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1.
Bioorg Chem ; 143: 107003, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38029570

RESUMO

Two synthetic methods were proposed for the preparation of a new series of thiophene-1,3,4-oxadiazole-thiazolidine-2,4-dione hybrids (TOT-1 to 15) and their structures were elucidated based on spectral data. Studies on cytotoxicity, ROS, cellular uptake and interactions of TOT-14 with calf thymus DNA were carried out. Anticancer activity of compounds, TOT-1 to 15 on breast cancer (MCF-7) cell lines was investigated. The IC50 values for the standard, epirubicin hydrochloride and TOT-12, 13, 14 and 15 were found to be 6.78, 5.52, 6.53, 4.83 and 5.57 µg/mL, respectively. Notably, TOT-14 exhibited a remarkable antiproliferative activity with a strikingly selective inhibitory effect compared to standard. This specific selectivity could be attributed to the synergistic effect of increased cellular uptake and generation of higher ROS in cancer cells after irradiation. The binding constant of 4.25 x 103 M-1 indicated the moderate interaction between TOT-14 and ct-DNA. The docking score of TOT derivativeswas substantially identical to the docking score of epirubicin hydrochloride. The designed molecules complied with the requirements for drug-likeness and ADME.


Assuntos
Antineoplásicos , Oxidiazóis , Tiazolidinedionas , Humanos , Relação Estrutura-Atividade , Células MCF-7 , Antineoplásicos/farmacologia , Antineoplásicos/química , Epirubicina/farmacologia , Tiofenos/farmacologia , Espécies Reativas de Oxigênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais
2.
Bioorg Chem ; 130: 106235, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375354

RESUMO

Thiazolidinedione (TZD) based medications have demonstrated to enhance the insulin sensitivity control, hyperglycemia, and lipid metabolism in patients with type 2 diabetes. Hence, in this study, a new series of novel coumarin-4-yl-1,2,3-triazol-4-yl-methyl-thiazolidine-2,4-diones (TZD1-TZD18) were synthesized via copper (I)-catalyzed azide-alkyne cycloaddition "Click Chemistry". The synthesized compounds were evaluated for their glucose uptake assay and in vitro cytotoxicity against HEK-293 (human embryonic kidney) cells which were compared with the standard drug Pioglitazone. Further, molecular docking analysis of these compounds was carried out to explain the in vitro results with PPARγ (PDB ID: 3CS8) and to better understand the bonding interactions with the target protein. The outcomes of in vitro assessment, molecular docking, and pharmacokinetics of the title compounds were revealed to be highly correlated. Interestingly, the compounds TZD4, TZD10, TZD14 and TZD16 were most efficient in lowering the blood glucose level compared with standard drug.


Assuntos
Cumarínicos , Diabetes Mellitus Tipo 2 , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Células HEK293 , Simulação de Acoplamento Molecular , Tiazolidinas/química , Tiazolidinas/farmacologia , Triazóis/química , Triazóis/farmacologia
3.
Mol Divers ; 26(2): 827-841, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33547619

RESUMO

For this work, two series of new piperazine derivatives (3a-o) and triazolo-pyrazine derivatives (3p-t) were synthesized in a single-step reaction. All twenty adducts were obtained in good to high yields and fully characterized by 1H NMR, 13C NMR, IR, and mass spectrometry techniques. To further confirm the chemical identity of the adducts, a crystal of N-{[(4-chlorophenyl)-3-(trifluoromethyl)]-5,6-dihydro-[1,2,4]triazolo[4,3-a]}pyrazine-7(8H)-carboxamide (3t) was prepared and analyzed using X-ray crystallography. In vitro screening of the antimicrobial activity of all compounds (3a-t) was evaluated against five bacterial and two fungal strains. This study disclosed that N-{[(3-chlorophenyl)]-4-(dibenzo[b,f][1,4]thiazepin-11-yl)}piperazine-1-carboxamide (3o) was the superior antimicrobial with good growth inhibition against A. baumannii. Furthermore, the results from the performed molecular docking studies were promising, since the observed data could be used to develop more potent antimicrobials.


Assuntos
Anti-Infecciosos , Pirazinas , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazina , Pirazinas/farmacologia , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 43: 128112, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33991632

RESUMO

A modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The biological outcomes as well as computational study suggested that the compounds originated to have elevated resemblance towards COX-2 enzyme than COX-1. The compounds 8i, 8l, 8q, 8r, 8s and 8t emerged as most potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l, 8n and 8r was respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Interestingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents.


