Search

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (triple-negative breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281 MM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282 MM for (6d), against MDAMB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values ranging from 16.8 ± 0.37 μM to 31.3 ± 0.86 μM against MDA-MB-231 and 13.5 ± 0.92 μM to 24.2 ± 0.21 μM against HepG2. In particular, spirooxindole derivatives incorporating 2,4-dichlorophenyl moiety were the most active, with an IC50 of 16.8 ± 0.37 μM for (9h) against MDA-MB-23 and 13.5 ± 0.92 μΜ for (9i) against HepG2. Interestingly, the IC50 of compound (6c) (7.2 μM) exhibited better activity than that of Sorafenib (positive control) (9.98 μΜ) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The theoretical examination of the interaction among formaldehyde, phosgene, and thiophosgene molecules on both pristine Zn12O12 nanocage and TM-decorated (Cu, Ni, Ti, and Cr) Zn12O12 nanocage is conducted using density functional theory (DFT). The Zn12O12 nanocage by doping of Cu, Ni, Ti, and Cr atoms remarks in altering the electronic properties and actively reassuring the adsorption of these toxic gases. The finding revealed that Zn12O12 nanocages doped with metal atoms enhance reactivity. In this study, the adsorption energy, dipole moment, charges from natural bond orbitals (NBO), global reactivity parameters, and frontier molecular orbitals (FMOs) were analyzed. The results show that phosgene and thiophosgene are physisorbed on Zn12O12 nanocage with adsorption energies of -10.63, and -9.41 kcal/mol, respectively. The decoration of Zn12O12 nanocage with transition metals (Cu, Ni, Ti, and Cr), efficiently enhanced the adsorption of H2CO, COCl2, and CSCl2. The adsorption of these harmful gases on TM-decorated Zn12O12 nanocage resulted in strong chemisorption. Among the selected warfare agents, CSCl2@Cr-Zn12O12 and H2CO@Ti-Zn12O12 show the highest value of adsorption energy (− 77.86 and − 75.37 kcal/mol, respectively). These complexes also exhibit high chemical hardness value and low softness value suggesting their higher stability and lower reactivity as compared to other complexes. Moreover, the results of recovery time suggested that COCl2 can be desorbed from Ni-Zn12O12 with a recovery time of 0.014 s. Therefore, it is suggested that the Ni-Zn12O12 nanocage may be used as a potential reusable sensor for the detection of phosgene at room temperature due to its high sensitivity and short recovery time. Additionally, the results suggested that the adsorption energy and electrical conductivity of toxic gases on decorated Zn12O12 nanocage increase, potentially improving sensitivity towards these toxic gases. [ABSTRACT FROM AUTHOR]