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1.
Eur J Med Chem ; 93: 599-613, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25234355

RESUMO

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a-g), 6(a-g), 9(a-i) and 12(a-h) were synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-ß -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 µM) and elective inhibition (91%) against the P38αkinase at10 µM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Células CACO-2 , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/química , Tiadiazóis/química
2.
Mini Rev Med Chem ; 14(8): 678-93, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25138092

RESUMO

The emergence of drug resistant strains of important human pathogens has created an urgent necessity to find new targets and novel antitubercular agents. According to the literature survey, we noticed that enoyl ACP reductase is one of the most promising targets. This enzyme is the most important catalyst for the FAS II synthesis of mycolic acid, which is the most essential component of the mycobacterial cell wall. This review summarizes the progress made in the design of enoyl ACP reductase inhibitors and the role played by 3D-structure of the enzyme in drug design process.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas/tendências , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Mycobacterium/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/uso terapêutico , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Estrutura Molecular , Mycobacterium/enzimologia , Tuberculose/tratamento farmacológico
3.
Eur J Med Chem ; 71: 199-218, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24292339

RESUMO

In order to develop a lead antimycobacterium tuberculosis compound, a series of 52, novel pyrrole hydrazine derivatives have been synthesized and screened which target the essential enoyl-ACP reductase. The binding mode of the compounds at the active site of enoyl-ACP reductase was explored using surflex-docking method. The binding model suggests one or two hydrogen bonding interactions between pyrrole hydrazones and InhA enzyme. Highly active compound 5r (MIC 0.2 µg/mL) showed hydrogen bonding interactions with Tyr158 and NAD(+) in the same manner as those of ligands PT70 and triclosan. The CoMFA and CoMSIA models generated with database alignment were the best in terms of overall statistics. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (r(pred)(2)) of 0.896 and 0.930, respectively.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Hidrazonas/química , Hidrazonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Humanos , Hidrazonas/síntese química , Ligantes , Simulação de Acoplamento Molecular , Oxirredutases/química , Oxirredutases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade , Tuberculose/tratamento farmacológico
4.
Eur J Med Chem ; 46(9): 4411-8, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21820217

RESUMO

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a-k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Espectrofotometria Infravermelho , Tiadiazóis/química
5.
Eur J Med Chem ; 44(7): 2923-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19128861

RESUMO

A novel series of optically active 2-aminobenzothiazole derivatives were synthesized by reaction of optically active amine (I) with thiophosgene to obtain optically active isothiocyanates (IIa-h) which on condensation with 4-fluoro-3-chloro aniline (III) yielded various optically active thioureas (IVa-h). Further oxidative cyclisation in the presence of bromine and chloroform yielded title compounds (Va-h). The structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass and HRMS. The compounds (IVa-h and Va-h) were evaluated for in vitro cytotoxicity against mouse Ehrlich Ascites Carcinoma (EAC) and two human cancer cell lines (MCF-7 and HeLa). In preliminary MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity studies the optically active thiourea derivatives (IVe, IVf and IVh) were found most effective. In EAC cells the IC(50) values for IVe, IVf, IVh and Vg were found in the range of 10-24 microM, whereas in MCF-7 and HeLa cells the IC(50) values were observed in the range of 15-30 microM and 33-48 microM, respectively. In alkaline comet assay the compounds (IVe and IVf) showed dose-dependent DNA damaging activity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzotiazóis/química , Desenho de Fármacos , Fenômenos Ópticos , Tioureia/síntese química , Tioureia/farmacologia , Animais , Antineoplásicos/química , Carcinoma de Ehrlich/patologia , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Humanos , Camundongos , Tioureia/química , Fatores de Tempo
6.
Bioorg Med Chem ; 16(1): 276-83, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17937989

RESUMO

A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives 15a-j have been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a-b and appropriately substituted alpha-bromo-1,2-(p-substituted)diaryl-1-ethanones 13a-h. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward COX-2 (80.6-49.4%) over COX-1 (30.6-8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory activity. These compounds also exhibited significant anti-inflammatory activity (70.09-42.32%), which is comparable to that of celecoxib in the carrageenan-induced rat paw edema method.