Assuntos
Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Química Verde , Oxidiazóis/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Micro-Ondas , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Picratos/antagonistas & inibidores
5.
Bioorg Med Chem Lett ; 41: 127984, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766768

RESUMO

Quinolin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones 8j-v were synthesized by click chemistry as an ultimate tactic where [3 + 2] cycloaddition of azides with terminal alkynes has been evolved. Herein, we are inclined to divulge the implication and prevalence of CuSO4·5H2O and THF/water promoted [3 + 2] cycloaddition reactions. The foremost supremacy of this method are transitory reaction times, facile workup, excellent yields (88-92%) with exorbitant purity and regioselective single product formation both under conventional and microwave method. Docking studies illustrated strong binding interactions with enzyme InhA-D148G (PDB ID: 4DQU) by means of high C-score values. The anti-tubercular and antifungal screening of synthesized compounds proclaimed promising activity. The in vitro and in silico studies imply that these triazoles appended quinolines may acquire the ideal structural prerequisites for auxiliary expansion of novel therapeutic agents.


Assuntos
Antifúngicos/farmacologia , Antituberculosos/farmacologia , Cobre/química , Micro-Ondas , Quinolinas/farmacologia , Triazóis/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antituberculosos/síntese química , Antituberculosos/química , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Catálise , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
6.
Bioorg Chem ; 114: 105046, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34126575

RESUMO

BACKGROUND: A hybrid molecule of different biologically active substances can improve affinity and efficiency compared to a standard drug. Hence based on this fact, we predict that a combination of fluorine, oxadiazole, sulfur, etc., may enhance α-glucosidase inhibition activity compared to a standard drug. METHODS: A series of novel 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol derivatives (2a-2i) were synthesized and characterized using spectroscopic techniques such as 1HNMR and LC-MS. In order to evaluate its bioactivity, in vitro α-amylase and α-glycosidase inhibitory activity were performed. In vivo study was carried using a genetic model, Drosophila melanogaster, for assessing the antihyperglycemic effects. RESULTS: The compounds 2a-2i demonstrated α-amylase inhibitory activity in the range of IC50 = 40.00-80.00 µg/ml as compare to standard acarbose (IC50 = 34.71 µg/ml). Compounds 2a-2i demonstrated α-glucosidase inhibitory activity in the range of IC50 = 46.01-81.65 µg/ml as compared to standard acarbose (IC50 = 34.72 µg/ml). Docking studies on a target protein, N-terminal subunit of human Maltase-glucoamylase (PDB:2QMJ) was carried and the compounds were found to dock into the active site of the enzyme (Fig. 1). The predicted binding energies of the compounds were calculated. The in vitro studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. Whereas in vivo study indicates that 2b, 2g, and 2i could lower glucose levels in the Drosophila, but then 17-30% reduced capacity than acarbose and may be overcome by adjusting their dosage. CONCLUSIONS: The in vitro and in vivo studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. This study has recognized that compounds like 2b, 2g, and 2i may be considered potential candidates for further developing a novel class of antidiabetic agents.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Oxidiazóis/farmacologia , Amilases/antagonistas & inibidores , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Feminino , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
7.
Drug Dev Res ; 81(1): 70-84, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31696542

RESUMO

In this study, we report the ring transformation of 3-arylsydnone into 1-aryl-1H-pyrazole-3-carbonitriles via [3 + 2] cycloaddition with acrylonitrile. 1-Aryl-1H-pyrazole-3-carbonitrile underwent [2 + 3] cycloaddition with sodium azide to afford 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles which were further subjected to N-alkylation with aryl/heteroaryl alkyl halides to afford 1,5- and 2,5-disubstituted tetrazoles. Furthermore, the title compounds were screened for in vivo antihyperglycemic activity using albino Wistar rats of either sex. Compounds 4a, 6b, 7a, 7b, 8b, and 9b showed maximum fall in the blood glucose levels in streptozotocin-induced diabetic rats after 5-7 days of administration. In support of antidiabetic activity, we also performed the experimental in vivo studies, namely, effect of compounds on enzymes (serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, creatinine, urea, and total protein), antihyperlipidemic, and histopathology. Moreover, the molecular docking study has been performed for potent molecules among the series with glycogen phosphorylase as target enzyme, and this study corroborated the experimental in vivo results.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Glicogênio Fosforilase/antagonistas & inibidores , Tetrazóis/administração & dosagem , Tetrazóis/síntese química , Acrilonitrila/química , Animais , Glicemia/efeitos dos fármacos , Reação de Cicloadição , Diabetes Mellitus Experimental/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ratos , Estreptozocina , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologia
8.
Bioorg Med Chem ; 27(20): 115054, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31471101

