Docking, síntese e avaliação citotóxica de novos análogos da nimesulida como potenciais agentes anticancerígenos

A nimesulida é um anti-inflamatório não esteroide, tendo também propriedades analgésicas e antipiréticas. Vários estudos demonstraram a sobreexpressão da enzima ciclooxigenase-2 em cancros sólidos, estando esta associada nomeadamente à produção da prostaglandina-E2, a qual potencializa a carcinogénese. Uma vez que a nimesulida e os seus análogos, bem como outros fármacos, inibem a ciclooxigenase-2, é expectável que apresentem propriedades anticancerígenas. Recentemente, várias orto-(alquilcalcogénio)-N-acetanilidas estruturalmente semelhantes à nimesulida foram sintetizadas e foi avaliada a sua potencial atividade anticancerígena. De facto, em estudos in vitro de proliferação celular apresentam atividade antiproliferativa seletiva para células cancerígenas, destacando-se as células do adenocarcinoma da próstata sensíveis a androgénios. Os compostos mais potentes foram as acetanilidas O- e/ou N-benzilícas e -hexílicas. Desta forma, tendo em conta os grupos já conhecidos de análogos da nimesulida que potenciam a atividade anticancerígena, foi sintetizada e caracterizada uma nova série de orto-(alquiltio)-N-alquilacetanilidas. Nesta série destaca-se a introdução dos grupos nitro e acetamida na posição 4 das acetanilidas e os grupos ligados ao grupo tio e/ou amida [hexilo, metilenociclohexilo e (2,4-dimetilbenzilo)]. Adicionalmente, foram avaliados os seus efeitos na viabilidade celular de fibroblastos normais da derme humana, em células do adenocarcinoma da próstata sensíveis a androgénios e em células epiteliais humanas do cancro da mama sensíveis a estrogénios. Os resultados obtidos confirmam que as acetanilidas desenvolvidas neste trabalho de dissertação são potenciais agentes anticancerígenos para o cancro da mama, realçando-se as acetanilidas com protão na posição 4 com grupos N- e S-hexílicos e a acetanilida com grupo acetamida na posição 4 e com grupo N-hexílico e S-(2,4-dimetilbenzílico). Os estudos de docking molecular foram realizados de forma a avaliar as energias de ligação e as possíveis interações com a ciclooxigenase-2, aromatase, recetor de androgénios e recetor alfa de estrogénios. Os resultados demonstraram que as acetanilidas podem ser potenciais inibidores da aromatase, e ligar-se a recetores de androgénios e a recetores alfa de estrogénios, embora não apresentem afinidade significativa para a ciclooxigenase-2.Nimesulide is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic properties. Several studies have demonstrated an overexpression of cyclooxygenase-2 in solid cancer. This overexpression of cyclooxygenase-2 is associated, namely, with an increased production of prostaglandin-E2 which therefore potenciate the carcinonegesis. Since nimesulide and its analogues, as well others drugs, inhibited cyclooxygenase-2, it is expectable that these compounds have anticancer activity. Recently, several ortho-(alkylchalcogen)-N-alkylacetanilides structurally resembling nimesulide were synthesized and their potencial anticancer activity was evaluated. In fact, in vitro, cell proliferation studies showed a selective antiproliferative activity for cancer cells, with prominence to the prostate cancer cell lines. The compounds that showed more anticancer activity were O- and/or N-benzylic and -hexyl acetanilides. Thus, taking in mind already known groups that potentiate the antiproliferation activity of nimesulide analogues, a set of new ortho-(alkylthio)-N-alkylacetanilides were synthesized and characterized. In this new serie was studied the introduction of the nitro and acetamide group at position 4, in which hexyl, methylcyclohexyl and/or 2,4-dimethylbenzyl are linked to thio and/or to an amide group. Additionally, cell viability of these acetanilides were evaluated against normal human dermal fibroblasts as well with human prostate and breast cancer cell lines. From the results obtained, acetanilides are a potencial anticancer agent for breast cancer. Although the best anticancer activity was presented in the acetanilides with a proton in position 4 with groups N- and S-hexyl and in the acetanilide with a group acetamide in the position 4 and with a group N-hexyl e S-(2,4-dimethylbenzyl). The docking molecular studies were performed in order to predict the binding energies and possible interactions with cyclooxygenase-2, aromatase, estrogen receptor and androgen receptor. The results of these studies can be potencial inhibitors for aromatase, androgen receptor and estrogen receptor, but this not occur for the cyclooxygenase-2

