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An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values ââof - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.
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Discovering new compounds capable of inhibiting physiologically and metabolically significant drug targets or enzymes is of paramount importance in biological chemistry. With this aim, new 5-nitroimidazole derivatives (1-4) were designed and synthesized, and their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were discovered using acetyl (butyryl) thiocholine and Ellman's reagents for spectrophotometric assay. The inhibitory profiles of the synthesized compounds were assessed by comparing their IC50 and Ki values. Results demonstrate significant inhibitory activity of all synthesized compounds against both AChE and BuChE compared to the reference compound, donepezil. Notably, compound 4 exhibited dual inhibition of these enzymes, showing the highest activity against Electrophorus electricus AChE (EeAChE) with a Ki value of 0.024±0.009 nM and against equine BuChE (eqBuChE) with a Ki value of 0.087±0.017 nM. Furthermore, molecular modeling was conducted to study the interaction modes of the most potent compound (4) and donepezil in the active site of their related enzymes' crystal structures (PDB ID: 4EY7 and 4BDS, respectively). Additionally, drug-likeness, ADME, and toxicity profiles of the compounds and metronidazole were predicted. The above results indicated that the dual inhibition of these enzymes is considered as a promising strategy for the treatment of neurological disorder especially Alzheimer's disease.
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Building on our previous work that discovered chalcone as a promising pharmacophore for anticancer activity, we have various other chalcone derivatives and have synthesized a series of novel bischalcone to explore their anticancer activity. Among all tested compounds, compounds 6a, 6b, and 6c showed the highest antiproliferative activity against A-549 cancer cell lines with the average IC50 values of 4.18, 4.52, and 5.05 µM, respectively. Moreover, compound 6c showed high antiproliferative activity against the Caco-2 cell line; thus, it was 2- and 4-fold more active than the reference compounds, i.e., methotrexate and capecitabine. Compound 6a also induced cell-cycle arrest in the S phase, whereas compounds 6b and 6c were observed to stop at the G0/G1 phase. Thereafter, we evaluated that compound 6c also had the highest apoptosis/necrosis ratio than other compounds and the standard compound. The anticancer property of the 6c was also supported by molecular docking studies carried out on the EGFR and HER2 receptors. Overall, we expect that these compounds can be further developed for the potential treatment of lung cancer.
Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Desenho de Fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In this study, for the first time, lactic acid was used as a bio-based green catalyst and reaction medium for the synthesis of 1,2,3,4-tetrasubstituted pyrrole derivatives from one-pot three-component reaction of commercially available primary amines, 1,3-dicarbonyl compounds, and trans-ß-nitrostyrene at room temperature. Thirty-three corresponding pyrroles, of which eight are novel and have been reported for the first time, were synthesized in high to excellent yields in lactic acid media and characterized by spectroscopic analysis. In all examined cases, lactic acid represented many advantages, including shorter reaction time, ease of product isolation, higher yields, no by-products, no chromatographic process, and lower volatility in the reaction. This bio-based green solvent can also be recycled and reused three times without loss of its efficiency as a catalyst and solvent.
Assuntos
PirróisRESUMO
In the present work, a series of bisbenzazole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of these compounds was investigated using MTT assay. Bisbenzazole derivatives showed significant antiproliferative activity against all the four tested cancer cell lines. Among the various bisbenzazole derivatives, bisbenzoxazole derivatives exhibited the most promising anticancer activity followed by bisbenzimidazole and bisbenzothiazole derivatives. All the derivatives were found to be less toxic as compared to methotrexate (positive control) in normal human cells, indicating selective and efficient antiproliferative activity of these bisbenzazole derivatives. The structure-activity relationships of heteroaromatic systems and linkers present in bisbenzazole derivatives were analyzed in detail. In silico ADMET prediction revealed that bisbenzazole is a drug-like small molecule with a favorable safety profile. Compound 31 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from methotrexate. Twenty-one bisbenzoxazole derivatives have been designed synthesized and evaluated to be an antiproliferative activity against four human tumor cell lines.
