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1.
Eur J Med Chem ; 184: 111768, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629164

RESUMO

Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazinas/farmacologia , Isatina/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/química , Isatina/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
2.
Eur J Pharm Sci ; 130: 124-136, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684659

RESUMO

A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h, 4-7, 8a-c, 9, 10a-c, 11 and 12a-d, were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC50 = 0.07 and 0.08 µM, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed.


Assuntos
Simulação por Computador , Citotoxinas/síntese química , Relação Quantitativa Estrutura-Atividade , Tiobarbitúricos/síntese química , Células CACO-2 , Citotoxinas/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Humanos , Células MCF-7 , Tiobarbitúricos/toxicidade
3.
Future Med Chem ; 10(24): 2771-2789, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30526032

RESUMO

AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 µM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.


Assuntos
Antineoplásicos/farmacologia , Nitrilos/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo
4.
Eur J Med Chem ; 160: 49-60, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30317025

RESUMO

In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38 cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98 µg/mL) and antifungal (MIC: 0.49-0.98 µg/mL) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81 µg/mL, respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Indóis/farmacologia , Tiazolidinas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Indóis/química , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenótipo , Células RAW 264.7 , Relação Estrutura-Atividade , Tiazolidinas/química
5.
Molecules ; 23(6)2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895744

RESUMO

In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a⁻n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a⁻d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Isatina/química , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Técnicas In Vitro , Células MCF-7 , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína X Associada a bcl-2/metabolismo
6.
Future Med Chem ; 10(10): 1159-1175, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29787297

RESUMO

BACKGROUND: Medicinal interest has focused on ß-carbolines as anticancer agents. METHODOLOGY/RESULTS: Several ß-carbolines were designed, synthesized and evaluated for their cytotoxic activity against MCF-7 and A-549 cancer cell lines using MTT assay. Compounds 13a, 13c, 13d and 20a were the most promising showing high selectivity indices. Compounds 13c and 20a showed potent inhibition of topoisomerase (topo-I) and kinesin spindle protein (KSP/Eg5 ATPase) which was confirmed by their docking results into the active site of both enzymes. In silico physicochemical calculations predicted that compounds 13a, 13d and 20a obeyed Lipinski's rule of five. CONCLUSION: Compounds 13c and 20a are multitarget anticancer leads that act as potent inhibitors for both topo-I and/or KSP ATPase.


Assuntos
Antineoplásicos/síntese química , Carbolinas/química , Desenho de Drogas , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Carbolinas/metabolismo , Carbolinas/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Meia-Vida , Humanos , Cinesina/antagonistas & inibidores , Cinesina/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
7.
Future Med Chem ; 10(12): 1405-1419, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788758

RESUMO

AIM: Mycobacterium tuberculosis, which causes tuberculosis, continues to infect millions of the global population, resulting in 1.8 million deaths worldwide in 2015. METHODOLOGY: Hybrids of 2-amino-4-methylthiazole bearing 5-acetyl/5-ethyl carboxylate functionality with 5-arylidene thiazolidinone moiety (6a-k and 9a-d) were synthesized and screened for antitubercular and antimicrobial activities. RESULTS & DISCUSSION: 5-ethyl carboxylate derivative 6k revealed half antitubercular activity (minimal inhibitory concentration = 1.56 µg/ml) than the acetyl analog 6c (minimal inhibitory concentration = 0.78 µg/ml), however, it exhibited more potent broad spectrum antibacterial and antifungal activities in addition to its excellent safety profile with high selectivity toward M. tuberculosis over normal human lung cells. Collectively, these data suggested that compound 6k can be considered as an ideal lead compound for further optimization.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Tiazolidinas/química , Tiazolidinas/farmacologia , Antituberculosos/síntese química , Linhagem Celular , Desenho de Drogas , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazolidinas/síntese química , Tuberculose/tratamento farmacológico
8.
J Enzyme Inhib Med Chem ; 33(1): 686-700, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29560733

RESUMO

On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC50=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Drogas , Hidrazonas/farmacologia , Indóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Indóis/síntese química , Indóis/química , Células MCF-7 , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Bioorg Chem ; 76: 332-342, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29227917

RESUMO

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.


Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Desenho de Drogas , Acetamidas/síntese química , Acetamidas/química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Ciprofloxacino/farmacologia , Clotrimazol/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios Enzimáticos , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Chem Cent J ; 11(1): 32, 2017 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-29086809

RESUMO

BACKGROUND: Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. RESULTS: A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 µg/mL. Molecular docking was performed on the active site of MK-2 with good results. CONCLUSION: Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.

11.
Chem Cent J ; 11(1): 42, 2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29086825

RESUMO

BACKGROUND: A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3a-t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs. RESULTS: Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL). CONCLUSION: The structure-activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.

12.
Eur J Med Chem ; 139: 250-262, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-28802125

RESUMO

Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 ± 0.21 µM), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 ± 0.37 µM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bcl-2, and the up-regulated active caspase-9 and caspase-3 levels.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Indóis/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
13.
Eur J Med Chem ; 138: 698-714, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28715707

RESUMO

The increased development of highly resistant bacterial strains and tuberculosis, constitute a serious public health threat, highlighting the urgent need of novel antibacterial agents. In this work, two novel series of nicotinic acid hydrazone derivatives (6a-r) and quinolone hydrazide derivatives (12a-l) were synthesized and evaluated as antimicrobial and antitubercular agents. The synthesized compounds were evaluated in vitro for their antibacterial, antifungal and antimycobacterial activities. Compounds 6f and 6p bearing the 3,4,5- (OCH3)3 and 2,5-(OCH3)2 benzylidene motifs were the most potent and as antibacterial, antifungal (MIC: 0.49-1.95 µg/mL) and (MIC: 0.49-0.98 µg/mL) respectively and antimycobacterial activity (MIC = 0.76 and 0.39 µg/mL) respectively. Besides, several derivatives, 6e, 6h, 6l-6o, 6q, 6r, 12a, 12b, 12e, 12h, 12k and 12l, exhibited significant antibacterial and antifungal activities with MIC values ranging from 1.95 to 7.81 µg/mL, they also displayed excellent to good activity against Mycobacterium tuberculosis with MIC range from 0.39 to 3.12 µg/mL. In addition, some of the most active compounds were tested for cytotoxic activities against human lung fibroblast normal cells (WI-38) and displayed low toxicity. Moreover, 2D-QSAR models to characterize the descriptors controlling the observed activities, were generated and validated.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Desenho de Drogas , Hidrazonas/farmacologia , Piridinas/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bactérias/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Hidrazonas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/química , Relação Quantitativa Estrutura-Atividade , Quinolonas/química
14.
Eur J Med Chem ; 124: 299-310, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27597407

RESUMO

A series of novel heterocyclic thioureas 3a-u containing sulfonamide moiety have been synthesized by the condensation of isothiocyanatobenzenesulfonamide 2 with a variety of heterocyclic amines. The newly synthesized heterocyclic thioureas were investigated for their antimicrobial and anticancer activity. The in vitro antibacterial and antifungal activity were done using well diffusion method. Interestingly, compounds 3j and 3m, showed similar or better activity compared with the reference drug against the tested microorganisms. Although, 3j was less active among its analogues to inhibit the breast carcinoma cells, it exhibit strong broad spectrum antimicrobial activities. However, The results of the cytotoxic activity revealed that compound 3p was the most active against the breast carcinoma cell line (MCF-7) giving promising IC50 value of 1.72 µg/mL, compared with reference drug (5-flourouracil) with IC50 value of 4.8 µg/mL. The most potent compounds in cytotoxic activity 3b and 3p were further docked inside the active site of CAIX and were found to exhibit a proper binding with the active site amino acids according to their bond lengths, angles and conformational energy.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tioureia/química , Anti-Infecciosos/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/metabolismo , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Domínio Catalítico , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/metabolismo
15.
Eur J Med Chem ; 108: 415-422, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26706352