Assuntos
Anti-Inflamatórios/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Tiadiazóis/síntese química , Animais , Anti-Inflamatórios/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase , Edema , Inflamação/tratamento farmacológico , Estrutura Molecular , Ratos , Análise Espectral , Tiadiazóis/farmacologia
7.
Journal of medicinal chemistry ; 49(2): 475-489, Dec. 2006. graf
Artigo em Inglês | MedCarib | ID: med-17419

RESUMO

Urokinase-type plasminogen activator (uPA), a trypsin-like serine protease, has been implicated in large number of malignancies, tumor cell invasion, angiogenesis and metastasis; hence, the potent and selective inhibitors of uPA may therefore be therapeutically useful drugs for treatment of various forms of cancer. A three-dimensional quantitative structure-activity relationship (3D QSAR) study was performed on five different chemical series reported as selective uPA inhibitors employing comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) techniques to investigate the structural requirements for substrates and derive a predictive model that may be used for the design of novel uPA inhibitors. Inclusion of ClogP did not improve the models significantly and exhibited comparable correlation coefficients with CoMFA steric and electrostatic models. 3D QSAR models were derived for 2-pyridinylguanidines (training set N = 25, test set N = 8), 4-aminoarylguanidines and 4-aminoarylbenzamidines (training set N = 29, test set N = 8), thiophene-2-carboxamindines (training set N = 64, test set N = 19), 2-naphthamidines (training set N = 32, test set N = 8), and 1-isoquinolinylguanidines (training set N = 29, test set N = 7). The CoMFA models with steric and electrostatic fields exhibited r2cv 0.452-0.722, r2ncv 0.812-0.986, r2pred 0.597-0.870, whereas CoMFA ClogP models showed r2cv 0.420-0.707, r2ncv 0.849-0.957, r2pred 0.600-0.870. The CoMSIA models displayed r2cv 0.663-0.729, r2ncv 0.909-0.998, r2pred 0.554-0.855. 3D contour maps generated from these models were analyzed individually, which provides the regions in space where interactive fields may influence the activity. Further, the predictive ability of 3D QSAR models was affirmed by predicting the activity of novel 2-naphthamidines. 3D QSAR models developed may be used in designing and predicting the uPA inhibitory activity of novel molecules.


Assuntos
Humanos , Ativador de Plasminogênio Tipo Uroquinase/análise , Ativador de Plasminogênio Tipo Uroquinase/síntese química , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/ultraestrutura
8.
Arzneimittelforschung ; 56(9): 631-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17063638

RESUMO

Glycolamide esters (compounds 1-17) of 2-(3-trifluoromethyl-phenylamino)nicotinic acid (niflumic acid, CAS 4394-00-7) have been synthesized and evaluated as possible prodrugs. In-vitro hydrolysis studies were conducted at selected pH values (1.2, 3.5, 4.8, 7.4 and 7.8) and in human plasma at 37 +/- 0.5 degree C using HPLC with UV detection. The aqueous (pH 7.4 and 7.8) and enzymatic rates of hydrolysis were substantially affected by the nature of promoieties in this series. The compounds showed good chemical stability in the buffers of low pH values (1.2, 3.5 and 4.8) and appreciable hydrolysis under alkaline conditions and in human plasma. They exhibited long hydrolytic half-lives of 7-46 h in aqueous buffer solutions (pH 7.4 and 7.8) and 14-21 min in human plasma, respectively. It was observed that N,N-disubstituted and cyclic glycolamide derivatives showed 2 fold more hydrolysis in the alkaline pH than monosubstituted derivatives, whereas the piperidino and thiomorpholino derivatives did not undergo chemical hydrolysis. The compounds contain two possible sites for hydrolysis with an increased hydrolytic susceptibility at the terminal aliphatic carbonyl site in aqueous buffers and human plasma solutions. They were found to be cleaved at two hydrolytic carbonyls, namely the nicotinyl (2-5 % in enzymatic hydrolysis) and the aliphatic site (7-55 % and 70-85 % in buffer and plasma hydrolysis, respectively) as revealed by HPLC analysis. The glycolamide ester prodrugs of niflumic acid underwent chemical and enzymatic hydrolysis to release mainly the metabolite 2-(3-trifluoromethyl-phenylamino) nicotinic acid carboxymethyl ester (III) and not the parent drug 2-(3-trifluoromethyl-phenylamino)nicotinic acid. The structure of the metabolite was confirmed by liquid chromatography-mass spectroscopy (LCMS).


