Synthesis, characterization and investigation of in vitro cytotoxic potential of some new complexes containing morpholine moiety

Abstract

In this work, a Schiff base ligand, 2-((3-(2-morpholinoethylamino)-N3-((pyridine-2-yl)methyl)propylimino)methyl)pyridine (H-16), was synthesized from the reaction of N1-(3-morpholinopropyl)-N1-((pyridine-2-yl)methyl)ethane-1,2-diamine (H-15) and pyridine-2-carbaldehyde. Its reduced Schiff base ligand, N1-(2-morpholinoethyl)-N1,N3-bis(pyridin-2-ylmethyl)propane-1,3-diamine (H-17), was also prepared. Metal complexes were synthesized by reacting the ligands with metal salts in ethanol, and the resulting products were characterized by elemental analysis, FT-IR, ESI-MS, and ¹H and ¹³C NMR spectroscopy. All synthesized compounds were tested in vitro to evaluate their cytotoxicity against DU-145, HeLa, HT-29, MCF-7, MDA-MB-231, PANC-1, PC-3, and U-87 cancer cells, or non-cancerous cell line (L-929). Cell viability was estimated using the MTT assay. Compounds with Ag⁺ and Cd²⁺ as central metal ions showed lowest the IC₅₀ values (< 20 µM), indicating higher cytotoxic activity. These compounds also exhibited higher cytotoxicty than cisplatin against the tested cancer cell lines. It was found that the compounds did not exhibit any cytotoxic activity against HeLa and MCF-7 cancer cells and L-929 non-cancer cells even the highest concentration (20 µM). Among the set of tested compounds with Ag⁺ and Cd²⁺ ions, the best selectivity index was observed for DU-145, HT-29, MDA-MB-231, PANC-1, PC-3, and U-87 cells (SI > 1.00). The nature of metal–ligand bonding in the complexes were investigated by Natural Bond Orbital analysis, Energy Decomposition Analysis and Energy Decomposition Analysis using Natural Orbitals for Chemical Valence variation.