Synthesis, cytotoxicity and in silico study of some novel benzocoumarin-chalcone-bearing aryl ester derivatives and benzocoumarin-derived arylamide analogs

Abstract

The development of new prostate cancer protein receptor cytochrome P450 17A1 inhibitors offers the possibility of generating structures of increased potency. To this end, the chalcone analogs 7 and 8 were prepared from treatment of methyl 3-oxo-3H-benzocoumarin-2-carboxylate (4) with aryl aldehydes. Treatment of 7 and 8 with three anti-inflammatory drugs, flurbiprofen, ketoprofen and ibuprofen, in the presence of POCl3/DMAP gave the ester analogs 9–12. Analogously, treatment of ethyl 3-oxo-3H-benzocoumarin-2-carboxylate (15), prepared previously from 2-hydroxy-1-naphthaldehyde (13) and dimethylmalonate (14), with various arylamines: 4-bromoaniline, 2-amino-6-methylpyridine, amino-antipyrine and 2-amino-5-nitrothiazole, in the presence of potassium tert-butoxide gave the benzocoumarine-3-arylamide analogs. The in vitro cytotoxic activities of 9–12 and 16–19 were evaluated against human prostate cancer cell lines (PC-3) and normal human liver epithelia (WRL-68) by MTT assay. Compounds 10 and 17 were the most active cytotoxic agents among the series against PC-3 cells with IC50 values of 71.35 and 78.25 μg mL–1 with SI values of 3.0 and 4.2, respectively (calculated from the cytotoxicity effects of 10 and 17 on the normal human liver epithelia [WRL-68]). Furthermore, compounds 11 and 12 were tested against breast cancer (HER2 cell lines), prostate cancer (DU-135 cell lines) and MCF-7 but were inactive. Molecular docking studies between the protein receptor CYPP450 17A1 and compounds 10 and 17 revealed that these compounds primarily form hydrophobic interactions with the receptor.

Hydroxy Chalcones and Analogs with Chemopreventive Properties

“…from the reaction of methyl 3-oxo-3H-benzocoumarin-2-carboxylate with aryl aldehyde [109]. The synthesis of several 2-benzylidene-1-indanone derivatives and the evaluation of their inhibitory activity on lipopolysaccharides-stimulated reactive oxygen species production in RAW 264.7 macrophages has been reported [110,111]. An SAR study disclosed that the presence of a hydroxy group in the C-5, C-6, or C-7 position of the indanone moiety is important for the inhibition of reactive oxygen species production in LPS-stimulated RAW 264.7 macrophages.…”

Untitled

“…The activity of the synthesized compounds against prostate carcinoma was tested, and the findings revealed that two of them were the most effective compounds among this group. As a result, these candidates appear to be the most attractive antiproliferative agents towards CYP450 dependent prostate carcinoma cells [97].…”

Untitled

“…Hyperglycemia and insulin resistance are hallmarks of type 2 diabetes, which eventually lead to a slew of long-term health problems as the disease progresses. These problems include renal and hepatic failure, neurological, retinal, and cardiovascular diseases [1]. Controlling hyperglycemia via targeting the inhibition of enzymes in the carbohydrate hydrolysis process, like α-glucosidase and αamylase, is one of the most effective treatment approaches for type 2 diabetes which should be considered [2].…”

“…The antidiabetic and antioxidative properties have taken on importance among the examined activities. As a result, benzocoumarins could serve as the structural templates for promising antidiabetic and antioxidative entities [1,40]. This study aimed to prepare new coumarindisubstituted benzene conjugates.…”