Synthesis and Investigation of Tricyclic Isoquinoline Derivatives as Antibacterial Agents

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Isoquinoline derivatives exhibit a range of biological properties, including antibacterial activity, and are thus attractive as a scaffold for developing broad-spectrum antibacterial compounds. A series of six isoquinoline-based compounds were synthesized using the reaction of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline with dimethyl acetylenedicarboxylate (DMAD) to provide the tricyclic (2Z)-[2-oxo-5,6-dihydropyrrolo[2,1,a]isoquinolin-3-ylidene]-2-ethanoate. The [2 + 3] cycloaddition of DMAD with C-6 and C-7 substituted 1-methyl-3,4-dihydroisoquinolines proceeded using aryl ethers or unsubstituted compounds, but not with amine, amide or nitro moieties at the C-7 position. Compounds 8d and 8f were found to have antibacterial properties against some Gram-positive pathogens (Staphylococcus aureus—8d = 16 µg/mL, 8f = 32 µg/mL; Streptococcus pneumoniae—8f = 32 µg/mL; and Enterococcus faecium—8d = 128 µg/mL, 8f = 64 µg/mL). Evaluation of their cytotoxic properties against mammalian cell lines revealed some cytotoxic effects (8b and 8d, 125 µM, 24 h, HEp-2 cells) and (8a, 8b, 8d = 125 µM, 8f = 62.5 µM, 24 h, McCoy B cells), suggesting limitations in their antibacterial applications without further development.