Assuntos
Anti-Inflamatórios não Esteroides/química , Ácido Niflúmico/análogos & derivados , Ácido Niflúmico/química , Pró-Fármacos/química , Anti-Inflamatórios não Esteroides/sangue , Tampões (Química) , Cromatografia Líquida de Alta Pressão , Hidrólise , Indicadores e Reagentes , Ácido Niflúmico/sangue , Padrões de Referência , Solubilidade , Espectrofotometria Ultravioleta
9.
J Med Chem ; 49(2): 475-89, 2006 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-16420035

RESUMO

Urokinase-type plasminogen activator (uPA), a trypsin-like serine protease, has been implicated in large number of malignancies, tumor cell invasion, angiogenesis and metastasis; hence, the potent and selective inhibitors of uPA may therefore be therapeutically useful drugs for treatment of various forms of cancer. A three-dimensional quantitative structure-activity relationship (3D QSAR) study was performed on five different chemical series reported as selective uPA inhibitors employing comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) techniques to investigate the structural requirements for substrates and derive a predictive model that may be used for the design of novel uPA inhibitors. ClogP has been used as an additional descriptor in the CoMFA analysis to study the effects of lipophilic parameters on activity. Inclusion of ClogP did not improve the models significantly and exhibited comparable correlation coefficients with CoMFA steric and electrostatic models. 3D QSAR models were derived for 2-pyridinylguanidines (training set N = 25, test set N = 8), 4-aminoarylguanidines and 4-aminoarylbenzamidines (training set N = 29, test set N = 8), thiophene-2-carboxamindines (training set N = 64, test set N = 19), 2-naphthamidines (training set N = 32, test set N = 8), and 1-isoquinolinylguanidines (training set N = 29, test set N = 7). The CoMFA models with steric and electrostatic fields exhibited r(2)(cv) 0.452-0.722, r(2)(ncv) 0.812-0.986, r(2)(pred) 0.597-0.870, whereas CoMFA ClogP models showed r(2)(cv) 0.420-0.707, r(2)(ncv) 0.849-0.957, r(2)(pred) 0.600-0.870. The CoMSIA models displayed r(2)(cv) 0.663-0.729, r(2)(ncv) 0.909-0.998, r(2)(pred) 0.554-0.855. 3D contour maps generated from these models were analyzed individually, which provides the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of serine proteases additionally helps in understanding the structural requirements of these inhibitors. Further, the predictive ability of 3D QSAR models was affirmed by predicting the activity of novel 2-naphthamidines. 3D QSAR models developed may be used in designing and predicting the uPA inhibitory activity of novel molecules.


Assuntos
Amidinas/química , Guanidinas/química , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/química , Isoquinolinas/química , Estrutura Molecular , Naftalenos/química , Piridinas/química , Eletricidade Estática , Tiofenos/química
10.
Arzneimittelforschung ; 56(11): 744-52, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17220052

RESUMO

In search for potential prodrugs for anti-inflammatory drug candidates in the niflumate series, novel morpholinoalkyl ester prodrugs of niflumic acid (CAS 4394-00-7) 5a-b were prepared by esterification of appropriate morpholinylalkyl alcohols 3a-b with niflumic acid 4 in the presence of dicyclohexyl carbodiimide (DCC) and catalyst dimethylamino pyridine (DMAP) at 0-5 degrees C. The structures were confirmed by elemental and spectral data (UV, IR, 1H-NMR, 13C-NMR, and EI-MS). The ester prodrugs 5a-b showed better solubility than the parent drug niflumic acid 4 in simulated gastric fluid (SGF) and phosphate buffer (pH 7.4). The in vitro hydrolysis studies were conducted at pH 1.3 (SGF), phosphate buffer (pH 7.4) and in human plasma diluted with phosphate buffer (pH 7.4) at 37+/-0.5 degrees C using HPLC with UV detection. The ester prodrugs 5a-b were quantitatively hydrolyzed to the parent drug niflumic acid 4 by enzymatic and/or chemical means. It is observed that an increase in the carbon chain length rendered the prodrugs 5a-b more stable in phosphate buffer (pH 7.4) than in pH 1.3 (SGF), but they were rapidly hydrolyzed in human plasma at 37+/-0.5 degrees C. They exhibited longer hydrolytic half-lives of 16.11-53.30 h in aqueous buffer solutions (pH 1.3 and 7.4) and 1.63-2.73 min in human plasma, respectively. The title compounds were evaluated in vivo for anti-inflammatory activity in carrageenan induced rat paw oedema model in rats at the doses 45, 90, 150 mg/kg b.w. The test compounds exhibited good anti-inflammatory activity (46.6-53.2 % at the dose of 150 mg/kg b. w.) with respect to niflumic acid (78.7 % at the dose of 90 mg/kg b.w.). The compounds were also screened for in vivo ulcerogenicity, it was observed that the prodrug 5b was significantly less irritating to gastric mucosa than compound 5a and the parent drug niflumic acid 4 following single and chronic oral administration in rats.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Niflúmico/análogos & derivados , Ácido Niflúmico/síntese química , Úlcera Gástrica/induzido quimicamente , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Carragenina , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Feminino , Pé/patologia , Mucosa Gástrica/patologia , Hidrólise , Indicadores e Reagentes , Cinética , Masculino , Morfolinas/síntese química , Morfolinas/farmacologia , Ácido Niflúmico/farmacologia , Ratos , Úlcera Gástrica/patologia
11.
Bioorganic & medicinal chemistry ; 13(8): 2773-2782, April 2005. ilustab^cgraf
Artigo em Inglês | MedCarib | ID: med-17443

