5-Chlorobenzofuran-2-carboxamides: From allosteric CB1 modulators to potential apoptotic antitumor agents

• Published in: European journal of medicinal chemistry Vol. 177; pp. 1 - 11
• Main Authors: Youssif, Bahaa G.M., Mohamed, Ashraf M., Osman, Essam Eldin A., Abou-Ghadir, Ola F., Elnaggar, Dina H., Abdelrahman, Mostafa H., Treamblu, Laurent, Gomaa, Hesham A.M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-09-2019
• Subjects: Anti-proliferative; Apoptotic assay; Benzofuran; Carboxamide; Caspases; CB1; Modulators; Anti-proliferative; Apoptotic assay; CB1; Benzofuran; Carboxamide; Caspases; Modulators
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.040

Cannabinoids as THC and the CB1 allosteric modulator CBD were reported to have antiproliferative activities with no reports for other CB1 allosteric modulators as the 5-chloroindole-2-carboxamide derivatives and their furan congeners. Based on the antiproliferative activity of two 5-chlorobenzofuran-2-carboxamide allosteric CB1 modulators, a series of novel derivatives was designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Some derivatives showed good antiproliferative activities against tumor cells as compounds 8, 15, 21 and 22. The most active compound 15 showed equipotent activity to doxorubicin. Compounds 7, 9, 15, 16, 21 and 22 increased the level of active caspase 3 by 4–8 folds, compared to the control cells in MCF-7 cell line and doxorubicin as a reference drug. Compounds 15 and 21, the most activecaspase-3 inducers, increase the levels of caspase 8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of Cytochrome C levels in MCF-7 cell lines. Compound 15 exhibited cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of MCF-7 cell line. The drug Likeness profile of the synthesized compounds showed that all the compounds were predicted to have high oral absorption complying with different pharmacokinetics filters.
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•A series of novel 5-chlorobenzofuran-2-carboxamide derivatives 14–25 was designed and synthesized based on the antiproliferative activities of two allosteric CB1 modulators 7 and 8 in 4 cancer cell lines.•Compounds 8, 15, 21 and 22 were the most active antiproliferative agents.•Compounds 15 and 21 increased the level of active caspase 3 by 6–8 folds.•Compounds showed programmed cell death and cell cycle arrest.•The newly compounds were predicted to have high oral absorption.