RESUMO
Imidazole-chalcone compounds are recognised for their broad-spectrum antimicrobial properties. Probiotic-friendly, selective new-generation antimicrobials prove to be more efficient in combating gastrointestinal system pathogens. The aim of this study is to identify imidazole-chalcone derivatives that probiotics tolerate and evaluate their in vitro synergistic antimicrobial effects on pathogens. In this study, fifteen previously identified imidazole-chalcone derivatives were analyzed for their in vitro antimicrobial properties against gastrointestinal microorganisms. Initially, the antimicrobial activity of pathogens was measured using the agar well diffusion method, while the susceptibility of probiotics was determined by microdilution. The chosen imidazole-chalcone derivatives were assessed for synergistic effects using the checkerboard method. Four imidazole-chalcone derivatives to which probiotic bacteria were tolerant exhibited antibacterial and antifungal activity against the human pathogens tested. To our knowledge, this study is the first to reveal the fractional inhibitory concentration (FIC) of combinations of imidazole-chalcone derivatives. Indeed, the minimum inhibitory concentrations (MIC) for morpholinyl- (ZDO-3f) and 4-ethylpiperazinyl- (ZDO-3 m) imidazole-chalcones were notably low when tested against E. coli and B. subtilis, with values of 31.25 µg/mL and 125 µg/mL, respectively. The combination of morpholinyl- and 4-ethylpiperazinyl derivatives demonstrated an indifferent effect against E. coli, but an additive effect was observed for B. subtilis. Additionally, it was observed that imidazole-chalcone derivatives did not exhibit any inhibitory effects on probiotic organisms like Lactobacillus fermentum (CECT-5716), Lactobacillus rhamnosus (GG), and Lactobacillus casei (RSSK-591). This study demonstrates that imidazole-chalcone derivatives that are well tolerated by probiotics can potentially exert a synergistic effect against gastrointestinal system pathogens.
Assuntos
Sinergismo Farmacológico , Imidazóis , Testes de Sensibilidade Microbiana , Probióticos , Probióticos/farmacologia , Imidazóis/farmacologia , Imidazóis/química , Chalcona/farmacologia , Chalcona/química , Chalcona/análogos & derivados , Antibacterianos/farmacologia , Antibacterianos/química , Chalconas/farmacologia , Chalconas/química , Trato Gastrointestinal/microbiologia , Humanos , Bactérias/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/químicaRESUMO
The frequent use of anti-inflammatory drugs and the side effects of existing drugs keep the need for new compounds constant. For this purpose, flurbiprofen and ibuprofen-like compounds, which are frequently used anti-inflammatory compounds in this study, were synthesized and their structures were elucidated. Like ibuprofen and flurbiprofen, the compounds contain a residue of phenylacetic acid. On the other hand, it contains a secondary amine residue. Thus, it is planned to reduce the acidity, which is the biggest side effect of NSAI drugs, even a little bit. The estimated ADME parameters of the compounds were evaluated. Apart from internal use, local use of anti-inflammatory compounds is also very important. For this reason, the skin permeability values of the compounds were also calculated. And it has been found to be compatible with reference drugs. The COX enzyme inhibitory effects of the obtained compounds were tested by in vitro experiments. Compound 2a showed significant activity against COX-1 enzyme with an IC50 = 0.123 + 0.005 µM. The interaction of the compound with the enzyme active site was clarified by molecular dynamics studies.
