Design, Synthesis, and Evaluation of a New Series of Thiazole-Based Anticancer Agents as Potent Akt Inhibitors

Abstract

In an attempt to develop potent anticancer agents targeting Akt, new thiazole derivatives (1–10) were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, and NIH/3T3 (healthy) mouse embryonic fibroblast cell lines. The most potent compounds were also investigated for their effects on apoptosis and Akt pathway. The most promising anticancer agent was found to be 2-[2-((4-(4-cyanophenoxy)phenyl)methylene)hydrazinyl]-4-(4-cyanophenyl)thiazole (6), due to its selective inhibitory effects on A549 and C6 cells with IC50 values of 12.0 ± 1.73 µg/mL and 3.83 ± 0.76 µg/mL, respectively. Furthermore, compound 6 increased early and late apoptotic cell population (32.8%) in C6 cell line more than cisplatin (28.8%) and significantly inhibited the Akt enzyme. The molecular docking study was performed to predict the possible binding modes of compounds A, 6, and 8 inside the active site of Akt (PDB code: 4EJN). Molecular docking simulations were found to be in accordance with in vitro studies and, hence, supported the biological activity. A computational study for the prediction of absorption, distribution, metabolism and excretion (ADME) properties of all compounds was also performed. On the basis of Lipinski’s rule of five, the compounds were expected to be potential orally bioavailable agents.

Ethyl Rosmarinate Protects High Glucose-Induced Injury in Human Endothelial Cells

“…Furthermore, a molecular docking study was performed to analyze the interactions of RA and RAE in the active site of Akt. Homo sapiens Akt (PDB code: 4EJN) was chosen for docking studies according to report before [24]. The docked poses and docking interactions of RAE and RA in the active site of Akt are depicted in Figure 4B–E.…”

Development and therapeutic potential of 2-aminothiazole derivatives in anticancer drug discovery

“…Based on Lipinski's rule of five, compound 99 was predicted as a potential orally bioavailable agent (Fig. 21) [112].…”

Efficient Synthesis, Antibacterial, Antifungal, Antioxidant and Cytotoxicity Study of 2‐(2‐Hydrazineyl)thiazole Derivatives

“…It has been revealed that compounds containing thiazole skeleton exhibit significant biological activities, which have pulled in consideration of researchers in both medicinal chemistry and chemical biology. In the domain of science, the thiazole skeleton is a key pharmacophore because of its ubiquity in a variety of biological properties . Few noteworthy examples of thiazole derivatives are depicted in Figure .…”

“…In the domain of science, the thiazole skeleton is a key pharmacophore because of its ubiquity in a variety of biological properties. [3][4][5][6][7][8][9][10] Few noteworthy examples of thiazole derivatives are depicted in Figure 1. Besides, the hydrazinylthiazolyl core is one of the important organic structures which have produced a profound interest in medicinal and industrial researchers.…”