Microwave-Assisted Synthesis of Coumarin-Azo Derivatives, In silico and In vitro Evaluation for Potential Antibacterial Agent

The overuse and lack of regulation of antibiotics has resulted in the emergence of antibiotic�resistant bacteria or superbugs. This cause a decline in the effectiveness of current antibiotics that are critical in modern medicine. Hence, the search of new and effective drugs in medicinal chemistry is in demand to combat the health crisis. Natural products serve as an excellent scaffold for the development of new and innovative synthetic drugs with exceptional pharmaceutical properties. Coumarin 1 is a natural compound with medicinal values that has excellent antibacterial effects by binding to the B subunit of DNA gyrase in bacterial cells. Chemical modification of the coumarin moiety with other active moieties and pharmacophores could be a promising strategy for developing new potential antibiotics. A series of halogenated coumarin-azo derivatives 27a-g were successfully synthesized via diazo coupling reaction, whereas halogenated coumarin-azo derivatives bearing active group (i.e., ester, nitrile, and carboxylic) 30a-g, 31a-g, 32a-g via diazo coupling, Knoevenagel condensation and hydrolysis. The synthesis of coumarin-triazene bearing alkoxy long chain 37a-c were obtained through multiple steps reaction such as etherification, hydrolysis, Knoevenagel and diazo coupling reaction. All the synthesized compounds were analyzed using Carbon, Hydrogen, Nitrogen and Sulfur (CHNS) elemental analyzer and characterized using Fourier Transform Infrared (FTIR), 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy. The physiochemical and pharmacokinetic properties of the synthesized compounds were evaluated, where coumarin derivatives 27a-g, 30a-g, 31a-g, and 32a-g satisfied all the parameters of Lipinski’s rule of 5 (Molecular weight < 500 g/mol, Lipophilicity < 5, Hydrogen bond donor < 5; Hydrogen bond acceptor < 10, Topology polar surface area < 140 Å, and Rotatable bond < 10) except for 37a-c. Molecular docking interaction with bacterial DNA gyrase protein were screened using AutoDock Vina and showed that halogenated coumarin-azo 31c, 32b and 32c scored excellent binding affinity of -8.1 kcal/mol against Escherichia coli, whereas 31c and 31e scored -9.0 kcal/mol against Staphylococcus aureus which are better compared to references compound clorobiocin (-6.7 and -7.0 kcal/mol, respectively). The incorporation of azobenzene and halogens increased the compounds' lipophilicity for better binding and interaction with enzymes' hydrophobic active sites. The binding affinity of coumarin-triazene 37a with additional aromatic groups and aliphatic chains (C10) was comparable (-6.7 and -6.1 kcal/mol) to the clorobiocin, likely due to the formation of additional hydrophobic interactions with the receptor. The antibacterial screening via agar well diffusion however, showed poor inhibition against E. coli and S. aureus. The in vitro bioassay suggests that the compounds have a limited ability to permeate the bacterial cell membrane and interact with the targeted enzyme

Síntesis, caracterización y actividad farmacológica de nuevos compuestos orgánicos derivados de la semicarbazona e isoniazida

