Design, Synthesis, and Antimalarial Evaluation of New Spiroacridine Derivatives

<b>Background/Objectives:</b> Malaria is a tropical disease mainly caused by <i>Plasmodium falciparum</i> and represents a global public health problem, with over 200 million cases and 500 thousand deaths reported worldwide. Considering its treatment limitations, it is essential to develop new compounds against malaria. In this context, acridine derivatives are privileged structures. <b>Methods:</b> Thus, new spiroacridines containing <i>N</i>-acylhydrazone (<b>AMTAC</b>) and <i>N</i>-phenylacetamide (<b>ACMD</b>) were synthesized and evaluated in malaria and cytotoxicity assays, as well as <i>in silico</i> studies. <b>Results:</b> As a result, five spiroacridines showed inhibitory activity over 70% against the <i>P. falciparum</i> 3D7-GFP strain at 10 μM, along with an IC₅₀ range of 2-4 μM. After a brief Structure-Activity Relationship (SAR) analysis, it was observed that the spiroacridine structure must be associated with the hydrazone moiety to successfully inhibit parasite growth. In addition, these molecules presented promising resistance profile, with selectivity for the parasite. After computational studies, spiroacridines showed better affinity with dihydrofolate reductase (DHFR), overcoming the quadruple mutant resistance to pyrimethamine, with more stability in complex with the enzyme. <b>Conclusions:</b> Therefore, the potential of spiroacridines against malaria, with moderate resistance and selectivity profile, as well as DHFR inhibition greater than pyrimethamine, was confirmed.