Abstract
Sixteen new phthalimide derivatives were synthesized and evaluated for their in vitro anti-microbial, anti-oxidant and anti-inflammatory activities. The cytotoxicity for all synthesized compounds was also determined in cancer cell lines and in normal human cells. None of the target derivatives had any cytotoxic activity. (ZE)-2-[4-(1-Hydrazono-ethyl)phenyl]isoindoline-1,3-dione (12) showed remarkable anti-microbial activity. Its activity against Bacillus subtilis was 133%, 106% and 88.8% when compared with the standard antibiotics ampicillin, cefotaxime and gentamicin, respectively. Compound 12 also showed its highest activities in Gram negative bacteria against Pseudomonas aeruginosa where the percentage activities were 75% and 57.6% when compared sequentially with the standard antibiotics cefotaxime and gentamicin. It was also found that the compounds 2-[4-(4-ethyl-3-methyl-5-thioxo-1,2,4-triazolidin-3-yl)phenyl]isoindoline-1,3-dione (13b) and 2-[4-(3-methyl-5-thioxo-4-phenyl-1,2,4-triazolidin-3-yl)phenyl]isoindoline-1,3-dione (13c) had anti-oxidant activity. 4-(N'-{1-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-ethylidene}-hydrazino)-benzenesulfonamide (17c) showed the highest in vitro anti-inflammatory activity of the tested compounds (a decrease of 32%). To determine the mechanism of the anti-inflammatory activity of 17c, a docking study was carried out on the COX-2 enzyme. The results confirmed that 17c had a higher binding energy score (−17.89 kcal/mol) than that of the ligand celecoxib (−17.27 kcal/mol).
Highlights
The most important biological activity properties that have been reported for phthalimide derivatives 1 are anti-cancer [1], anti-microbial [2,3], anti-oxidant [4] and anti-inflammatory [5]
Reaction of 2-(4-acetyl-phenyl)-isoindoline-1,3-dione (9), which was prepared according to the reported method [19], with equimolar amounts of primary amine derivatives, namely 1-aminotriazole, 4-amino1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (4-aminophenazone) and 5-amino-3-methyl-1-phenyl1H-pyrazole-4-carbonitrile in absolute ethanol at reflux temperature for 8 h to give isoindoline-1,3-dione derivatives 10a–c
The results showed confirmed that the NF-κB pathway was targeted by the phthalimide derivatives (Figure 3)
Summary
The most important biological activity properties that have been reported for phthalimide (isoindoline-1,3-dione) derivatives 1 are anti-cancer [1], anti-microbial [2,3], anti-oxidant [4] and anti-inflammatory [5]. According to the World Health Organization (WHO), infectious and parasitic diseases are still the second cause of death worldwide. This is assumed to be due to resistance to the anti-microbial agents used. There are a number of studies showing that compounds bearing a phthalimide core may be a scaffold for designing new anti-microbial agents [2]. Earlier described synthons have been reported to have anti-microbial [8], anti-oxidant [9] and anti-inflammatory [10,11,12,13] activities, apart from other pharmacological actions like anti-convulsant [14], CNS depressant [15], anti-tumor [1,16], anti-proliferative [17] and anti-pyretic [18] effects
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