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This study aimed to evaluate the metal chelation of new derivatives of pyrazino[1,2\u2010<jats:italic>a<\/jats:italic>]benzimidazole and investigate their antiproliferative properties. The density functional theory method has been employed to evaluate the complexation properties of new synthetic pyrazino[1,2\u2010<jats:italic>a<\/jats:italic>]benzimidazole derivatives possessing the 4\u2010OMe, 2,4\u2010dimethyl, and 3,4,5\u2010trimethoxy substitution on N\u20102 phenyl ring with divalent magnesium, iron, and copper. The free energies for the water\u2010ligand exchange reactions were employed to investigate the thermodynamic stability, water exchange properties, and electronic properties in the gas phase. Natural population analysis was employed to estimate atomic partial charges, second\u2010order interactions between the filled and vacant orbitals, and the occupancies of the metals' valence s, p, and d orbitals. Among pyrazino[1,2\u2010<jats:italic>a<\/jats:italic>]benzimidazole derivatives, the 3,4,5\u2010trimethoxy substituted pyrazino[1,2\u2010<jats:italic>a<\/jats:italic>]benzimidazole shows better electron donor ability. This compound also reduced proliferation and increased the apoptosis of human glioblastoma cancer cells.<\/jats:p>","DOI":"10.1002\/jbt.23155","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T07:21:26Z","timestamp":1657092086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antiproliferative activity of new derivatives of pyrazino[1,2\u2010<i>a<\/i>]benzimidazole: Integrated cell\u2010based assay and computational studies with divalent magnesium, iron, and copper ions"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2854-9567","authenticated-orcid":false,"given":"Mahban","family":"Rahimifard","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Research Center Shahid Beheshti University of Medical Sciences  Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nafiseh","family":"Jalalimanesh","sequence":"additional","affiliation":[{"name":"School of Chemistry, College of Science University of Tehran  Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8545-2705","authenticated-orcid":false,"given":"Mahsa A.","family":"Movahed","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Pharmaceutical Chemistry Shahid Beheshti University of Medical Sciences  Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoudreza","family":"Hadjighassem","sequence":"additional","affiliation":[{"name":"Brain and Spinal Cord Injury Research Center, Neuroscience Institute Tehran University of Medical Sciences  Tehran Iran"},{"name":"Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine Tehran University of Medical Sciences  Tehran Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Razieh","family":"Pourahmad Jaktaji","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Sciences Shahrekord University  Shahrekord Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeinab","family":"Bagheri","sequence":"additional","affiliation":[{"name":"Faculty of Life Sciences and Biotechnology Shahid Beheshti University G.C.  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