Assuntos
AntineoplásicosRESUMO
AIMS: Flavonoids and related compounds, such as quercetin-based antiviral drug Gene-Eden-VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS-CoV proteases. In this study, we aimed to compare the anti-SARS CoV-2 activities of both newly synthesized chalcone derivatives and these two drugs. METHODS: Determination of the potent antiviral activity of newly synthesized chalcone derivatives against SARS-CoV-2 by calculating the RT-PCR cycling threshold (Ct ) values. RESULTS: Antiviral activities of the compounds varied because of being dose dependent. Compound 6, 7, 9, and 16 were highly effective against SARS-CoV-2 at the concentration of 1.60 µg/mL. Structure-based virtual screening was carried out against the most important druggable SARS-CoV-2 targets, viral RNA-dependent RNA polymerase, to identify putative inhibitors that could facilitate the development of potential anti-coronavirus disease-2019 drug candidates. CONCLUSIONS: Computational analyses identified eight compounds inhibiting each target, with binding affinity scores ranging from -4.370 to -2.748 kcal/mol along with their toxicological, ADME, and drug-like properties.
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COVID-19 , Chalcona , Chalconas , Antivirais/farmacologia , Antivirais/uso terapêutico , Chalcona/farmacologia , Chalconas/farmacologia , Humanos , SARS-CoV-2RESUMO
Prostate cancer is the most frequently diagnosed tumor in men and the second leading cause of cancer-associated mortality in most developed countries. 3,5-Diaryl substituted pyrazole derivatives (20-28) were prepared starting from related chalcones and biologically evaluated for in vitro growth inhibition activity against PC3 and DU145 human prostate cancer cell lines. Compounds 23, 26, and 28 were found to be more potent as compared to the other halogen-substituted derivatives. Especially, the 2-bromo-substituted pyrazole derivative (26) was found to be more potent against PC3 and DU145 cells. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) are known to be expressed in DU145 and PC3 cancer cells. The binding mode of the most selective compound 26 toward EGFR and VEGFR2 was investigated by employing docking simulations based on GLIDE standard precision (-5.912 and -6.949 kcal/mol, respectively).
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Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Células PC-3 , Neoplasias da Próstata/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
The present study was carried out in the attempt to synthesize a new class of potential anticancer agents comprising eleven compounds (24-34) sharing the 3,5-diarylisoxazole as a core. The chemical structure of the new synthesized compounds was established by IR, 1H NMR, 13C NMR and elemental analysis. Their biological potential towards prostate cancer was evaluated by using cancer PC3 cells and non-tumorigenic PNT1a cells. Interestingly, compound 26 distinguished from others with a quite high selectivity value that is comparable to 5-FU. The binding mode of 26 towards Ribosomal protein S6 kinase beta-1 (S6K1) was investigated at a molecular level of detail by employing docking simulations based on GLIDE standard precision as well as MM-GBSA calculations.
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Antineoplásicos/farmacologia , Isoxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoxazóis/síntese química , Isoxazóis/metabolismo , Simulação de Acoplamento Molecular , Células PC-3 , Ligação Proteica , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
A novel class of fluoro-substituted tris-chalcones derivatives (5a-5i) was synthesized from phloroglucinol and corresponding benzaldehydes. A three step synthesis method was followed for the production of these tris-chalcone compounds. The structures of the newly synthesized compounds (5a-5i) were confirmed on the basis of IR, 1H NMR, 13C NMR, and elemental analysis.The compounds' inhibitory activities were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). These chalcone derivatives had Ki values in the range of 19.58-78.73â¯nM for hCA I, 12.23-41.70â¯nM for hCA II, 1.09-6.84â¯nM for AChE, 8.30-32.30â¯nM for BChE and 0.93⯱â¯0.20-18.53⯱â¯5.06â¯nM against α-glycosidase. These results strongly support the promising nature of the tris-chalcone scaffold as selective carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase inhibitor. Overall, due to these derivatives' inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer's disease; type-2 diabetes mellitus that are associated with high enzymatic activity of carbonic anhydrase, acetylcholine esterase, butyrylcholinesterase, and α-glycosidase.