Assuntos
Ciclo-Oxigenase 1 , Inibidores de Ciclo-Oxigenase , Flurbiprofeno , Ibuprofeno , Simulação de Dinâmica Molecular , Flurbiprofeno/farmacologia , Flurbiprofeno/química , Ibuprofeno/farmacologia , Ibuprofeno/química , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/síntese química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/síntese química , Humanos , Domínio Catalítico , Fenilacetatos/química , Fenilacetatos/farmacologiaRESUMO
Cancer remains a significant health challenge globally, requiring the development of targeted chemotherapeutics capable of specifically inhibiting cancer cell growth. Angiogenesis is one of the key features of tumor growth and metastasis and is, therefore, an important target for the treatment of many tumors. The vascular endothelial growth factor (VEGF) signaling pathway has proven to be a promising lead in anticancer therapy due to the central role it plays in tumor angiogenesis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a key mediator in the signaling pathway regulating angiogenesis. Targeting VEGFR-2 may disrupt angiogenesis, leading to a reduction in tumor blood supply and tumor progression. The design, synthesis, and assessment of novel VEGFR-2 inhibitor derivatives are the focus of this study, with particular emphasis on incorporating the pyrazole-thiadiazol pharmacophore into the molecular structure. Taking advantage of the pharmacophoric properties of pyrazole and 1,3,4-thiadiazol, compounds with different substituents in the main structure were designed and synthesized. The compounds were also evaluated for antiproliferative activity against cancer cell lines. Compound 4e demonstrated the highest activity among all compounds, with an IC50 of 9.673 ± 0.399⯵M against HT-29â¯cells and 23.081 ± 0.400⯵M against NIH3T3 cells. To further support the inhibitory activity of compound 4e, an in silico study was performed. Compound 4e demonstrated strong binding to the active site of VEGFR-2 in molecular docking studies, forming hydrogen bonds with key amino acid residues. The stability of the compound in the enzyme's active site was demonstrated through molecular dynamics simulations.
RESUMO
In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a-h were characterized using 1H NMR, 13C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7.34 ± 0.21 µM and 4.56 ± 0.18 µM, respectively. These results were compared to standard drugs, doxorubicin (IC50 = 12.420 ± 0.5 µM) and Hoechst 33342 (IC50 = 0.422 ± 0.02 µM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.
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Carbonic anhydrase (CA) enzymes are a common catalytic enzyme in many organisms. Vertebrates and invertebrates have different CA isoforms. Sixteen different isozymes of the α-CA isoform found in vertebrates have been identified so far. The main task of this enzyme is to catalyze the reversible conversion of carbon dioxide into bicarbonate and hydrogen ions in the body. It is widely distributed in many organs and tissues. They are involved in important physiological processes such as pH and CO2 homeostasis, biosynthetic reactions such as gluconeogenesis, lipogenesis, ureagenesis, bone resorption, calcification, tumorigenicity, and electrolyte secretion. As a result of the literature research, it has been determined that the most effective inhibitor of the carbonic anhydrase enzyme is sulfonamides. The R group in the general molecular structure of R-SO2-NH2 generally consists of aromatic or heteroaromatic ring systems. The sulfonamides interact strongly with the Zn2+ ions in the active site of the enzyme. In this study, 10 sulfonamide derivatives were synthesized. Analyses of the obtained compounds are evaluated by using 1H NMR, 13C NMR and HRMS spectroscopic methods. The inhibition effect of the obtained compounds on the carbonic anhydrase enzyme was investigated by means of in vitro kit method. For the selected compounds, docking studies were performed and the enzyme active sites and binding points were determined. It was revealed that the strongest interaction with CA enzymes (CA-I, CA-II, CA-IX, CA-XII) active sites was observed with the compound 2e.
Assuntos
Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Animais , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Estrutura Molecular , Domínio Catalítico , Sulfonamidas/farmacologia , Sulfonamidas/química , Relação Estrutura-AtividadeRESUMO
Donepezil is one of the most used drugs in the treatment of Alzheimer's disease. Its activity as an AChE inhibitor makes new studies with these enzyme inhibitors attractive. For this purpose, in this study, 12 compounds including thiosemicarbazone pharmacophore, have been synthesized for the treatment of the Alzheimer's disease. 3,4-Dimethoxybenzene or 1,3-benzodioxolone rings were used for the PAS region. The substituted piperazine benzene structure is preferred for the CAS region. At the same time, the thiosemicarbazone pharmacophore structure with known ChE enzyme inhibition potential was used as a bridge connecting the CAS and PAS regions. Structure determination of compounds 3a-3l were revealed using 13 C-NMR, 1 H-NMR, and HRMS spectroscopic methods. The inhibition profile of obtained compounds (3a-3l) against ChE was evaluated using in vitro modified Ellman method. Compounds 3a, 3b, 3f, 3g and 3i exhibited inhibitory activity against the AChE enzyme. Compound 3a showed the highest inhibitory potential with an IC50 = 0.030 ± 0.001 µM. As a result of molecular docking studies, compound 3a displayed important interactions compared to other active derivatives. Molecular dynamics studies are important to see the stability of the complex formed by ligand and protein. RMSD, RMSF ang Rg parameters were calculated via dynamic studies. In conclusion, compound 3a may be a potential AChE enzyme inhibitor with its strong inhibitory potential and behavior in silico.