RESUMO

Many bis-isatins and isatins with hydrazide extension were reported to have a potential anti-proliferative effects against different cancer cell lines and cancer targets. In this study, four series of bis-isatins with hydrazide linkers were synthesized. These compounds were investigated for their antitumor activity by assessing their cytotoxic potency against HepG2, MCF-7 and HCT-116 cancer cell lines. Compound 21c possessed significant cytotoxic activity against MCF-7 (IC50 = 1.84 µM) and HCT-116 (IC50 = 3.31 µM) that surpasses the activity of doxorubicin against both cell lines (MCF-7; IC50 = 2.57 µM and HCT-116; IC50 = 3.70 µM). Cell cycle analysis and annexin V-FITC staining of MCF-7 cells treated with 21c suggested that the cytotoxic effect of the compound could be attributed to its pro-apoptotic activity.


Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Hidrazonas/farmacologia , Isatina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células Hep G2 , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Concentração Inibidora 50 , Isatina/análogos & derivados , Isatina/química , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 103: 583-93, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26408817

RESUMO

New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrases Carbônicas/metabolismo , Inibidores Enzimáticos/farmacologia , Isatina/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Anidrase Carbônica IX , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Isatina/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Relação Estrutura-Atividade , Sulfonamidas/química
17.
Eur J Med Chem ; 85: 480-6, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25113876

RESUMO

RAB1 5 is a lead antibacterial agent in which trimethoprim is linked to phthalazine moiety. Similarly, our strategy in this research depends on the interconnection between some sulfa drugs and certain phthalazin-1(2H)-one scaffolds in an attempt to enhance their antibacterial activity. This approach was achieved through the combination of 4-substituted phthalazin-1(2H)-ones 9a, b or 14a, b with sulfanilamide 1a, sulfathiazole 1b or sulfadiazine 1c through amide linkers 6a, b to produce the target compounds 10a-d and 15a-e, respectively. The antibacterial activity of the newly synthesized compounds showed that all tested compounds have antibacterial activity higher than that of their reference sulfa drugs 1a-c. Compound 10c represented the highest antibacterial activity against Gram-positive bacteria Streptococcus pneumonia and Staphylococcus aureus with MIC = 0.39 µmol/mL. Moreover, compound 10d displayed excellent antibacterial activity against Gram-negative bacteria Escherichia coli and Salmonella typhimurium with MIC = 0.39 and 0.78 µmol/mL, respectively.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Desenho de Drogas , Ftalazinas/química , Ftalazinas/farmacologia , Enxofre/química , Bactérias/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
18.
Arch Pharm (Weinheim) ; 346(9): 688-98, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24006310

RESUMO

A series of 3,4-bis-chalcone-N-arylpyrazoles 3a-k was prepared from diacetyl pyrazoles 2a-e. The reaction of 2d and 2e with hydrazine hydrate gave pyrazolo[3,4-d]pyridazine derivatives 4a-b. Furthermore, the reaction of 2a-e with thiosemicarbazide afforded pyrazolo[3,4-d]pyridazine thiocyanate salts 5a-e. The synthesized compounds were subjected to in vivo anti-inflammatory and ulcerogenic activity measurements, in addition to determination of their in vitro COX selectivity, to give a full profile about their anti-inflammatory activities. Compounds 3c, 3f, 3i, and 3e showed significant anti-inflammatory activity among the synthesized compounds. Moreover, docking studies were performed to give an explanation for their anti-inflammatory activity through COX selectivity.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Pirazóis/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Inflamação/patologia , Masculino , Simulação de Acoplamento Molecular , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Pirazóis/síntese química , Pirazóis/química , Ratos , Úlcera Gástrica/induzido quimicamente
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