RESUMO

Nucleoside bases like uracil, pharmacophoric triazoles and benzimidazolones have been used during the present study to design molecular matrices for antitubercular activity, employing Click Chemistry. Click triazoles 4/7/10 have been obtained by the reaction of 4-(Azidomethyl)-2H-chromen-2-ones/quinolin-2(1H)-ones 3 and propargyl ethers 2/6/9 derived from theophylline/6-methyl uracil/2-benzimidazolone respectively. In addition to spectral data structures have been confirmed by single crystal X-ray diffraction studies in case of uracil bis alkyne (6) and theophylline mono triazole (4c). Theophylline linked mono triazoles, 4(a-d) and 6-methyl uracil linked bis triazoles, 7(a-e) have been found to inhibit Mycobacterium tuberculosis H37Rv with MIC values in the range 55.62-115.62 µM. Benzimidazolone bis triazoles, 10(a-n) showed better activity with MIC in the range 2.33-18.34 µM. Molecular modeling studies using Surflex-Dock algorithm supported our results.


Assuntos
Algoritmos , Antituberculosos/farmacologia , Cumarínicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Triazóis/farmacologia , Uracila/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Química Click , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Uracila/análogos & derivados , Uracila/química
9.
Bioorg Chem ; 84: 202-210, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30502632

RESUMO

ß-Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer's disease. In this paper, we report the synthesis and the for ß-secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [b] pyran derivatives. One-pot synthesis of tetrahydrobenzo [b] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl-) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC50 value in nanomolar range. All the synthesized compounds were docked onto the active site of ß-Secretase enzyme.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteases/síntese química , Piranos/química , Aldeídos/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Humanos , Concentração Inibidora 50 , Líquidos Iônicos/química , Inibidores de Proteases/metabolismo , Piranos/síntese química , Piranos/metabolismo , Relação Estrutura-Atividade
10.
Bioorg Chem ; 87: 302-311, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30913465

RESUMO

A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using 1H NMR, 13C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Ureia/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bactérias/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
11.
Bioorg Chem ; 92: 103217, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31479986

RESUMO

Herein, we describe the successful design and synthesis of seventeen new 1,4-diazinanes, compounds commonly known as piperazines. This group of piperazine derivatives (3a-q) were fully characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. The molecular structure of piperazine derivative (3h) was further established by single crystal X-ray diffraction analysis. All reported compounds were evaluated for their antibacterial and antifungal potential against five bacterial (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) and two fungal strains (Candida albicans and Cryptococcus neoformans). The complete bacterial screening results are provided. As documented, piperazine derivative 3e performed the best against these bacteria. Additionally, data obtained during molecular docking studies are very encouraging with respect to potential utilization of these compounds to help overcome microbe resistance to pharmaceutical drugs, as explicitly noted in this manuscript.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Piperazina/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Arch Pharm (Weinheim) ; 352(10): e1900013, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31397503

RESUMO

Coumarin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4H)-ones (8k-z) were synthesized via copper(I)-catalyzed azide-alkyne cycloaddition click chemistry. The synthesized hybrid molecules were characterized by spectral studies. Compounds 8k-z were screened for their in vitro anti-TB activity by using the Microplate Alamar Blue assay and for cytotoxicity using the MTT assay. Some of the compounds were found to be most potent against the tested Mycobacterium tuberculosis H37Rv strain with a MIC of 1.60 µg/ml. Further, docking the compounds into the InhA binding pocket showed strong binding interactions and effective overall docking scores were recorded. The drug-likeness and toxicity studies were computed using Molinspiration and Protox, respectively.