Assuntos
Doença de Alzheimer , Tiossemicarbazonas , Humanos , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Simulação de Dinâmica Molecular , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/uso terapêutico , Inibidores Enzimáticos/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Lung cancer is one of the most common cancer types of cancer with the highest mortality rates. However, while epidermal growth factor receptor (EGFR) is an important parameter for lung cancer, EGFR inhibitors also show great promise in the treatment of the disease. Therefore, a series of new EGFR inhibitor candidates containing thiadiazole and pyrazole rings have been developed. The activities of the synthesized compounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cytotoxicity assay, analysis of mitochondrial membrane potential (MMP) by flow cytometry, and EGFR inhibition experiments. Molecular docking and molecular dynamics simulations were performed as in silico studies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 ± 0.164; 1.537 ± 0.097; and 8.493 ± 0.667 µM values, respectively. As a result of MMP by flow cytometry, compound 6g showed 80.93% mitochondrial membrane potential. According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a value of IC50 = 0.024 ± 0.002 µM.
RESUMO
Uncontrolled use of antifungal drugs affects the development of resistance to existing drugs. Azole antifungals constitute a large part of antifungal therapy. Therefore, there is a need for new azole antifungals. Within the scope of this study, 17 new triazole derivative compounds were synthesized. Structure determinations were clarified by spectroscopic analysis methods (1H-NMR, 13C-NMR, HRMS). In addition, structure matching was completed using two-dimensional NMR techniques, HSQC, HMBC and NOESY. The antifungal effects of the compounds were evaluated on Candida strains by means of in vitro method. Compound 5d showed activity against Candida glabrata with a MIC90 = 2 µg/mL. Compound 5d showed activity against Candida krusei with a MIC90 = 2 µg/mL. This activity value, which is higher than fluconazole, is promising. In addition, the biofilm inhibition percentages of the compounds were calculated. Molecular docking and molecular dynamics simulations performed with compound 5d are in harmony with activity studies.
RESUMO
In this study, 12 novel 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-3-ethyl-4-(substitutephenyl)-2,3-dihydrothiazole derivatives were obtained. Among these compounds, 2-((1-(4-(1H-imidazol-1-yl)phenyl)ethylidene)hydrazineylidene)-4-([1,1'-biphenyl]-4-yl)-3-ethyl-2,3-dihydrothiazole (4h) was chosen as the most active derivative in the series. According to the MTT results, compounds 4h and 4k showed activity with IC50 =4.566±0.246â µM and IC50 =4.537±0.463â µM, respectively. Unlike other derivatives, compound 4h carries a phenyl ring in the 4th position of the phenyl ring. This bulky group allowed the compound to settle in the enzyme active site. Dynamic studies show that the stability of the compound does not change over 40â ns. RMSD, RMSF and Rg parameters all remained within acceptable limits. The uninterrupted aromatic hydrogen bonding of the enzyme active site with the important amino acids Cys919, Glu885 and Asp1046 proves the inhibitory potential of compound 4h on the VEGFR-2 enzyme. It is thought that more active compounds will be reached with the derivatives to be synthesized starting from compound 4h.