RESUMO

A series of indole/benzoimidazole-5-carboxamidines have been reported to inhibit various trypsin-like serine proteases viz. uPA, tPA, factor Xa, thrombin, plasmin, and trypsin, which are involved in various types of pathophysiological conditions such as cancer progression, thrombosis etc. Inhibition of these protease enzymes may serve as therapeutic agents in various types of cancer as well serve as anticoagulant or antithrombotic agents. The dual inhibitory action may result in poor clinical candidates. 3D-QSAR models were generated for indole/benzoimidazole-5-carboxamidines using the CoMFA technique to study their selectivity trends toward various trypsin-like serine proteases. Molecular superimposition was carried out on the template structure using atom-based RMS fit method. The CoMFA models were established from the training set of 25–29 molecules and validated by predicting the activities of seven–eight test set molecules. The CoMFA models generated using steric and electrostatic fields for tPA, fXa, thrombin, plasmin, and trypsin inhibition exhibited better statistical significance than the CoMFA models generated using ClogP as an additional descriptor. Thus, the validated CoMFA models with steric and electrostatic fields were used to generate 3D contour maps, which may provide possible modification of molecules for better selectivity/activity. The present 3D-QSAR studies emphasize the selectivity trends of indole/benzoimidazole-5-carboxamidines, which may be obliging in designing novel selective serine protease inhibitors of therapeutic interest.


Assuntos
Humanos , Inibidores de Serino Proteinase/análise , Inibidores de Serino Proteinase/farmacologia
12.
Arzneimittelforschung ; 55(2): 107-13, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15787278

RESUMO

New N1-aral-N4- (3-chloro-4-fluorophenyl)thiosemicarbazones (2a-h) and their Cu(I) complexes (3a-h) have been prepared and characterized by elemental analysis and spectral methods (IR and 1H-NMR). Thiosemicarbazones 2a-h bind to copper(I) as bidentate ligand via nitrogen and thione sulphur centers to afford 3a-h. Both ligands and their complexes are screened against Escherichia coli (National Collection of Type Culture 10418) and Staphylococcus aureus (National Collection of Type Culture 5571) to evaluate their antibacterial properties and against human virulent H37Rv strain of Mycobacterium tuberculosis for their antitubercular properties. Ligands 2d-h showed promising antibacterial activity while their Cu(I) complexes 3d-h exhibited excellent activity. The compounds 2a, 2d, 2f, 2g and their Cu(I) complexes 3a, 3d, 3f and 3g were evaluated for their antitubercular activity. It was observed that compounds 2a, 2g, 3a, 3d showed moderate activity while 3f and 3g exhibited promising antitubercular activity.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Campos Eletromagnéticos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrofotometria Infravermelho
13.
Bioorg Med Chem ; 13(8): 2773-82, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15781388

RESUMO

A series of indole/benzoimidazole-5-carboxamidines have been reported to inhibit various trypsin-like serine proteases viz. uPA, tPA, factor Xa, thrombin, plasmin, and trypsin, which are involved in various types of pathophysiological conditions such as cancer progression, thrombosis etc. Inhibition of these protease enzymes may serve as therapeutic agents in various types of cancer as well serve as anticoagulant or antithrombotic agents. The dual inhibitory action may result in poor clinical candidates. 3D-QSAR models were generated for indole/benzoimidazole-5-carboxamidines using the CoMFA technique to study their selectivity trends toward various trypsin-like serine proteases. Molecular superimposition was carried out on the template structure using atom-based RMS fit method. The CoMFA models were established from the training set of 25-29 molecules and validated by predicting the activities of seven-eight test set molecules. The CoMFA models generated using steric and electrostatic fields for tPA, fXa, thrombin, plasmin, and trypsin inhibition exhibited better statistical significance than the CoMFA models generated using ClogP as an additional descriptor. Thus, the validated CoMFA models with steric and electrostatic fields were used to generate 3D contour maps, which may provide possible modification of molecules for better selectivity/activity. The present 3D-QSAR studies emphasize the selectivity trends of indole/benzoimidazole-5-carboxamidines, which may be obliging in designing novel selective serine protease inhibitors of therapeutic interest.