Assuntos
Antituberculosos/síntese química , Química Click/métodos , Cumarínicos/síntese química , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Triazóis/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Triazóis/química , Triazóis/farmacologia
13.
Drug Dev Res ; 80(3): 368-385, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30609096

RESUMO

Hit, Lead & Candidate Discovery A variety of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl)phenyl) quinazolin-4(3H)-ones have been synthesized by treating 3-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)-2-(methyl/phenyl)-quinazolin-4(3H)-one with a variety of secondary amines. Graph theoretical analysis was used in identification of drug target that is, NMDAR (N-methyl-d-aspartate receptors). The observed reports of in silico modeling and ligand based toxicity, metabolism prediction studies were encouraging us to synthesize of title compounds and evaluate their antiepileptic effects. The title compounds were tested for its antiepileptic potency by MES and scPTZ model. Rotorod test is used to assess its neurotoxicity. In the preliminary test it was found that in MES test, analogs 6d, 6e, 6f, and 6l were potent; whereas in scPTZ test analogs 6d, 6e, 6f, and 6k displayed potent antiepileptic activity. Additionally these five derivatives were tested in rats orally at a dose of 30 mg/kg and found that compounds 2-methyl-3-(4-(5-morpholino-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6e and 2-methyl-3-(4-(5-(piperidin-1-yl)-1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4(3H)-one 6f exhibited superior activity than reference Phenytoin. In MES test, these derivatives 6e and 6f showed activity at 30 mg/kg i.p. dose after 0.5 hr and 4.0 hr. In scPTZ test these derivatives 6e and 6f showed activity at 100 and 300 mg/kg i.p. dose after 0.5 hr and 4.0 hr, respectively.


Assuntos
Anticonvulsivantes , Modelos Teóricos , Quinazolinonas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/toxicidade , Simulação por Computador , Masculino , Camundongos , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/uso terapêutico , Quinazolinonas/toxicidade , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Teste de Desempenho do Rota-Rod , Convulsões/tratamento farmacológico
14.
Bioorg Chem ; 78: 185-194, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29579642

RESUMO

An efficient, high yields and rapid synthesis of N-tert-butyl-4-(4-substituted phenyl)-2-((substituted-2-oxo-2H-chromen-4-yl)methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxamide derivatives (4a-4j) under microwave-irradiation has been described. All the newly synthesized compounds (4a-4j) were characterized by elemental analysis and spectroscopic studies. The synthesised compounds (4a-4j) were evaluated for their antibacterial activity by agar-well diffusion method and anti-inflammatory activity by egg albumin denaturation method. The compound (4f) exhibits antibacterial effect with MIC-2.5 µg/mL against gram positive S. aureus bacterial strain compared to standard ciprofloxacin drug (MIC-10 µg/mL). The compound (4c) shows an inhibition of heat induced protein denaturation 75.42% at a concentration of 31.25 µg/ml and is almost ten times more active than compared to standard aceclofenac drug (5.50%). Molecular docking study has been performed for all the synthesized compounds with S. aureus dihydropteroate synthetase (DHPS) and results obtained are quite promising.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Micro-Ondas , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Albuminas/metabolismo , Animais , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Galinhas , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
15.
Bioorg Chem ; 81: 440-453, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30223149

RESUMO

In an effort to produce new lead antimycobacterial compounds, herein we have reported the synthesis of a sequence of new pyrrolyl benzamide derivatives. The new chemical entities were screened to target enoyl-ACP reductase enzyme, which is one of the key enzymes of M. tuberculosis that are involved in type II fatty acid biosynthetic pathway. Compound 3q exhibited H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that binds the active site of InhA. All the pyrrolyl benzamide compounds were evaluated as inhibitors of M. tuberculosis H37Rv as well as inhibitors of InhA. Among them, few representative compounds were tested for mammalian cell toxicity on the human lung cancer cell-line (A549) and MV cell line that presented no cytotoxicity. Five of these compounds exhibited a good activity against InhA.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/química , Benzamidas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Células A549 , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico/efeitos dos fármacos , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo
16.
Bioorg Med Chem Lett ; 27(10): 2174-2180, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28372908

RESUMO

We report herein, first ever synthesis of series of novel differently substituted quinoxalinyl chalcones using Claisen Schmidt condensation, its molecular docking studies, and potential to be good anti-microbial, anti-tubercular and anti-cancer agents. The antimicrobial studies were carried out against Staphylococcus aureus, Escherichia coli and Candida albicans using disc diffusion procedure. The selected chalcones were tested for anti-cancer and cytotoxicity activity against MCF-7 cancer cell line using MTT assay method. All the synthesized compounds were screened for in vitro anti-tubercular screening against MtbH37RV strains by Alamar blue dye method. These results were compared with molecular docking studies carried out on Mycobacterium tuberculosis enzyme enoyl ACP reductase using Surflex-Dock program that is interfaced with Sybyl-X 2.0. SAR analysis for antimicrobial and antitubercular activity has also been proposed.