Assuntos
Imidazóis , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Estrutura Molecular , Relação Estrutura-Atividade , Imidazóis/química , Simulação de Acoplamento MolecularRESUMO
Modification of drugs used in the clinic is a frequently used method with regards to medicinal chemistry in the development of new drugs. Acetazolamide is a drug in clinical use as a CA inhibitor. Within the scope of this study, the 'N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide' structure, which is acetazolamide residue, was kept constant; various mercaptan substitutions were made from methylene adjacent to the carbonyl group in the structure. Compounds 4c, 4d, 4e, 4 g, 4h, 4i, and 4j exhibited inhibitor activity against CA enzyme with IC50=0.238 ± 0.010, 0.161 ± 0.007, 0.067 ± 0.002, 0.084 ± 0.003, 0.033 ± 0.001, 0.049 ± 0.002 and 0.187 ± 0.008 µM, respectively. The intermolecular interactions of the promising compounds with aromatase enzyme were investigated through the SP docking approach, which revealed significant binding interaction energies associated with these compounds. To measure the stability of the compounds in the enzyme active site, dynamic studies were performed at 100 ns. In addition to the RMSD, RMSF parameters, the interaction ratios of compound 4h with amino acids in the enzyme active site and the interaction histograms were also investigated. The results obtained are quite promising. Continuous interactions were exhibited with Thr199, Glu106, His96, His94 and His119, which are important for the CA enzyme.Communicated by Ramaswamy H. Sarma.
RESUMO
Cyclooxygenase, also known as prostaglandin H2 synthase (PGH2), is one of the most important enzymes in pharmacology because inhibition of COX is the mechanism of action of most nonsteroidal anti-inflammatory drugs. In this study, ten thiazole derivative compounds had synthesized. The analysis of the obtained compounds was performed by 1 H NMR and 13 C NMR methods. By this method, the obtained compounds could be elucidated. The inhibitory effect of the obtained compounds on cyclooxygenase (COX) enzymes was investigated. The encoded compounds 5a, 5b, and 5c were found to be the most potent compared to the reference compounds ibuprofen (IC50 = 5.589 ± 0.278 µM), celecoxib (IC50 = 0.132 ± 0.004 µM), and nimesulide (IC50 = 1.692 ± 0.077 µM)against COX-2 isoenzyme. The inhibitory activity of 5a, 5b, and 5c is approximate, but the 5a derivative proved to be the most active in the series with an IC50 value of 0.180 ± 0.002 µM. The most potent COXs inhibitor was 5a, which was further investigated for its potential binding mode by a molecular docking study. Compound 5a was found to be localized at the active site of the enzyme, like celecoxib, which has a remarkable effect on COXs enzymes.
Assuntos
Inibidores de Ciclo-Oxigenase 2 , Farmacóforo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Celecoxib , Simulação de Acoplamento Molecular , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
As lung cancer was placed foremost part among other types of cancer in terms of mortality. Recent researches are widely focused on developing multi-targeted and site-specific targeted drug designs. In the present study, we designed and developed a series of quinoxaline pharmacophore derivatives as active EGFR inhibitors for the treatment of non-small cell lung cancer. The compounds were synthesized through a condensation reaction between hexane-3,4-dione and methyl 3,4-diaminobenzoate as a first step. Their structures were confirmed by 1 H-NMR, 13 C-NMR, and HRMS spectroscopic methods. Cytotoxicity (MTT) were applied to determine anticancer activity of the compounds against breast (MCF7), fibroblast (NIH3 T3), and lung (A549) cell lines as EGFR inhibitors. Doxorubicin was used as a reference agent, compound 4i exhibited a significant effect among other derivatives with IC50 = 3.902 ± 0.098 µM value against A549 cell line. The docking study showed that the best position on EGFR receptor could be observed with 4i. From the obtained evaluations of the designed series, compound 4i was a promising agent as EGFR inhibitor for further investigation and evaluation studies in the future.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Quinoxalinas/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Receptores ErbB/metabolismo , Desenho de Fármacos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/químicaRESUMO
Cancer is a progressive disease that is frequently encountered worldwide. The incidence of cancer is increasing with the changing living conditions around the world. The side-effect profile of existing drugs and the resistance developing in long-term use increase the need for novel drugs. In addition, cancer patients are not resistant to bacterial and fungal infections due to the suppression of the immune system during the treatment. Rather than adding a new antibacterial or antifungal drug to the current treatment plan, the fact that the drug with anticancer activity has these effects (antibacterial and antifungal) will increase the patient's quality of life. For this purpose, in this study, a series of 10 new naphthalene-chalcone derivatives were synthesized and their anticancer-antibacterial-antifungal properties were investigated. Among the compounds, compound 2j showed activity against the A549 cell line with an IC50 = 7.835 ± 0.598 µM. This compound also has antibacterial and antifungal activity. The apoptotic potential of the compound was measured by flow cytometry and showed apoptotic activity of 14.230%. The compound also showed 58.870% mitochondrial membrane potential. Compound 2j inhibited VEGFR-2 enzyme with IC50 = 0.098 ± 0.005 µM. Molecular docking studies of the compounds were carried out by in silico methods against VEGFR-2 and caspase-3 enzymes.
