMO

Acarbose and voglibose are well-known α-amylase inhibitors used for the management of type-II diabetes mellitus. Unfortunately, these well-known and clinically used inhibitors are also associated with several adverse effects. Therefore, there is still need to develop the safer therapy. Despite of a broad spectrum of biological significances of pyrazolone, it is infrequently evaluated for α-amylase inhibition. Current study deals with the synthesis and biological screening of aryl and arylidene substituted pyrazolones 1-18 for their potential α-amylase inhibitory activity. Structures of synthetic derivatives 1-18 were identified by different spectroscopic techniques. All compounds 1-18 (IC50 = 1.61 ±â€¯0.16 µM to 2.38 ±â€¯0.09 µM) exhibited significant to moderate inhibitory potential when compared to standard acarbose (IC50 = 1.46 ±â€¯0.26 µM). A number of derivatives including 8-12 (IC50 = 1.68 ±â€¯0.1 µM to 1.97 ±â€¯0.07 µM) and 14-16 (IC50 = 1.61 ±â€¯0.16 µM to 1.93 ±â€¯0.07 µM) were found to be significantly active. Limited SAR suggested that different substitutions on compounds do not have any significant effect on the inhibitory potential. Compounds were found to be mixed-type inhibitors revealed by kinetic studies. However, in silico study was identified a number of key features participating in the interaction with the binding site of α-amylase enzyme.


Assuntos
Inibidores Enzimáticos/farmacologia , Pirazolonas/farmacologia , alfa-Amilases/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade , alfa-Amilases/metabolismo
9.
ChemMedChem ; 13(22): 2390-2399, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30182456

RESUMO

To explore the potential biological activities of trifluoromethyl heterocycles, we recently developed a synthetic approach to access a series of α-trifluoromethyl-α,ß-unsaturated lactones and trifluoromethyl pyrazolinones. The compounds were tested for their antimicrobial activity, and we found that some compounds had anti-influenza viral activity. The ß-aryl-α-trifluoromethyl α,ß-unsaturated lactone derivatives 5 g (5-(4-chlorophenyl)-5-methyl-4-phenyl-3-(trifluoromethyl)furan-2-one), 7 b (4-(4-methoxyphenyl)-3-(trifluoromethyl)spiro[furan-5,1'-indane]-2-one), and the trifluoromethyl pyrazolinone 12 c (1-(6-methoxy-2-naphthyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrazolo[1,2-a]pyridazin-3-one) were found to possess promising inhibitory activity against influenza virus type A, strain A/WSN/33 (H1N1). These three hit compounds were successfully optimized, and we identified that the most potent compound 5 h (5-(4-chlorophenyl)-4-(6-methoxy-2-naphthyl)-5-methyl-3-(trifluoromethyl)furan-2-one) showed inhibitory activity against various types of influenza A and B viruses in the low-micromolar range without showing cytotoxicity. Moreover, 5 h was more effective against the clinical isolate A/California/7/2009 (H1N1pdm) strain than the influenza viral polymerase inhibitor, favipiravir (T-705). We also delineated the structure-activity relationship and obtained mechanistic insight into inhibition of the viral polymerase.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Pirazolonas/farmacologia , RNA Nucleotidiltransferases/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/química , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/enzimologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/enzimologia , Lactonas/síntese química , Lactonas/química , Células Madin Darby de Rim Canino , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
10.
Bioorg Chem ; 78: 103-114, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29550530

RESUMO

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72-54.54%) and perfect ED50 values (ED50 = 0.044-0.104 mmol/kg) relative to celecoxib (ED50 = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Lipoxigenase/farmacologia , Pirazolonas/farmacologia , Compostos de Sulfidrila/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Araquidonato 5-Lipoxigenase/metabolismo , Carragenina , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Drogas , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pirazolonas/síntese química , Pirazolonas/química , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Estômago/patologia , Compostos de Sulfidrila/química , Úlcera/tratamento farmacológico , Úlcera/metabolismo , Úlcera/patologia
11.
Bioorg Chem ; 77: 507-514, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29454828

RESUMO

Herein, condensation of aryl(hetaryl)pyrazole-4-carbaldehydes 1(a-c) with substituted pyrazolones 2(a-d) lead to the corresponding arylidene-pyrazolones 3(a-l) which were tested against α-glucosidase enzyme. The synthesized compounds displayed moderate to good activity. Among these, a coumarin derivative 3k exhibited excellent results (IC50 2.10 ±â€¯0.004 µM) in comparison to clinical drug acarbose (IC50 37.38 ±â€¯0.12 µM). The ligand-protein interactions were identified through docking and stabilizing energy calculations.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Simulação de Acoplamento Molecular , Pirazolonas/farmacologia , alfa-Glucosidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 146: 47-59, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407972

