4-aminoacridine and 4,9-diaminoacridine derivatives as potential antiproliferative hits

Acridine (AC) derivatives have attracted much attention due to their broad spectrum of biological activity. Though quinacrine (QN), an AC derivative, was the first clinically tested synthetic antimalarial drug, this heteroaromatic core is well-know to exhibit other interesting bioactivities, such as antiproliferative properties. One cost-effective strategy to accelerate drug development is to repurposed/rescued compounds originally developed against a given disease and abandoned owing resistance issues or toxicity. In this context, our research group has been working on the chemical modifications of the classical antimalarial no longer used QN. Here, we report the synthesis of 4-aminoacridine and 4,9-diaminoacridines derivatives that were further evaluated for their in vitro activity against MKN-28 and Caco-2 cell lines. Both families confirmed their potential by showing antiproliferative activity in the µM range. Noteworthy, 4-aminoacridines derivatives presented lower toxicity against normal HFF-1 cells than their parent compound QN.

Acknowledgements: This work was developed within the scope of projects UIDB/50006/2020 and PTDC/BTM-SAL/29786/2017, financed by national funds through the Fundação para a Ciência e Tecnologia (FCT). MF thanks the FCT for the doctoral grant SFRH/BD/147345/2019.