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Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease that is characterized by memory and cognitive impairments that predominantly affects the elderly and is the most common cause of dementia. As is known, the AChE enzyme consists of two parts. In this work, 10 new hydrazones (3a-3j) were designed and synthesized. Naphthalene, indole, benzofuran and benzothiophene rings were used to interact with the PAS region. 4-fluorophenyl and 4-fluorobenzyl structures were preferred for interaction with the CAS region. In biological activity studies, the AChE and BChE inhibitory potentials of all compounds were evaluated using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant activity against AChE. The compounds 3i and 3j displayed IC50 values of 0.034 and 0.027 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also displayed a significant inhibition against AChE. In addition, the antioxidant activities of the compounds were also evaluated. Derivatives 3i and 3j, which emerged active from both in vitro activity studies, were subjected to in vitro PAMPA tests to determine BBB permeability. Further docking simulation also revealed that these compounds (3i, 3j and donepezil) interacted with the enzyme active site in a similar manner to donepezil. A few parameters derived from MD simulation trajectories were computed and validated for the protein-ligand complex's stability under the dynamic conditions.Communicated by Ramaswamy H. Sarma.
RESUMO
Alzheimer's disease (AD) is a neurological, progressive illness that typically affects the elderly and is clinically distinguished by memory and cognitive decline. Due to a number of factors, including the absence of a radical treatment, an increase in the patient population over time, the high cost of care and treatment, and a significant decline in patients' quality of life, the importance of this disease has increased. These factors have all prompted increased interest among researchers in this field. The chemical structure of the donepezil molecule, the most popular and effective treatment response for AD, served as the basis for the design and synthesis of 42 novel indan-1-one derivatives in this study. Using IR, 1H, and 13C NMR as well as mass spectroscopic techniques, the compounds' structures were identified. Research on the compounds' antioxidant activities, cholinesterase (ChE) enzyme inhibition, monoamine oxidase (MAO) A and B inhibitory activities, ß-amyloid plaque inhibition, and cytotoxicity impact was carried out. Inhibition of ß-amyloid plaque aggregation; effective inhibition of AChE, BChE, and MAO-B enzymes; and significant antioxidant activity were all demonstrated by compounds D28-D30 and D37-D39. Because of their various actions, it was hypothesized that the related compounds may be useful in treating AD symptoms as well as providing palliative care.
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The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the in vitro fluorometric method. Additionally, amyloid beta (Aß)-aggregation inhibitory effects of active compounds were evaluated by means of an in vitro kit-based method. The biological evaluation showed that compounds 4a, 4d, 4f, 4h, 4k and 4m displayed significant activity against AChE and MAO-B enzymes. Compound 4f displayed inhibitory activity against AChE and MAO-B enzyme with IC50 values of 23.4 ± 1.1 nM and 40.3 ± 1.7 nM, respectively. It has been revealed that compound 4f may have the potential to inhibit AChE and MAO-B enzymes, as well as the ability to prevent the formation of beta amyloid plaques accumulated in the brains of patients suffering from AD. In silico studies also support the obtained biological activity findings. Compound 4f provided strong interactions with the active site of both enzymes. In particular, the interaction of compound 4f with flavin adenine dinucleotide (FAD) in the MAO-B enzyme active site is a promising and exciting finding.