RESUMO

Human carbonic anhydrases (hCAs, EC 4.2.1.1) IX and XII are overexpressed in a wide variety of cancers and are considered available drug targets for anti-tumor therapy since their inhibition has been shown to reduce tumor growth and metastasis. A set of coumarin derivatives (1-10) and several 1-aryl and 2-aryl-substituted chromeno[4,3-c]pyrazol-4-ones (11-37) and pyrano[4,3-c]pyrazol-4-ones (38-39) were synthesized and tested against the tumor-associated hCAs IX and XII and the cytosolic isoforms hCAs I and II. Several compounds were potent (Ki < 41 nM) and selective inhibitors of the hCA IX (13, 14, 19, 21, 25, 31, 33, 37 and 39), some derivatives (6, 11 and 17) were active against both hCA IX and XII isoforms (Ki = 5.6-9.6 nM), while none were effective against the off-target cytosolic hCAs I and II. Some selected inhibitors (6, 11, 13, 19, 21, 25, 31 and 39) showed activity as antiproliferative agents on HT-29 colon cancer cell lines both in normoxic and hypoxic conditions. This finding led us to hypothesize for these derivatives more than one mechanism of action, involving hCAs IX and XII inhibition in hypoxia and other not identified target(s) in normoxia.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IV/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Cromonas/farmacologia , Cumarínicos/farmacologia , Pirazolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Bioorg Med Chem Lett ; 28(5): 952-957, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29426771

RESUMO

As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in- have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX-1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, 1H NMR, 13C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Drogas , Simulação de Acoplamento Molecular , Pirazolonas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antipirina/síntese química , Antipirina/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
14.
Med Chem ; 14(5): 536-548, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29332595

RESUMO

BACKGROUND: Pyrazolones have identified as significant antioxidant agents and many marketed and clinically prescribed NSAIDs have pyrazolone ring as main scaffold. METHOD: Keeping in consideration the antioxidant potential of pyrazolone scaffold, new bispyrazolones 3-30 were synthesized by a green and enviroment friendly reaction route, in which two equivalents of 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-ol were treated with one equivalent of benzaldehyde derivatives without any catalyst. All compounds were structurally characterzied by 1H-NMR and FAB analysis. 13C-NMR of selected compounds was also recorded. All compounds gave satisfactory elemental analyses and found in good agreement with calculated values. RESULTS: Synthetic bis-pyrazolones 3-30 were evaluated for their oxidative burst inhibitory effect of zymosan stimulated whole blood phagocytes by using luminol enhanced chemilluminescence technique. All molecules demonstrated the potent ROS inhibition activity in the range of IC50 = 1.2 ± 0.1-48.8 ± 3.9 µM as compared to the standard ibuprofen (IC50 = 54.2 ± 9.2 µM). The purity of active compounds was checked by HPLC. CONCLUSION: This study has identified a number of non-acidic lead molecules for future research on ROS inhibitors.


Assuntos
Antioxidantes/farmacologia , Pirazolonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Química Verde , Ibuprofeno/farmacologia , Fagócitos/efeitos dos fármacos , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
15.
Int J Biol Macromol ; 108: 1035-1044, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29122717

RESUMO

TiO2/Fe3O4, TiO2/Fe3O4/chitosan and Methylpyrazolone functionalized TiO2/Fe3O4/chitosan (MPyTMChi) were successfully prepared. The chemical structure of the prepared materials was confirmed by FT-IR spectra, XRD, SEM and TEM. BET surface area increased from 2.4 to 3.1m2/g, Eg decreased from 2.58 to 2.25eV and more quenching of PL emission spectra was observed upon functionalization of TMChi by MPy. Moreover, high Ti and oxygen percentages were detected by EDX. Magnetization value (Ms) reached 21 emu.g-1 for MPyTMChi. MPyTMChi showed enhanced photocatalytic degradation rate of methylene blue (MB) dye under visibe light irradiation (99.8% after 40min) as compared with that for TiO2/Fe3O4 (96.7% after 100min) and TMChi (98.9% after 60min), respectively. It was regarded that the photocatalytic degradation of MB dye on MPyTMChi follows apparent pseudo-first-order according to the Langmuir-Hinshelwood (L-H) model and kapp value was 0.089min-1. Active species trapping experiment revealed that h+ and O2- played the main role in the photodegradation of MB dye while OH quenching did not greatly affect photodegradation rate. Additionally, MPyTMChi can be efficiently reused for six repetitive cycles. MPyTMChi showed higher antimicrobial activity against gram-positive, gram- negative bacterial and fungal strains while large inhibition zone was observed for gram-positive bacteria.