Assuntos
Inibidores da Anidrase Carbônica/química , Chalconas/química , Inibidores da Colinesterase/química , Inibidores de Glicosídeo Hidrolases/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Anidrase Carbônica I/química , Anidrase Carbônica II/química , Inibidores da Anidrase Carbônica/síntese química , Chalconas/síntese química , Inibidores da Colinesterase/síntese química , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Estrutura MolecularRESUMO
In this study, a series of B-ring fluoro substituted bis-chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and evaluated for their ability to inhibit xanthine oxidase (XO) and growth inhibitory activity against MCF-7 and Caco-2 human cancer cell lines, in vitro. According to the results obtained, the bis-chalcone with fluoro group at the 2 (4b) or 2,5-position (4g) of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 7 fold higher than allopurinol. The binding modes of the bis-chalcone derivatives in the active site of xanthine oxidase were explained using molecular docking calculations. Also, compound 4g and 4h showed in vitro growth inhibitory activity against a panel of two human cancer cell lines 1.9 and 6.8⯵M of IC50 values, respectively.
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Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalcona/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Neoplasias da Mama/patologia , Domínio Catalítico , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of novel phloroglucinol derivatives were designed, synthesized, characterized spectroscopically and tested for their inhibitory activity against selected metabolic enzymes, including α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCA I and II). These compounds displayed nanomolar inhibition levels and showed Ki values of 1.14-3.92 nM against AChE, 0.24-1.64 nM against BChE, 6.73-51.10 nM against α-glycosidase, 1.80-5.10 nM against hCA I, and 1.14-5.45 nM against hCA II.
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Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Anidrases Carbônicas/metabolismo , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Floroglucinol/farmacologia , Animais , Anidrases Carbônicas/isolamento & purificação , Relação Dose-Resposta a Droga , Electrophorus , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Cavalos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Floroglucinol/síntese química , Floroglucinol/química , Relação Estrutura-AtividadeRESUMO
Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9-15, and 20-23) using a structure-activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC50 values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12-14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.
Assuntos
Anti-Infecciosos/farmacologia , Chalconas/farmacologia , Flúor/química , Chalconas/química , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of novel fluoro-substituted chalcone derivatives have been synthesized. All synthesized compounds were characterized by (1)H nuclear magnetic resonance (NMR), (13)C NMR, and elemental analysis. Their anti-proliferative activities were evaluated against five cancer cells lines, namely, A549, A498, HeLa, A375, and HepG2 using the MTT method. Most of the compounds showed moderate to high activity with IC50 values in the range of 0.029-0.729µM. Of all the synthesized compounds, 10 and 19 exhibited the most potent anti-proliferative activities against cancer cells, and 10 was identified as the most promising compound.
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Antineoplásicos/farmacologia , Chalcona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of polymethoxylated-pyrazoline benzene sulfonamides were synthesized, investigated for their cytotoxic activities on tumor and non-tumor cell lines and inhibitory effects on carbonic anhydrase isoenzymes (hCA I and hCA II). Although tumor selectivity (TS) of the compounds were less than the reference compounds 5-Fluorouracil and Melphalan, trimethoxy derivatives 4, 5, and 6 were more selective than dimethoxy derivatives 2 and 3 as judged by the cytotoxicity assay with the cells both types originated from the gingival tissue. The compound 6 (4-[3-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl] benzene sulfonamide) showed the highest TS values and can be considered as a lead molecule of the series for further investigations. All compounds synthesized showed superior CA inhibitory activity than the reference compound acetazolamide on hCA I, and II isoenzymes, with inhibition constants in the range of 26.5-55.5 nM against hCA I and of 18.9-28.8 nM against hCA II, respectively.
