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Eur J Pharm Sci ; 130: 124-136, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684659


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.

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
Tuberculosis (Edinb) ; 108: 106-113, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29523309


Tuberculosis remains a major health problem accentuated by the rise of resistance to all available drugs. Therefore, this study was launched to discover a novel antituberculosis agent from wild Egyptian Sahara plants. Twelve such plants were screened, in vitro, for their activity against various Mycobacterium species. The most active plant, Euphorbia paralias, was further fractionated with different organic solvents, and the activity of the obtained fractions was determined by the agar diffusion and broth microdilution methods. The methanol fraction was the most active against Mycobacterium spp., and was non-toxic in doses up to 10 g/kg of animal weight. Its main component was separated by column chromatography, and then identified by ultraviolet spectroscopy and nuclear magnetic resonance analysis as quercetin-3-O-ß-D-glucoside. Docking analysis suggested that quercetin-3-O-ß-D-glucoside inhibits the glutamine synthetase enzyme, a promising target for the development of antituberculosis drugs. This prediction was confirmed by an in vitro glutamine synthetase biosynthetic assay. To the best of our knowledge, and based on bioinformatics mining of the BioPhytMol database, this is the first report on the antimycobacterial activity of Euphorbia paralias plant. It is also the first report on the inhibition of mycobacterial glutamine synthetase by the flavonoid quercetin.

Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Euphorbia , Glucosídeos/farmacologia , Glutamato-Amônia Ligase/antagonistas & inibidores , Mycobacterium/efeitos dos fármacos , Quercetina/análogos & derivados , Antituberculosos/química , Antituberculosos/isolamento & purificação , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Egito , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Euphorbia/química , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glutamato-Amônia Ligase/química , Glutamato-Amônia Ligase/metabolismo , Espectroscopia de Ressonância Magnética , Metanol/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium/enzimologia , Fitoterapia , Plantas Medicinais , Conformação Proteica , Quercetina/química , Quercetina/isolamento & purificação , Quercetina/farmacologia , Solventes/química , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade
J Enzyme Inhib Med Chem ; 33(1): 686-700, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29560733


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.

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
Eur J Med Chem ; 124: 299-310, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27597407


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.

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