RESUMO
Our previous studies on FabG have identified two compounds 5-bromo-2-(thiophene-2-carboxamido) benzoic acid (A) and ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate(B) as best hits with allosteric mode of inhibition. FabG is an integral part of bacterial fatty acid biosynthetic system FAS II shown to be an essential gene in most ESKAPE Pathogens. The current work is focussed on lead expansion of these two hit molecules which ended up with forty-three analogues (twenty-nine analogues from lead compound A and fourteen compounds from lead compound B). The enzyme inhibition studies revealed that compound 15 (effective against EcFabG, AbFabG, StFabG, MtFabG1) and 19 (inhibiting EcFabG and StFabG) had potency of broad-spectrum inhibition on FabG panel.
Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases/antagonistas & inibidores , Pseudomonas/efeitos dos fármacos , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxirredutases/metabolismo , Pseudomonas/enzimologia , Relação Estrutura-AtividadeRESUMO
Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 µg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Background: Tuberculosis is well-known airborne disease caused by Mycobacterium tuberculosis. Available treatment regimen was unsuccessful in eradicating the deaths caused by the disease worldwide. Owing to the drawbacks such as prolonged treatment period, side effects, and drug tolerance, there resulted in patient noncompliance. In the current study, we attempted to develop inhibitors against unexplored key target glutamate racemase. Methods: Lead identification was done using thermal shift assay from in-house library; inhibitors were developed by lead derivatization technique and evaluated using various biological assays. Results: In indazole series, compounds 11 (6.32 ± 0.35 µM) and 22 (6.11 ± 0.51 µM) were found to be most promising potent inhibitors among all. These compounds also showed their inhibition on replicating and nonreplicating bacteria. Conclusion: We have developed the novel inhibitors against M. tuberculosis capable of inhibiting active and dormant bacteria, further optimization of inhibitor derivatives can results in better compounds for eradicating tuberculosis.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Indazóis/química , Indazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidoglicano/metabolismo , Animais , Sobrevivência Celular , Farmacorresistência Bacteriana , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Células RAW 264.7 , Relação Estrutura-AtividadeRESUMO
A series of new edaravone derivatives 3-7 have been synthesized, characterised using various spectroscopic techniques and screened for their in vitro anti-cancer, antioxidant activities. Structure of 5d was further substantiated through single crystal X-ray diffraction. Among the tested, 5l exhibited pronounced activity against PC3 cancer cells. Compounds 5i, 5l, 7c showed potent activity against A549 cancer cells. Products 5k, 6, 7c demonstrated good antioxidant activity with MIC values of 18.60, 16.27, 16.07µg/mL respectively. Further the reported analogues were also tested on normal HEK293T cells and displayed low to good safer profiles. Derivatives 5l and 7c have come out to be safer potent anticancer, antioxidant agents. Additionally, the target products were subjected to their molecular properties prediction and drug likeness by employing Molinspiration and Osiris property explorer toolkits. None of them violated Lipinski's boundaries classifying the title compounds as potential anticancer and antioxidant agents.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Antipirina/análogos & derivados , Administração Oral , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antipirina/química , Antipirina/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Técnicas de Química Sintética , Simulação por Computador , Cristalografia por Raios X , Edaravone , Humanos , Espectroscopia de Ressonância MagnéticaRESUMO
To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of Schiff bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to Knoevenagel condensation. To evaluate their structures 1H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 µM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity.
RESUMO
Lysine É-aminotransferase (LAT) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of Mycobacterium tuberculosis (MTB), as observed by its up-regulation by ~40-fold during this stage. We have used the crystal structure of MTB LAT in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with IC50 ranging from 18.06 to > 90 µm. We have synthesized 21 compounds based on the identified lead, and compound 21 [2,2'-oxybis(N'-(4-fluorobenzylidene)acetohydrazide)] was found to be the most active with MTB LAT IC50 of 0.81 ± 0.03 µm. Compound 21 also showed a 2.3 log reduction in the nutrient-starved MTB model and was more potent than standard isoniazid and rifampicin at the same dose level of 10 µg/mL.
