Design, Synthesis and Evaluation of Photophysical and Biological Properties of Tetrafluoroacridine

Abstract

1,4,5,8-Tetrafluoroacridine was successfully synthesized from 1,4,5,8-tetrafluoroacridone through transfer hydrogenation using an in-house ruthenium pincer catalyst followed by in situ dehydration. The synthetic protocol involves the copper-catalyzed coupling of 2-amino-3,6-difluorobenzoic acid 1 and 1,4-difluoro-2-iodobenzene 2 to obtain 3 followed by cyclization using polyphosphoric acid to get the 1,4,5,8-tetrafluoroacridone 4. Common synthetic strategies for converting 4 to the 1,4,5,8-tetrafluoroacridine 5 were unsuccessful and the transfer hydrogenation approach proved to be most fruitful. 1,4,5,8-Tetrafluoroacridone 4 can be N-methylated to give 9. The investigation into the photophysical properties of 4, 5, and 9 revealed that the average photoluminescence (PL) lifetime of the acridine derivatives was longer in the aqueous medium than in ethanol and methanol, indicating the influence of the solvent environment on the excited-state dynamics. To assess their potential therapeutic applications, the cytotoxic activity of these compounds was evaluated against AGS and IMR-32 cells, and compound 9 showed significant activity. The addition of methyl group to the acridone was found helpful in enhancing the solubility and biological activity. © 2024 Wiley-VCH GmbH.