Open AccessSynthesis, Cytotoxicity Evaluation, and Computational Insights of Novel 1,4-Diazepane-Based Sigma Ligands
Author(s) -
Daniele Zampieri,
Sara Fortuna,
Antonella Calabretti,
Maurizio Romano,
Renzo Menegazzi,
Dirk Schepmann,
Bernhard Wünsch,
Maria Grazia Mamolo
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00524
Subject(s) - cytotoxicity , chemistry , quinoline , antioxidant , combinatorial chemistry , abts , stereochemistry , biochemistry , in vitro , organic chemistry , dpph
Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane 2c , 3c and quinoline 2d , 3d -substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H 2 O 2 . The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative 2c due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.