Sintetiza y caracteriza compuestos derivados de la semicarbazona con fragmentos indol e isoxazol, así como, compuestos derivados de la isoniazida con fragmentos isoxazol. Para el caso de los compuestos derivados de la semicarbazona se evalúa su posible actividad antibacteriana en las cepas Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa y Escherichia coli. Así mismo, para el caso de los compuestos derivados de la isoniazida se evaluará su actividad antimicobacteriana frente a las cepas de Mycobacterium tuberculosis H37Rv y TB DM 97. De los resultados obtenidos; los compuestos 11-18 ensayados frente a la cepa sensible TB H37Rv y los compuestos 12-14, 16 y 17 ensayados frente a la cepa resistente TB DM 97, resultaron ser activos con valores MICs en el rango de 0.34-0.41 y 12.41-24.82 µM, respectivamente. Estos resultados fueron comparados con la actividad encontrada para el fármaco isoniazida frente a la cepa sensible H37Rv (0.91 µM) y resistente, TB DM 97 (29.17 µM). Por otro lado, el compuesto 1 fue previamente sintetizado por otros autores donde dos señales correspondientes al RMN 1H del fragmento indol fueron erróneamente asignadas, así mismo, desarrollaron el estudio de la actividad antiplaquetaria. Por lo que, el aporte realizado en el presente trabajo a esta molécula resulta ser una nueva contribución, debido a que los datos espectroscópicos bidimensionales permitieron la correcta asignación de las señales y los resultados de la actividad antibacteriana son nuevos ensayos realizados sobre este compuesto

Über ABCG2-Inhibitoren mit Heteroaryl-phenylamid- und Carborancarboxamid-Grundstruktur

Der Ansatz, die Multidrug-Resistenz eines Tumors über einen Modulator bzw. Inhibitor aufzuheben, wurde in dieser Arbeit mit der Darstellung potenter, selektiver und untoxischer Hemmstoffe für den Transporter ABCG2 verfolgt und in vitro untersucht. Im ersten Teil Heteroaryl-phenylamide (Kapitel 3) werden die biochemischen Ergebnisse einer einhundertzwölf Verbindungen umfassenden Substanzbibliothek erörtert. Die Verbindungen wurden auf Basis vorangegangener Untersuchungen zu tariquidarabgewandelten ABCG2-Inhibitoren gestaltet. Für die biologische Charakterisierung dieser Substanzklasse sind Verbindungen mit unterschiedlichen Substituenten und veränderter Grundstruktur dargestellt worden. Es hat sich herausgestellt, dass der Grundkörper, ein N-(2-(2-Phenyl-2H-tetrazol-5 yl)phenyl)-benzamid, nicht nur für die Fähigkeit zur Inhibition vorausgesetzt werden muss, sondern auch gleichzeitig eine der höchsten Wirksamkeiten zeigte. Sämtliche Variationen der amidischen als auch der tetrazolischen Brücken führten zu Absenkung der Hemmstärke bis hin zu Inaktivität. Die meisten Substituenten und Abwandlungen der Phenylringe reduzierten ebenfalls das inhibitorische Vermögen. Für einige Derivate wurde ein günstiger therapeutischer Index ermittelt und somit eine Empfehlung für Untersuchungen in vivo ausgesprochen. Im zweiten Teil Carborancarboxamide (Kapitel 4) werden die Entdeckung und der Ausbau einer neuen ABCG2-Inhibitorenklasse, deren gemeinsames Merkmal ein Carborancarboxamid ist, erörtert. Anhand der biologischen Daten von zweiundvierzig Derivaten hat sich herausgestellt, dass neben dem Carboran als essentiellem Bestandteil der Substanzklasse die am Stickstoff der Amidbrücke gebundenen, mit elektronenziehenden Substituenten ausgestatteten Benzothiazol-2-yl- oder Thiazol-2-yl-Partialstrukturen hohe inhibitorische Aktivitäten gegenüber ABCG2 hervorrufen. Die Toxizitätsdaten untersuchter Verbindungen zeigen, dass diese für Untersuchungen in vivo in Betracht gezogen werden können