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ORIGINAL PAPER

Design, synthesis and antiproliferative activity of new amine, amino acid and dipeptide‑coupled benzamides as potential sigma‑1 receptor Eman Youssef1 · Mohamed Abd El‑Moneim2 · Walid Fathalla1   · Mohamed S. Nafie3  Received: 8 November 2019 / Accepted: 26 April 2020 © Iranian Chemical Society 2020

Abstract 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 ­IC50 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. Keywords  DCC coupling · Azide coupling · Benzamides · Benzoxazine · Antiproliferative · Docking · Sigma-1 receptor

Introduction Cancer is recognized as the second deadliest disease in human lives, according to the WHO Agency and international cancer agencies (around 9.6 million deaths in 2018) [1]. The highest causes of cancer mortality include liver, prostate, breast, stomach and lung cancer [2]. It has become a significant health problem over the last 50 years and one of Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1373​8-020-01947​-6) contains supplementary material, which is available to authorized users. * Walid Fathalla [email protected] * Mohamed S. Nafie [email protected] 1



Physics and Math. Engineering Department, Faculty of Engineering, Port-Said University, Port Said, Egypt

2



Chemistry Department, Faculty of Science, Port-Said University, Port Said, Egypt

3

Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt



the most terrible afflictions in the world. Cancer comprises a group of complex and heterogeneous diseases characterized by uncontrolled cellular proliferation in response to a myriad of biochemical, genetic and epigenetic changes [3]. In cancer treatment, sigma receptor (σR) family was seen as an effective target. Some of cancer cell lines, including prostate, lung and breast, have found a high density of σRs. σ proteins in the literature have