Assuntos
Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , L-Lisina 6-Transaminase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/uso terapêutico , Ligação de Hidrogênio , Concentração Inibidora 50 , L-Lisina 6-Transaminase/metabolismo , Tuberculose Latente/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives 5a-5l, 7a-7e and 9 have been synthesised and screened for in vitro antimycobacterial activity against Mycobacterium smegmatis MC-155. In addition these compounds have also been screened for cytotoxic activity against cancer cell lines HT-29, MDA-MB-231 by MTT colorimetric assay. The compounds are well characterized by spectral analysis viz. (1)H NMR, (13)C NMR, FT-IR, mass and HRMS. Screening results indicate that compounds 5g, 7a possess good antitubercular activity with MIC value 65.74 and 40.86, respectively, compounds 5g, 7a, 7b, 7d, 7e and 9 displayed promising cytotoxic activity against the cell lines tested. 5g and 7a stand out to be potent antimycobacterial and anticancer agents among the tested series. Further the title compounds were also tested on human normal cells HEK293T and are found to be safer with lesser cytotoxicity. It is interesting to observe that compound 5g has come out to be safer, potent anticancer and antimycobacterial agent.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HT29 , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
PURPOSE: Anomalies of Akt regulation, including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point. A novel scaffold of Akt inhibitors was developed through virtual screening of chemical databases available at Birla Institute of Technology and Science, Pilani, Hyderabad, based on docking studies using Maestro. A benzothienopyrimidine derivative (BIA-6) was identified as a potential lead molecule that inhibited Akt1 enzyme activity with an IC50 of 256 nM. MATERIALS AND METHODS: BIA-6 was tested for in vitro Akt1 inhibition using a fluorescence resonance energy transfer kit. Anti-proliferative activity was tested in NCI-H460, A549, NCI-H1975, and NCI-H2170 cell lines. The effect of the compound on p-Akt (S(473)) was estimated. RESULTS: BIA-6 allosterically caused a dose dependent reduction of growth of cell lines with a half maximal growth inhibition (GI50) range of 0.49 µM to 6.6 µM. Cell cycle analysis indicated that BIA-6 caused a G1 phase arrest at < 100 nM but led to apoptosis at higher doses. BIA-6 also exhibited synergism with standard chemotherapeutic agents. CONCLUSION: BIA-6 is a novel, allosteric Akt inhibitor with potent anti-cancer activity in lung cancer cell lines, that effectively blocks the phosphoinositide-3 kinase/Akt pathway with a high margin selectivity towards normal cells.
Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/genética , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , MutaçãoRESUMO
A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 µM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line.
Assuntos
Acetatos/farmacologia , Antibacterianos/farmacologia , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirróis/farmacologia , Acetatos/síntese química , Acetatos/química , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
This Letter reports the synthesis and evaluation of some thiazolylhydrazone derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The cytotoxic activities of all compounds were also evaluated. The compounds exhibited promising antimycobacterial activity with MICs of 1.03-72.46 µM and weak cytotoxicity (8.9-36.8% at 50 µg/mL). Among them, 1-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine 10 was found to be the most active compound (MIC of 1.03 µM) with a good safety profile (16.4% at 50 µg/mL). Molecular modeling studies were done to have an idea for the mechanism of the action of the target compounds. According the docking results it can be claimed that these compounds may bind most likely to TMPK than InhA or CYP121.
Assuntos
Antibacterianos/farmacologia , Hidrazonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Tecomella undulata is traditionally claimed in the treatment of various disease ailments including obesity and cancer. Till now there are no studies about anti-obesity activity of Tecomella undulata bark. AIM OF THE STUDY: The present study was aimed to establish a scientific evidence for anti-obesity efficiency of ethyl acetate extract of Tecomella undulata bark (EATUB). Further to standardize the active fractions of EATUB using different biomarkers. MATERIALS AND METHODS: We investigated activity of EATUB fractions (F1-F7) using 3T3-L1 fibroblasts. Further, F1-mediated effects were characterized by determining mRNA and protein levels of SIRT1, one of the key targets for the treatment of obesity, using semi-quantitative RT-PCR (sqRT-PCR) and western blot analysis. The consequences of modulation of SIRT1 on mRNA and protein levels of various adipogenesis mediators like PPARγ, C/EBPα, E2F1, leptin, adiponectin and LPL were also studied. In vivo studies were performed using High Fat Diet (HFD) obese mice. RESULTS: Our data showed that compared to controls, preadipocytes and adipocytes incubated with F1 exhibited a significant decrease in adipogenesis and lipogenesis. In addition, sqRT-PCR and western blot analysis showed significant increase in SIRT1 and adiponectin levels and decrease in PPARγ, C/EBPα, E2F1, leptin and LPL levels in preadipocytes and adipocytes. In vivo studies of F1 in HFD induced obese mice showed significant improvement in lipid profile and glucose levels. The bioactive fraction (F1) was determined to possess 4.95% of ferulic acid. CONCLUSION: Thus, our findings signified the beneficial effects of Tecomella undulata bark in pharmacologic interventions related to obesity and metabolic disorders. Ferulic acid and rutin are being reported and quantified for the first time from the bark of Tecomella undulata.
Assuntos
Fármacos Antiobesidade/farmacologia , Bignoniaceae/química , Obesidade/tratamento farmacológico , Casca de Planta/química , Extratos Vegetais/farmacologia , Células 3T3-L1 , Acetatos/química , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Animais , Fármacos Antiobesidade/química , Biomarcadores/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Linhagem Celular , Dieta Hiperlipídica , Fator de Transcrição E2F1/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glucose/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Obesos , Obesidade/metabolismo , PPAR gama/metabolismo , Extratos Vegetais/química , Sirtuína 1/metabolismo , Triglicerídeos/metabolismoRESUMO
The four-component reaction of ethyl-3-oxo-4-(arylsulfanyl)butanoate, substituted aromatic aldehydes and ammonium acetate afforded novel ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylates. These tetrahydro-pyridine esters upon dehydrogenation with dichlorodicyanobenzoquinone (DDQ) afforded highly functionalized pyridines in excellent yields. These novel heterocycles were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv using agar dilution method. Among the compounds screened, ethyl 2,6-di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecarboxylate was found to be the most active with a minimum inhibitory concentration of 1.33 microM against Mycobacterium tuberculosis and is 5.74 and 38.17 times more potent than the first line anti-tuberculosis (TB) drugs, ethambutol and pyrazinamide respectively.