CuII complexes with N-(5-(methylthio)-1,3,4-thiadiazol-2-yl)benzamides: Synthesis, characterization and biological evaluation

• Fluorinated N -(5-(methylthio)-1,3,4-thiadiazol-2-yl)benzamide derivatives. • Planar cis -orientation of the carboxamide oxygen and the thiadiazole sulfur atoms. • Centrosymmetric Cu(II) complexes with the benzamide-type ligands. • Cytotoxicity against MCF-7 cells and non-tumorigenic HaCaT cells. 4-Fluoro- N -(5-(methylthio)-1,3,4-thiadiazol-2-yl)benzamide (HL 1 ) and 2,3,4,5,6-pentafluoro- N -(5-(methylthio)-1,3,4-thiadiazol-2-yl)benzamide (HL 2 ) were prepared through reaction with 2-amino-5-(methylthio)-1,3,4-thiadiazole and the corresponding aroyl chlorides. They have a planar cis -orientation concerning the carboxamide oxygen atom and the thiadiazole sulfur atom. The short intramolecular S∙∙∙O contact upon the cis -orientation in HL 1 was studied by DFT calculations. The HL molecules are luminescent in the solid-state and solution. The reaction of HL 1 with CuCl 2 ∙2H 2 O in methanol/dichloromethane mixture produces [Cu(CH 3 OH) 2 Cl 2 (HL 1 ) 2 ] ( 1 ) and [Cu(L 1 ) 2 ] ( 2 ). Compound 2 is formed when NEt 3 is used, or the used copper salt is replaced by Cu(Ac) 2 ∙H 2 O. Given the low solubility of compound 2 , a reaction of HL 2 with CuCl 2 ∙2H 2 O was performed in methanol with the addition of NEt 3 as supporting base, yielding [Cu(L 2 ) 2 ] ( 3 ) and polymorph 3B . The molecular structures of the products were determined by single-crystal XRD. All compounds were characterized by elemental analysis, FT-IR and UV-Vis/DRS spectroscopies, and ESI mass spectrometry. HL 1 , HL 2 and compound 1 were also analyzed by NMR spectroscopy. HL 1 , HL 2 , and complexes 1 and 3 were evaluated for their cytotoxicity against MCF-7 cells and non-tumorigenic HaCaT cells. Complexes 1 and 3 exhibited cytotoxic activity against MCF-7, with CC₅₀ values of 5.02 ± 1.97 µM and 7.88 ± 2.16 µM, respectively, while the ligands HL 1 and HL 2 are non-cytotoxic at the tested concentrations.