Assuntos
Amidinas/química , Relação Quantitativa Estrutura-Atividade , Inibidores de Serino Proteinase/química , Amidinas/farmacologia , Cristalografia por Raios X , Inibidores do Fator Xa , Fibrinolisina/antagonistas & inibidores , Modelos Moleculares , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serino Proteinase/farmacologia , Especificidade por Substrato , Trombina/antagonistas & inibidores , Ativador de Plasminogênio Tecidual/antagonistas & inibidores , Tripsina/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores
14.
Bioorg Med Chem ; 12(21): 5651-9, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15465343

RESUMO

A series of 2-sulfonamido/trifluoromethyl-6-(4'-substituted aryl/heteroaryl)imidazo[2,1-b]-1,3,4-thiadiazole derivatives (II) have been synthesized by reaction of 2-amino-5-sulfonamido/trifluoromethyl-1,3,4-thiadiazoles and an appropriate alpha-haloaryl/heteroaryl ketones. Further 5-bromo (III), 5-thiocyanato (IV), 5-gaunylhydrazone (V) derivatives were synthesized in order to study the effect of these substituents on biological activity. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass and HRMS. The selected compounds were evaluated for their preliminary in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain using radiometric BACTEC and broth dilution assay methods. The results show that compounds 5, 7, 8, 10 and 12 exhibited moderate to good anti-tubercular activity with percentage inhibition of 29, 43, 58, 31 and 41, respectively, at a MIC of >6.25 microg/mL. Compound 18 showed a MIC of 20 microg/mL.


Assuntos
Antituberculosos/síntese química , Imidazóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Tiadiazóis/síntese química , Antituberculosos/farmacologia , Imidazóis/farmacologia , Mycobacterium tuberculosis/fisiologia , Tiadiazóis/farmacologia
15.
Bioorganic and medicinal chemistry ; 12(21): 5651-5659, July, 2004. ilustab
Artigo em Inglês | MedCarib | ID: med-17553

RESUMO

A series of 2-sulfonamido/trifluoromethyl-6-(40-substituted aryl/heteroaryl)imidazo[2,1-b]-1,3,4-thiadiazole derivatives(II) have been synthesized by reaction of 2-amino-5-sulfonamido/trifluoromethyl-1,3,4-thiadiazoles and an appropriate a-haloaryl/heteroaryl ketones. Further 5-bromo (III), 5-thiocyanato (IV), 5-gaunylhydrazone (V) derivatives were synthesized in order to study the effect of these substituents on biological activity. Structures of these compounds were established by IR, 1H NMR,13C NMR, Mass and HRMS. The selected compounds were evaluated for their preliminary in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain using radiometric BACTEC and broth dilution assay methods. The results show that compounds 5, 7, 8, 10 and 12 exhibited moderate to good anti-tubercular activity with percentage inhibition of 29, 43, 58, 31and 41, respectively, at a MIC of > 6.25lg/mL. Compound 18 showed a MIC of 20lg/mL.


Assuntos
Humanos , Tiadiazóis/farmacologia , Tiadiazóis/farmacocinética , Sulfonamidas/química , Sulfonamidas/síntese química , Sulfonamidas/farmacologia
16.
Arzneimittelforschung ; 52(11): 817-21, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12489252

RESUMO

In order to reduce the gastric irritation caused by direct contact mechanism of the carboxylic acid group, a series of glycolamide esters of niflumic acid (CAS 4394-00-7) (1) have been prepared as bio-labile prodrugs by reacting appropriate 2-chloroacetamides with niflumic acid. The required 2-chloroacetamides were obtained by the condensation of chloroacetyl chloride and corresponding amine. Their structures were confirmed by UV, IR and 1H NMR spectra. Selected compounds were evaluated for anti-inflammatory activity in carrageenan induced paw oedema in rats at the doses of 45, 90 and 150 mg/kg b.w. Prodrugs showed comparable anti-inflammatory activity (67.1-79.4%) at 150 mg/kg b.w. with respect to niflumic acid (70.3%) at 45 mg/kg b.w., indicating moderate release of niflumic acid in vivo. The highest activity was observed with diethylamine (4) and pyrrolidine (9) derivatives.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Niflúmico/síntese química , Ácido Niflúmico/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Animais , Carragenina , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Indicadores e Reagentes , Masculino , Ratos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
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