RESUMO
STAT3 signaling is known to be associated with tumorigenesis and further cancer cell-intrinsic activation of STAT3 leads to altered regulation of several oncogenic processes. Given the importance of STAT3 in cancer development and progression particularly breast cancer, it is crucial to discover new chemical entities of STAT3 inhibitor to develop anti-breast cancer drug candidates. Herein, 4-benzyl-2-benzylthio-5-methyl-1H-imidazole (2a) and 4-benzyl-5-methyl-2-[(2,6-difluorobenzyl)thio]-1H-imidazole (2d) from a group of thirty imidazole-bearing compounds showed greater STAT3 inhibition than their lead compounds VS1 and the oxadiazole derivative MD77. Within all tested compounds, ten derivatives effectively inhibited the growth of the two tested breast cancer cells with IC50 values ranging from 6.66 to 26.02 µM. In addition, the most potent derivatives 2a and 2d inhibited the oncogenic function of STAT3 as seen in the inhibition of colony formation and IL-6 production of breast cancer cell lines. Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the STAT3-SH2 domain. Collectively, our present study suggests 2-substituted-4-benzyl-5-methylimidazoles are a new class of anti-cancer drug candidates to inhibit oncogenic STAT3 function.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/química , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Interleucina-6/metabolismo , Simulação de Acoplamento Molecular , Fator de Transcrição STAT3/antagonistas & inibidores , Relação Estrutura-Atividade , Domínios de Homologia de srcRESUMO
AIM: The development of a new class of antimicrobial agents is the optimal lifeline to scrap the escalating jeopardy of drug resistance. EXPERIMENTAL: This study aims to design and synthesize a series of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines, to develop agents having antimicrobial activity through potential inhibition of dihyropteroate synthase enzyme. The target compounds have been evaluated for their in-vitro antimicrobial activity. RESULTS & DISCUSSION: Compounds 5b, 5c were equipotent (minimal inhibitory concentration = 12.5 µg/ml) to ampicillin. The docking patterns of 5b and 5c demonstrated that both fit into Bacillus Anthracis dihydropteroate synthase pterin and p-amino benzoic acid-binding pockets. Moreover, their physicochemical properties and pharmacokinetic profiles recommend that they can be considered drug-like candidates. The results highlight some significant information for the future design of lead compounds as antimicrobial agents.
Assuntos
Anti-Infecciosos/síntese química , Bacillus anthracis/enzimologia , Proteínas de Bactérias/metabolismo , Di-Hidropteroato Sintase/metabolismo , Quinazolinonas/química , Triazóis/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Bacillus anthracis/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Di-Hidropteroato Sintase/antagonistas & inibidores , Desenho de Fármacos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5⯵g/mL vs levofloxacin 12.5⯵g/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents.
Assuntos
Antibacterianos/farmacologia , Di-Hidropteroato Sintase/antagonistas & inibidores , Desenho de Fármacos , Quinoxalinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/metabolismo , Domínio Catalítico , Di-Hidropteroato Sintase/química , Di-Hidropteroato Sintase/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Levofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/metabolismo , Relação Estrutura-Atividade , Yersinia pestis/enzimologiaRESUMO
Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their cytotoxic potency against certain human tumor cell lines. Five representative active anticancer compounds 6a, 6c, 6d, 17a and 18a were subjected to docking using MOE program on the 3D structure of two enzymes, namely; thymidylate synthase and dihydrofolate reductase. The antimicrobial activities of the synthesized compounds were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella flexneri and Candida albicans. Compounds 2c, 7a and 9c showed broad spectrum antimicrobial activity.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Pirimidinas/química , Pirimidinas/metabolismo , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/química , Timidilato Sintase/metabolismoRESUMO
A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg).
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Edema/tratamento farmacológico , Granuloma/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Pirimidinas/farmacologia , Cauda/efeitos dos fármacos , Tiofenos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Formaldeído , Granuloma/induzido quimicamente , Masculino , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Tiofenos/síntese química , Tiofenos/química , TerebintinaRESUMO
Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2â³,3â³-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.