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Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Pirazóis/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
Vascular endothelial growth factor receptor 2 (VEGFR-2) stands as a prominent therapeutic target in oncology, playing a critical role in angiogenesis, tumor growth, and metastasis. FDA-approved VEGFR-2 inhibitors are associated with diverse side effects. Thus, finding novel and more effective inhibitors is of utmost importance. In this study, a deep learning (DL) classification model was first developed and then employed to select putative active VEGFR-2 inhibitors from an in-house chemical library including 187 druglike compounds. A pool of 18 promising candidates was shortlisted and screened against VEGFR-2 by using molecular docking. Finally, two compounds, RHE-334 and EA-11, were prioritized as promising VEGFR-2 inhibitors by employing PLATO, our target fishing and bioactivity prediction platform. Based on this rationale, we prepared RHE-334 and EA-11 and successfully tested their anti-proliferative potential against MCF-7 human breast cancer cells with IC50 values of 26.78±4.02 and 38.73±3.84â µM, respectively. Their toxicities were instead challenged against the WI-38. Interestingly, expression studies indicated that, in the presence of RHE-334, VEGFR-2 was equal to 0.52±0.03, thus comparable to imatinib equal to 0.63±0.03. In conclusion, this workflow based on theoretical and experimental approaches demonstrates effective in identifying VEGFR-2 inhibitors and can be easily adapted to other medicinal chemistry goals.
Assuntos
Antineoplásicos , Proliferação de Células , Aprendizado Profundo , Descoberta de Drogas , Inibidores de Proteínas Quinases , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Estrutura Molecular , Simulação de Acoplamento Molecular , Relação Dose-Resposta a DrogaRESUMO
Cumulative escalation in antibiotic-resistant pathogens necessitates the quest for novel antimicrobial agents, as current options continue to diminish bacterial resistance. Herein, we report the synthesis of di-heterocyclic benzazole structures (12-19) and their in vitro evaluation for some biological activities. Compounds 16 and 17 demonstrated potent antibacterial activity (MIC = 7.81 µg/mL) against Staphylococcus aureus, along with significant anti-biofilm activity. Noteworthy is the capability of Compound 17 to inhibit biofilm formation by at least 50% at sub-MIC (3.90 µg/mL) concentration. Furthermore, both compounds exhibited the potential to inhibit preformed biofilm by at least 50% at the MIC concentration (7.81 µg/mL). Additionally, Compounds 16 and 17 were examined for cytotoxic effects in HFF-1 cells, using the MTT method, and screened for binding interactions within the active site of S. aureus DNA gyrase using in silico molecular docking technique, employing AutoDock 4.2.6 and Schrödinger Glidse programs. Overall, our findings highlight Compounds 16 and 17 as promising scaffolds warranting further optimization for the development of effective antibacterial and anti-biofilm agents.
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Antibacterianos , Biofilmes , DNA Girase , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , DNA Girase/metabolismo , Humanos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Relação Estrutura-Atividade , Linhagem Celular , Domínio CatalíticoRESUMO
Aim: Investigating molecules having toxicity and chemical similarity to find hit molecules. Methods: The machine learning (ML) model was developed to predict the arylhydrocarbon receptor activity of anti-Parkinson's and US FDA-approved drugs. The ML algorithm was a support vector machine, and the dataset was Tox21. Results: The ML model predicted apomorphine in anti-Parkinson's drugs and 73 molecules in FDA-approved drugs as active. The authors were curious if there is any molecule like apomorphine in these 73 molecules. A fingerprint similarity analysis of these molecules was conducted and found tetrahydrocannabinol (THC). Molecular docking studies of THC for dopamine receptor 1 (affinity = -8.2 kcal/mol) were performed. Conclusion: THC may affect dopamine receptors directly and could be useful for Parkinson's disease.
Arylhydrocarbon receptor has tissue-specific roles in xenobiotic metabolism, the immune system, inflammation and cancer. Studies showed that carbidopa and dopamine are agonists of arylhydrocarbon receptor. Parkinson's disease is a neurodegenerative disease and depends on the dopamine system's dysregulation. There is a strong relationship between the dopamine system and cannabinoids. In this study, the possibility of the agonist effect of tetrahydrocannabinol on dopamine receptors was investigated by a machine learning method.