RESUMO
In this study, 15 thiosemicarbazone derivatives were synthesized. Analysis of the obtained compounds was performed by means of 1 H-NMR, 13 C-NMR and high resolution mass spectroscopy (HRMS) spectroscopic methods. The inhibition effect of the obtained compounds on cholinesterase and monoaminoxidase (MAO) enzymes were investigated with in vitro methods. None of the compounds showed significant activity on the butyrylcholinesterase enzyme. On the other hand, compounds 3b, 3c, 3e, 3k, 3l, 3m, 3n and 3o displayed significant activity on acetylcholinesterase (AChE) while compounds 3f, 3i, 3k, 3l, 3m, 3n, 3o also showed remarkable effects on monoamine oxidase-B (MAO-B) enzymes. For the selected compounds, docking studies were performed and the enzyme active site and binding modes were determined. It was revealed that the strongest interaction with AChE and MAO-B enzyme active sites was observed with the compound 3k. Another important factor in the treatment of diseases affecting the central nervous system such as Alzheimer's is the ability of the compounds to cross the blood-brain barrier (BBB). Additionally, the agents planned for the treatment of these diseases must also pass the blood-brain barrier. Therefore, in silico BBB penetration properties of active compounds were investigated.
Assuntos
Doença de Alzheimer , Tiossemicarbazonas , Humanos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Tiossemicarbazonas/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Monoaminoxidase/metabolismo , Simulação de Acoplamento Molecular , Estrutura MolecularRESUMO
In this study, novel pyridine-containing thiazolyl hydrazone derivatives were synthesized. Structure determinations of the compounds were performed using 1H NMR, 13C NMR and HRMS techniques. The biological activities of the compounds were evaluated against MAO enzymes by in vitro fluorometric method. As a result of activity studies, compound 3a showed selective inhibitory activity against MAO-B enzyme with IC50 = 0.088 + 0.003 µM. The selectivity index of this compound is greater than 1136. Molecular docking studies were carried out using 2V5Z crystal. It has been observed that docking studies and activity studies are in harmony.
Assuntos
Inibidores da Monoaminoxidase , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Piridinas , Estrutura MolecularRESUMO
Aromatase inhibitors are the most used anticancer drug group in breast cancer cases. The development of resistance in cancer patients over time and the side effects of existing drugs make the need for new and effective agents permanent. In this study, 10 novel pyrimidine-triazole derivatives were synthesized and their anticancer activities were investigated. Compounds 5c and 5g showed inhibitor activity against MCF-7 cell line with IC50 =1.573±0.020; 3.698±0.056â µM value, respectively. As a result of inâ vitro aromatase enzyme inhibition test, compounds 5c and 5g were exhibited significant activity with IC50 =0.082±0.007â µM and IC50 =0.198±0.015â µM, respectively. Estimated physicochemical parameters were calculated using the online SwissADME program for all compounds. Interaction modes of the compounds 5c and 5g were investigated against aromatase enzyme by means of docking studies. As a result of the studies, the importance of the triazole ring for aromatase inhibition has been understood.
Assuntos
Antineoplásicos , Aromatase , Antineoplásicos/química , Aromatase/metabolismo , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn2+ in their structure, can be easily inhibited by dithiocarbamate compounds. In addition, CA enzyme inhibitory activities are known in groups such as sulfonamide and methylsulfonyl. For this purpose, in this study, a series of 23 new dithiocarbamate-methylsulfonyl derivatives were synthesized and their CA enzyme inhibitory activities were investigated. The inhibition potentials of the obtained compounds against the human CA I and CA II enzymes were investigated by the in vitro enzyme isolation method. It is seen that the compounds show activity at the nanomolar level. Molecular docking studies of the compounds were carried out by in silico methods. The poses of compounds 2a, 2e, 2o, and 2t are presented.