Assuntos
Anti-Infecciosos/síntese química , Anti-Inflamatórios/síntese química , Ftalazinas/síntese química , Triazóis/síntese química , Anti-Infecciosos/toxicidade , Anti-Inflamatórios/toxicidade , Desenho de Fármacos , Descoberta de Drogas , Testes de Sensibilidade Microbiana , Ftalazinas/farmacologia , Ftalazinas/toxicidade , Relação Estrutura-Atividade , Triazóis/farmacologia , Triazóis/toxicidadeRESUMO
In this study, we report the synthesis and antimicrobial evaluation of several new thiazolo[4,5-d]pyrimidine derivatives, namely 7-substituted amino-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 4a-e, 8, 13, 15, ethyl 2-cyano-2-(7-substituted-5-methyl-3-phenylthiazolo [4,5-d]-pyrimidin-2(3H)-ylidene)acetates 5a-b, 2-(7-substituted-5-methyl-3-phenylthiazolo[4,5-d]pyrimidin-2(3H)-ylidene)malononitriles 6a-b, 5-methyl-7-morpholino-3-phenylthiazolo[4,5-d] pyrimidine-2(3H)-one 7, and 7-[4-(1-substituted-5-phenyl-4,5-dihydro-1H-pyrazolin-3-yl)anilino]-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 10-12. Some of the tested compounds were more active against C. albicans than E. coil and P. aeruginosa, and all were inactive against S. aureus.
Assuntos
Anti-Infecciosos/síntese química , Pirimidinas/síntese química , Tiazóis/síntese química , Anti-Infecciosos/farmacologia , Testes de Sensibilidade Microbiana , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
Two novel series of quinoxalines derived from 3-phenylquinoxalin-2(1H)-one and 2-hydrazino-3-phenylquinoxaline, namely 1-substituted-3-phenylquinoxaline-2(1H)-ones, 2a-c, 3a-d, and 4; 2-(3-oxo-3,3a,4,5,6,7-hexahydroindazol-2-yl)-3-phenylquinoxaline 6; N- cyclopentylidene or benzylidene-N'-(3-phenylquinoxaline-2-yl)hydrazines, 7 and 18; 1-substituted-4-phenyl-1,2,4-triazolo[4,3-a]quinoxalines, 9, 10, 12, 13, 14, and 16 have been synthesized in order to evaluate their antitumor and antimicrobial activities. Preliminary screening at NCI showed that compounds 2b, 2c, 3b, 3c, and 9 exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-6) to 10(-5) molar concentrations. Compound 3b was the most active with a broad spectrum of activity. Compound 3c showed selectivity towards CNS-cancer SF-639, leukemia CCRF-CEM, and melanoma SK-MEL-5 (GI(50) = 4.03, 6.46, and 4.17 microM, respectively). On the other hand, the in vitro microbiological data revealed that the prepared compounds showed mild antimicrobial activity.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Quinoxalinas/síntese química , Triazóis/síntese química , Anti-Infecciosos/química , Antineoplásicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Cefotaxima/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dimetilformamida/farmacologia , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Nistatina/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
Four novel series of 1,4-naphthoquinone derivatives namely 2,3-disubstiuted 4-[(benzothiazol-2-yl)hydrazono]-1,4-dihydronaphthalen-1-one 4a-c, N1-(2,3-disubstituted-4-oxo-1,4-dihydronaphthalen-1-ylidene)-N2-(benzotriazol-1-yl)acetic acid hydrazide 5a-c, 2,3-disubstituted 4-[(5-aryl-2,3-dihyrothiazol-2-ylidene)hydrazono]-1,4-dihydronaphthalen-1-one 7a-c, and 3-methyl-2-substituted carbamoyl or thiocarbamoyl-hydrazinocarbonylmethylthio-1,4-dihydronaphthalene-1,4-dione 9a-c were synthesized. Three of the new compounds were chosen by NCI to be evaluated as anticancer agents and they showed promising activity. All the prepared compounds were tested as antimicrobial agents.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade MicrobianaRESUMO
Two novel series of 1,4-naphthoquinone derivatives have been synthesized namely; N-ethoxycarbonyl-2-ethoxycarbonyloxy-3- alkyl-1,4-naphthoquinon-1-substituted phenylhydrazones 3a-f and 2-chlorocetyloxy-3-alkyl-1,4-naphthoquinone-1-substituted phenylhydrazones 4a-d. The antimicrobial activity as well as anticancer activity of these compounds have been evaluated. The acute toxicity of the active compounds was determined.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Animais , Antibacterianos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Artemia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Naftoquinonas/toxicidade , Espectrofotometria InfravermelhoRESUMO
2, 9-Disubstituted quinolino[2', 3'-5, 4](3-pyrazolino)pyrimidin-2-ones and purin-4-ones were synthesized and their benzodiazepine receptor activity was evaluated for their ability to displace [(3)H]R015-1788 from its specific binding in bovine brain membranes. Compound 5c caused 83 +/- 8 %inhibition in [(3)H]R015-1788 specific benzodiazepine receptor binding followed by compounds 5f, 5h, and 5i while other analogs were inactive at 10 microM concentration.