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Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Apomorfina , Dronabinol/farmacologia , Simulação de Acoplamento Molecular , Agonistas de DopaminaRESUMO
The increase in the drug-resistant strains of Mycobacterium tuberculosis has led researchers to new drug targets. The development of new compounds that have effective inhibitory properties with the selective vital structure of Mycobacterium tuberculosis is required in new scientific approaches. The most important of these approaches is the development of inhibitor molecules for Mycobacterium cell wall targets. In this study, first of all, the antitubercular activity of 23 benzimidazole derivatives was experimentally determined. And then molecular docking studies were carried out with 4 different targets: Arabinosyltransferase C (EmbC), Filamentous Temperature Sensitive Mutant Z (FtsZ), Protein Tyrosine Phosphatase B (PtpB), and Decaprenylphosphoryl-ß-D-ribose-2'-oxidase (DprE1). It has been determined that benzimidazole derivatives show activity through the DprE1 enzyme. It is known that DprE1, which has an important role in the synthesis of the cell envelope from Arabinogalactan, is also effective in the formation of drug resistance. Due to this feature, the DprE1 enzyme has become an important target for drug development studies. Also, it was chosen as a target for this study. This study aims to identify molecules that inhibit DprE1 for the development of more potent and selective antitubercular drugs. For this purpose, molecular docking studies by AutoDock Vina, and CDOCKER and molecular dynamics (MD) simulations and in silico ADME/Tox analysis were implemented for 23 molecules. The molecules exhibited binding affinity values of less than -8.0 kcal/mol. After determining the compound's anti-TB activities by a screening test, the best-docked results were detected using compounds 20, 21, and 30. It was found that 21, was the best molecule with its binding affinity value, which was supported by MD simulations and in silico ADME modeling results.Communicated by Ramaswamy H. Sarma.
Assuntos
Antituberculosos , Mycobacterium tuberculosis , Antituberculosos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Benzimidazóis/farmacologiaRESUMO
Background: Phortress produces reactive electrophilic metabolites that form DNA adducts only in sensitive tumor cells. The authors converted the 2-phenylbenzothiazole nucleus in phortress to 2-aryl and -heteroaryl benzoxazole derivatives (11 new and 14 resynthesized). All synthesized compounds were studied for antitumor activity in various cancer cells. Materials & methods: Cytotoxicity, cell morphology, flow cytometry and cell-cycle analyses of compounds were performed and more active derivatives were tested in the MCF-7 cell line. Conclusion: Methyl 2-(thiophen-2-yl)benzo[d]oxazole-6-carboxylate (BK89) has a higher effect than fluorouracil to induce apoptotic cell death (apoptosis value of 49.44%). Cell-cycle analysis shows that the compounds BK89 and methyl 2-(furan-2-yl)benzo[d]oxazole-6-carboxylate (BK82) can be used as potential cell-cycle blockers by arresting MCF-7 cells in G0/G1 phase at rates of 63% and 85%, respectively.
There is an urgent need to develop potent and selective anticancer agents. In this study, the design and applications of compounds sensitive to specific cancer cells and targeting cancer cells were investigated. The results show that the synthesized compounds can be antiproliferative drug candidates for breast cancer. These compounds may shed light on cancer treatment and cancer research.
Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Apoptose , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazóis , Relação Estrutura-AtividadeRESUMO
A series of new chalcones containing fluoro atom at B ring have been designed, synthesized, and evaluated to be antiproliferative activity against a panel of human tumor cell lines. Some of the analogs (8, 9, 12, 45, 46 and 48) displayed powerful antiproliferative effects to certain human tumor cells, but all of them were devoid of any cytotoxicity towards the normal HEK 293. Acridine orange staining data supported that the cytotoxic and antiproliferative effects of the synthesized analogs on tumor cells are mediated through apoptosis. The compounds 12 and 46 manifested concentration-dependent antiproliferative activity in human hepatocellular carcinoma cell lines using an xCELLigence assay. The structures and antiproliferative activity relationship were further supported by in silico molecular docking study of the compounds against tubulin protein which suggests our compounds interference to cell division. Communicated by Ramaswamy H. Sarma.