Functionalization of 9-thioxanthone at the 1-position: from arylamino derivatives to [1]benzo(thio)pyrano[4,3,2-de]benzothieno[2,3-b]quinolines of biological interest

Abstract Original 1-amino substituted thioxanthone derivatives were easily prepared from the bare heterocycle by a deprotometalation-iodolysis-copper-catalyzed C-N bond formation sequence. This last reaction delivered mono- or/and diarylated products depending on the aniline involved. 1-Amino-9-thioxanthone was also prepared and reacted with 2-iodoheterocycles. Interestingly, while 1-(arylamino)-9-thioxanthones could be isolated, their subsequent cyclization was found to deliver original hexacyclic derivatives of helicoidal nature. Evaluation of their photophysical properties revealed high fluorescence in polar media, indicating potential applications for biological imaging. These compounds being able to inhibit PIM1 kinase, their putative binding mode was examined through molecular modeling experiments. Altogether, these results tend to suggest the discovery of a new family of fluorescent PIM inhibitors and pave the way for their future rational optimization.