RESUMEN
Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation. In this context, several studies have identified spirooxindoles as an effective class of CDK2 inhibitors. In the present study, three spirooxindoles (SOI1, SOI2, and SOI3) were studied to understand their inhibitory mechanism against CDK2 through a structure-based approach. Molecular docking and molecular dynamics (MD) simulations were performed to explore their interactions with CDK2 at the molecular level. The calculated binding free energy for the spirooxindole-based CDK2 inhibitors aligned well with experimental results regarding CDK2 inhibition. Energy decomposition (ED) analysis identified key binding residues, including I10, G11, T14, R36, F82, K89, L134, P155, T158, Y159, and T160, in the CDK2 active site and T-loop phosphorylation. Molecular mechanics (MM) energy was identified as the primary contributor to stabilizing inhibitor binding in the CDK2 protein structure. Furthermore, the analysis of binding affinity revealed that the inhibitor SOI1 binds more strongly to CDK2 compared to the other inhibitors under investigation. It demonstrated a robust interaction with the crucial residue T160 in the T-loop phosphorylation site, responsible for kinase activation. These insights into the inhibitory mechanism are anticipated to contribute to the development of potential CDK2 inhibitors using the spirooxindole scaffold.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina , Indoles , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oxindoles , Inhibidores de Proteínas Quinasas , Compuestos de Espiro , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 2 Dependiente de la Ciclina/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Oxindoles/química , Oxindoles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Indoles/química , Indoles/farmacología , Termodinámica , Relación Estructura-Actividad , Estructura Molecular , Unión Proteica , EspirooxindolesRESUMEN
The use of click chemistry as a smart and suitable method for the development of new heterogeneous catalysts is based on metal-organic frameworks as well as the production of organic compounds. The development of the click chemistry method can provide a new strategy to achieve superior properties of MOFs. Here, the two metals Co and Fe are used to create a bimetallic-organic framework. In the following, the click chemistry and postmodification method are well organized and an acidic heterogeneous porous catalyst is developed. This prepared catalyst was used as a highly efficient catalyst for the preparation of new spiro-oxindoles obtained through click chemistry with good to excellent yields (80-94%). This presented catalytic system can compete with the best reported catalytic systems. The findings showed that the presence of Co and Fe metals in the MOF, and the presence of the triazole ring on the catalyst, can increase the catalytic efficiencies. This study offers novel insights into the architecture of Metal-Organic Frameworks (MOFs), click chemistry, and biologically active compounds. Additionally, the research explores the antibacterial properties of the synthesized spiro-oxindoles and catalysts. The findings reveal significant antibacterial activities of the synthesized compounds against S. aureus, MRSA, and E. coli bacteria.
Asunto(s)
Escherichia coli , Estructuras Metalorgánicas , Espirooxindoles , Staphylococcus aureus , Antibacterianos/farmacologíaRESUMEN
This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1H-NMR, 13C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %).
Asunto(s)
Antibacterianos , Antioxidantes , Indoles , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Estructura Molecular , Oxindoles/farmacología , Oxindoles/química , Oxindoles/síntesis química , Picratos/antagonistas & inhibidores , Pseudomonas aeruginosa/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/síntesis química , Espirooxindoles , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Isatina/síntesis química , Isatina/química , Isatina/farmacologíaRESUMEN
Fibrillation of proteins and polypeptides, which leads to the deposition of plaques in cells and tissues has been widely associated with many neuropathological diseases. Inhibition of protein misfolding and aggregation is crucial for the prevention and treatment of these conditions. The growing interest in identifying inhibitor molecules to prevent the formation of fibrils in vivo has led to the results highlighted in this study. Due to their hydrophobic structure and potential to readily cross the blood brain barrier, a library of spirooxindole compounds were synthesized with those labelled Hd-63, Hd-66 and Hd-74 proving to be the most potent against fibril formation. Our spectroscopic analysis provides detailed insight, that the introduction of these spirooxindole compounds leads to morphological changes in the mechanism of fibril formation which prevent the formation of highly ordered fibrils, instead results in the formation of disordered aggregates which are not fibrillar in nature.
Asunto(s)
Amiloide , Benzopiranos , Enfermedades Neurodegenerativas , Nitrilos , Oxindoles , Compuestos de Espiro , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Espirooxindoles , Péptidos/químicaRESUMEN
This scientific review documents the recent progress of C3-spirooxindoles chemistry (synthesis and reaction mechanism) and their bioactivities, focusing on the promising results as well as highlighting the biological mechanism via the reported molecular docking findings of the most bioactive derivatives. C3-Spirooxindoles are attractive bioactive agents and have been found in a variety of natural compounds, including alkaloids. They are widely investigated in the field of medicinal chemistry and play a key role in medication development, such as antivirals, anticancer agents, antimicrobials, etc. Regarding organic synthesis, several traditional and advanced strategies have been reported, particularly those that started with isatin derivatives.