Assuntos
Quitosana/química , Luz , Azul de Metileno/química , Nanocompostos/química , Fotólise , Pirazolonas/química , Técnicas de Química Sintética , Óxido Ferroso-Férrico/química , Metilação , Estrutura Molecular , Nanocompostos/ultraestrutura , Pirazolonas/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
16.
Molecules ; 22(11)2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29068409

RESUMO

Five novel compounds, methyl 5-(acetyloxy)-1-(6-bromo-2-pyridinyl)-1H-pyrazole-3-carboxylate (1), methyl 1-(6-bromo-2-pyridinyl)-5-hydroxy-1H-pyrazole-3-carboxylate (2), Trimethyl 1,1',1''-tris(6-bromo-2-pyridinyl)-5,5''-dihydroxy-5'-oxo-1',5'-dihydro-1H,1''H-4,4': 4',4''-terpyrazole-3,3',3''-tricarboxylate (H2L¹, 3), [Cu2(L²)2]·CH3OH (4), H2L2A·CH3CN (5) were synthesized. Compounds 1-5 characterized by elemental analysis, IR, and X-ray single-crystal diffraction. And 1-3 were also characterized by ¹H NMR, 13C NMR and ESI-MS. The H2L¹, H2L² were formed by in-situ reaction. H2L² and H2L2A are mesomer compounds which have two chiral carbons. The antitumor activity of compounds 1-5 against BEL-7404, HepG2, NCI-H460, T-24, A549 tumor cell lines were screened by methylthiazolyl tetrozolium (MTT) assay. The compounds 1, 2 showed weakly growth inhibition on the HepG2 cell lines. The HepG2 and A549 cell lines showed higher sensitivity to compound 4, while the IC50 values are 10.66, 28.09 µM, respectively. It is worth noting that compounds 1-5 did not show cytotoxicity to human normal liver cell line HL-7702, suggesting its cytotoxic selectivity on these tumor cell lines.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirazolonas/síntese química , Pirazolonas/farmacologia , Células A549 , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre , Cristalografia por Raios X , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazolonas/química , Solventes/química , Relação Estrutura-Atividade
17.
ACS Chem Neurosci ; 8(11): 2522-2534, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28783948

RESUMO

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Pirazolonas/farmacologia , Pirimidinonas/farmacologia , Rivastigmina/farmacologia , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/química , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Estresse Oxidativo , Fragmentos de Peptídeos/química , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Pirazolonas/síntese química , Pirazolonas/química , Pirimidinonas/síntese química , Pirimidinonas/química , Rivastigmina/síntese química , Rivastigmina/química
18.
Org Biomol Chem ; 15(27): 5709-5718, 2017 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-28650044

RESUMO

An asymmetric formal one-pot reaction of 4-hydroxycoumarins with unsaturated pyrazolones has been developed by merging a chiral bifunctional organocatalyst with molecular iodine, which furnished a series of optically active spiro[dihydrofurocoumarin/pyrazolone] heterocycles with spiro quaternary stereogenic centers in moderate to excellent yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1 dr) and good to excellent enantioselectivities (up to 99% ee). The application in the gram-scale synthesis of chiral spiro[dihydrofurocoumarin/pyrazolone] compounds was also successfully realized.


Assuntos
Furocumarinas/síntese química , Pirazolonas/síntese química , Compostos de Espiro/síntese química , Ciclização , Furocumarinas/química , Estrutura Molecular , Pirazolonas/química , Compostos de Espiro/química
19.
Bioorg Med Chem Lett ; 27(13): 2996-3002, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28512022

RESUMO

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-g and coumarin containing hydrazide-hydrazone analogues 4a-e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28-1.69µM, which were comparable to those of isoniazid. The cytotoxicity (IC50>200µM) to the "normal cell" model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-e, was noticeably milder compared to that of their hydrazone analogues 4a-e (IC50 33-403µM). Molecular docking studies on compounds 4a-e and 5b-g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.


Assuntos
Antibacterianos/farmacologia , Hidrazinas/farmacologia , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidrazinas/química , Hidrazonas/química , Estrutura Molecular , Mycobacterium tuberculosis/citologia , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
20.
Chem Biol Drug Des ; 88(6): 832-843, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27565954

RESUMO

A new series derived from 4-(2-chloroacetyl)-1,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one was synthesized, characterized and its pharmacological activity toward aromatase enzyme inhibition was screened and compared to the reference native ligand letrozole. The most active compound of the series was 16, showing IC50 value of 0.0023 ± 0.0002 µm compared to letrozole with IC50 of 0.0028 ± 0.0006 µm. In addition, compounds 26 and 36 exhibit good inhibition activities close to letrozole with IC50 values 0.0033 ± 0.0001 and 0.0032 ± 0.0003 µm, respectively. Moreover, molecular docking studies were conducted to support the findings.


Assuntos
Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Pirazolonas/síntese química , Pirazolonas/farmacologia , Inibidores da Aromatase/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Pirazolonas/química , Análise Espectral/métodos , Termodinâmica
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