Abstract
Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products, together with their reported bioactivities, the present work was aimed at combining both moieties in one molecular skeleton and to synthesize and characterize a novel series of chalone-based phenothiazine derivatives. For this purpose, 2-acetylphenothiazine was N-alkylated, followed by the Claisen-Schmidt reaction to produce the chalcones with good yield. Antioxidant activity, as evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, was assessed to determine if their antioxidant potential was comparable with ascorbic acid, and attributable to the phenothiazine core. Screening anticancer activities of the synthesized chalone-based phenothiazine derivatives against human breast cancer cell line MCF-7 cells, and human hepatocellular carcinoma HepG-2 cells, compared with standard drugs cisplatin and doxorubicin, was evaluated. The results revealed that compounds 4a, 4b, 4d, 4h, 4j, 4k, 4m, 4o, and 4p were good against human hepatocellular carcinoma HepG-2 cells, and among these compounds 4b and 4k were the most effective compounds, with IC50 values of 7.14 μg/mL and 7.6 1 μg/mL, respectively. On the other hand, compounds 4a, 4b, 4k, and 4m were good against human breast cancer cell line MCF-7 cells and, among these compounds, 4k and 4b were the most effective compounds, with IC50 values of 12 μg/mL and 13. 8 μg/mL, respectively. The overall results suggest that these compounds could, potentially, be further modified for the formation of more potent antioxidant and anticancer agents.
Highlights
Studies related to pathology and prevention have received significant attention, especially in regard to the effect of free radicals in causing many diseases in addition to the role of antioxidants in preventing diseases [1,2]
2-acetylphenothiazine (1) was N-alkylated with dodecyl iodide via SN 2 reaction by phase transfer catalysis using tert-butyl ammonium iodide (TBAI) as the catalyst in a heterogeneous basic medium to afford the corresponding product (2) in a good yield
Dodecyl iodide was selected as the alkylating agent to introduce a long chain, as it would improve the solubility of the final product in common organic solvents and lead to better absorption of chalcone by living cells
Summary
Studies related to pathology and prevention have received significant attention, especially in regard to the effect of free radicals in causing many diseases in addition to the role of antioxidants in preventing diseases [1,2]. Glutathione synthesized in the cells protects them from harmful objects and oxidative damage [3]. Smoking and malnutrition can lead to lipid peroxidation, oxidative damage to DNA and proteins, etc., which necessitates taking medication doses of antioxidants to prevent the occurrence of some chronic diseases such as many cancers, cardiovascular diseases and neurological diseases [4]. Studies have shown that increasing the production of free radicals or decreasing the efficiency of the defense systems in the human body, greatly affects the occurrence of Alzheimer’s disease. Most natural antioxidants have restricted therapeutic success due to their poor solubility in both aqueous or lipid systems, which prevents them from reaching the target cells [7,8]
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