New 4-aminoacridine-cinnamic acid conjugates as multi-stage antimalarial hits

The eradication of malaria remains to be achieved, mainly due to the continued spread of drugresistant parasites. To overcome this, multi-stage drugs have been prioritized in antimalarial drug discovery, since targeting more than one process in the Plasmodium’s life cycle may increase efficiency, while decreasing the chances of resistance emergence by the parasite. Quinacrine (QN) was the first synthetic antiplasmodial drug active against blood forms of the Plasmodium parasite but was rapidly superseded by chloroquine (CQ) which has greater safety, efficiency, and bioavailability. Analysing the QN structure, its acridine core is a fusion between the heterocycle core of CQ and primaquine (PQ), another antiplasmodial drug active against liver forms of the parasite, and able to block malaria transmission. A new family of QN derivatives reported by us, 4-aminoacridines, corresponding to the merge of CQ core and PQ, showed moderate dual-stage antimalarial activity. We have now developed a second generation of 4-aminoacridines (Fig.1) through their conjugation to cinnamic acids (CA) of natural origin that have been reported to enhance antimalarial activity when conjugated to antimalarials. In this communication, we will present the chemical synthesis of this new family of N-cinnamoyl-4-aminoacridines and the in vitro assessment or their activity against a) liver stages of P. berghei, b) erythrocytic forms of P. falciparum, and c) early and mature gametocytes of P. falciparum. Results demonstrate that the conjugation of the CA moiety to the 4-aminoacridine core delivers new compounds with enhanced in vitro activity against all three stages of the malaria parasite lifecycle inside mammalian hosts.

Keywords

Malaria

URI

http://hdl.handle.net/10400.22/27030

Citation

Fonte, M., Fontinha, D., Moita, D., Prades, O., Padilla, Y., Ferraz, R., Fernàndez-Busquets, X., Prudêncio, M., Gomes, P., & Teixeira, C. (2022). New 4-aminoacridine-cinnamic acid conjugates as multi-stage antimalarial hits. Libro de resúmenes del XXVI Encontro Internacional Galego‐Portugués de Química., 553. https://www.colquiga.org/_files/ugd/398543_55f54cb41f0849d2b908563d15c992b5.pdf