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1.
Arch Pharm (Weinheim) ; 352(11): e1900033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31475759

RESUMO

The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, 1 H NMR, 13 C NMR, mass spectroscopy, and elemental analysis. The IC50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Tiazóis/farmacologia , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Ligantes , Células MCF-7 , Estrutura Molecular , Ribonucleotídeo Redutases/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química
2.
Drug Dev Res ; 79(8): 406-425, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30343499

RESUMO

Hit, Lead & Candidate Discovery After acetylcholine is released into the synaptic cleft, it is reabsorbed or deactivated by acetylcholinesterase (AChE). Studies on Alzheimer's disease (AD) in the mid-20th century proved that cognitive dysfunctions are associated with cholinergic neurotransmission. Drugs, such as tacrine, rivastigmine, donepezil, and galantamine are known as acetylcholinesterase inhibitors. However, these drugs have limited use in advanced AD and dementia. Recently, the anticholinesterase activity of various heterocyclic-framed compounds, including piperazine derivatives, has been investigated, and compounds with similar effects to known drugs have been identified. The aim of this study was to design new donepezil analogs. In this study, 66 original piperazinyl thiazole derivatives were synthesized by the reaction of piperazine N'-benzoyl thioamides and bromoacetophenones to inhibit AChE. Biological activity was measured by the Ellman method. Compounds 35, 38, 40, 45, 57, and 61 showed a high inhibitory effect among the series (80.36%-83.94% inhibition), and donepezil had a 96.42% inhibitory effect. The IC50 values of compounds 35, 38, and 40, were calculated as 0.9767 µM, 0.9493 µM, and 0.8023 µM, respectively. Compound 45 (IC50 = 1.122), Compound 57 (IC50 = 1.2130) and 61 (IC50 = 0.9193) also exhibited good activity on AChE. Molecular modeling studies were in agreement with the predictions. Trp286, Arg296, and Tyr341 were the key amino acids at the active site. Both donepezil and synthesized compounds seemed to interact with these residues.


Assuntos
Inibidores da Colinesterase/química , Donepezila/química , Modelos Moleculares , Piperazina/química , Tiazóis/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Humanos , Simulação de Acoplamento Molecular/métodos , Piperazina/farmacologia , Tiazóis/farmacologia
3.
Bioorg Med Chem ; 26(8): 1986-1995, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29525337

RESUMO

Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC50:0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site.


Assuntos
Aromatase/metabolismo , Inibidores Enzimáticos/química , Tiazóis/química , Aromatase/química , Sítios de Ligação , Domínio Catalítico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Tiazóis/metabolismo , Tiazóis/farmacologia
4.
Arch Pharm (Weinheim) ; 351(3-4): e1700272, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29522642

RESUMO

Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Fenóis/farmacologia , Piridinas/farmacologia , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Piridinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
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