Assuntos
Anti-Infecciosos/síntese química , Chalconas/química , Enoil-CoA Hidratase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/farmacologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Desenho de Fármacos , Enoil-CoA Hidratase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Estrutura Terciária de Proteína , Staphylococcus aureus/efeitos dos fármacos
17.
Bioorg Med Chem ; 25(4): 1413-1422, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28094219

RESUMO

Bacterial infections are increasingly difficult to combat as bacteria evolve resistance to antibiotic drugs and have severely compromised the arsenal of antibiotic drugs. On the other hand matrix metalloproteinases (MMPs) play a fundamental role in inflammation and extracellular matrix degradation in physiological and pathological conditions. In search of potent antibiotic, taking coumarin and dihydropyrimidinone as lead compound, a green, eco-friendly and efficient protocol has been developed and synthesized the dihydropyrimidin-2(1H)-one/thione derivatives of coumarin 3/4 from substituted 4-formylcoumarins 2 and ethylacetoacetate using urea/thiourea in the presence of catalytic amount of ceric ammonium nitrate is reported. All the synthesized compounds were evaluated for their antibacterial activity against four bacterial strains by broth dilution method. The tested compounds have exhibited promising in vitro potency with low MIC values against the drug susceptive S. aureus strain with low MIC values ranging from 0.2 to 6.25µg/mL. The in vivo anti-inflammatory potency of 3a-e and 4a-e by gelatin zymography is comparable to that of tetracycline. Molecular docking study performed for all the synthesized compounds with S. aureus DNA gyrase and results obtained were quite promising.


Assuntos
Antibacterianos/farmacologia , Cumarínicos/farmacologia , Pirimidinonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade
18.
Bioorg Chem ; 75: 181-200, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28961440

RESUMO

In efforts to develop new antitubercular agents, we report here the synthesis of a series of novel pyrrole hydrazine derivatives. The molecules were evaluated against inhibitors of InhA, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of the mycobacterial cell wall as well as inhibitors of Mycobacterium tuberculosis H37Rv. The binding mode of compounds at the active site of enoyl-ACP reductase was explored using the surflex-docking method. The model suggests one or two H-bonding interactions between the compounds and the InhA enzyme. Some compounds exhibited good activities against InhA in addition to promising activities against M. tuberculosis.


Assuntos
Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Hidrazinas/química , Oxirredutases/antagonistas & inibidores , Pirróis/química , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Domínio Catalítico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ligação de Hidrogênio , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/metabolismo
19.
Bioorg Med Chem Lett ; 26(19): 4709-4713, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27595420

RESUMO

2-Propargylthiobenzimidazole 1, 4-bromomethyl coumarins/1-aza-coumarins 2/3 and sodium azide have been reacted in one pot under Click chemistry conditions to give exclusively 1,4-disubstituted triazoles 5a-n. Anti-tubercular assays against M. tuberculosis (H37Rv) coupled with in silico molecular docking studies indicated that dimethyl substituents 5c and 5d showed promising activity with higher C-score values.


Assuntos
Antituberculosos/química , Benzimidazóis/química , Química Click , Triazóis/química , Simulação de Acoplamento Molecular
20.
Bioorg Chem ; 59: 151-67, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25800133

RESUMO

Enoyl acyl carrier protein reductase (ENR)is an essential type II fatty acid synthase (FAS-II) pathway enzyme that is an attractive target for designing novel antitubercular agents.Herein, we report sixty-eight novel pyrrolyl substituted aryloxy-1,3,4-thiadiazoles synthesized by three-step optimization processes. Three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for pyrrolyl substituted aryloxy-1,3,4-thiadiazole series of InhA inhibitors using the comparative molecular field analysis (CoMFA).Docking analysis of the crystal structure of ENR performed by using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of pyrrolyl substituted aryloxy 1,3,4-thiadiazole into hydrophobic pocket of InhA enzyme. Based on docking and database alignment rules, two computational models were established to compare their statistical results. The analysis of 3D contour plots allowed us to investigate the effect of different substituent groups at different positions of the common scaffold. In vitro testing of ligands using biological assays substantiated the efficacy of ligands that were screened through in silico methods.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Tiadiazóis/química , Tiadiazóis/farmacologia , Antituberculosos/síntese química , Proteínas de Bactérias/metabolismo , Desenho de Fármacos , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Oxirredutases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Tiadiazóis/síntese química , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
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