Design, synthesis and antiproliferative activity of new amine, amino acid and dipeptide-coupled benzamides as potential sigma-1 receptor

• Published in: Journal of the Iranian Chemical Society 2020-10, Vol.17 (10), p.2515-2532
• Main Authors: Youssef, Eman, El-Moneim, Mohamed Abd, Fathalla, Walid, Nafie, Mohamed S.
• Format: Article
• Language: English
• Subjects: Amines; Amino acids; Analytical Chemistry; Anticancer properties; Antiproliferatives; Benzoic acid; Benzoxazines; Biochemistry; Biotechnology; Chemical synthesis; Chemistry; Chemistry and Materials Science; Coupling (molecular); Cytotoxicity; Esters; Inorganic Chemistry; Molecular docking; Organic Chemistry; Original Paper; Physical Chemistry; Receptors
• ISSN: 1735-207X; 1735-2428
• DOI: 10.1007/s13738-020-01947-6

N -Alkyl-2-(substitutedbenzamido) benzamides and methyl 2-(2-(substitutedbenzamido) benzamido) alkanoates were prepared by either the reaction of amines or amino acid esters with benzoxazine derivatives or the DCC coupling of 2-substitutedbenzamido benzoic acid with amines or amino acid esters. Methyl 2-(2-(4-chlorobenzamido)benzamido alkanoates were used as the key intermediate for the preparation of dipeptide-coupled benzamides via azide and DCC coupling methods. The investigated compounds were subjected to in silico molecular docking as agonist for human σ1 receptor through their binding energies and analysis of ligand–receptor interactions and prediction study to their physicochemical properties and drug-likeness scores. Moreover, compounds with the highest binding affinity toward the target were screened against breast MCF-7 and liver A549 cancer cell lines to test their cytotoxic activities. Compounds 11a , 3a , 8c , 12a and 13b showed potent cytotoxic activity for the tested compounds against MCF-7 cell line with low IC 50 values, especially for 11a (5.3 µM compared to the standard drug 5-FU 5.8 µM). Based on the identification of this hit candidate, new potent σ1 receptor with anti-cancer activity could be designed.