Browsing by Author "Fontinha, Diana"
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- 4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial HitsPublication . Fonte, Mélanie; Tassi, Natália; Fontinha, Diana; Bóuzon-Arnáiz, Inês; Ferraz, Ricardo; Araújo, Maria J.; Fèrnandez-Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, CátiaMulti‐stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine‐based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine‐sensitive and ‐resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual‐stage antiplasmodial hits.
- Drug-derived surface-active ionic liquids: a cost-effective way to expressively increase the blood-stage antimalarial activity of primaquinePublication . Silva, Ana Teresa; Oliveira, Isabel S.; Gomes, Joana; Aguiar, Luísa; Fontinha, Diana; Duarte, Denise; Nogueira, Fátima; Prudêncio, Miguel; Marques, Eduardo F.; Teixeira, Cátia; Ferraz, Ricardo; Gomes, PaulaInspired by previous disclosure of room-temperature ionic liquids derived from primaquine and cinnamic acids, which displayed slightly enhanced blood-stage activity compared to the parent drug, we have now combined this emblematic antimalarial with natural fatty acids. This affords surface-active ionic liquids whose liver-stage antiplasmodial activity is either retained or slightly enhanced, while revealing blood-stage antiplasmodial activity at least one order of magnitude higher than that of the parent compound. These findings open new perspectives towards the cost-effective recycling of classical drugs that are either shelved or in decline, and which is not limited to antimalarial agents.
- New 4-aminoacridine-cinnamic acid conjugates as multi-stage antimalarial hitsPublication . Fonte, Mélanie; Fontinha, Diana; Moita, Diana; Prades, Omar; Padilla, Yunuen; Ferraz, Ricardo; Fernàndez-Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, CátiaThe 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.
- A new strategy against malaria – antimalarial ionic liquids derived from aminoquinolines and fatty acidsPublication . Silva, Ana Teresa; Teixeira, Cátia; Fontinha, Diana; Prudêncio, Cristina; Prudêncio, Miguel; Gomes, Paula; Ferraz, RicardoBased on the recent promising results obtained by us, where ionic liquids (ILs) derived from primaquine were found as triple-stage antimalarial hits, we have now produced, by simple, quantitative, and low-cost methods, new ILs via simple acid-base titration of antimalarial aminoquinolines (primaquine and chloroquine) with natural fatty acids (Figure 1). We have also synthesized, in good to high yields, the covalent amide analogues of these ILs (Figure 1), in order to establish how the nature of the chemical bond (ionic ammonium carboxylate versus covalent amide) between both building blocks influences the physico-chemical and biological properties of the final compounds. Results obtained thus far allow us to conclude that both ionic and covalent compounds (i) have higher thermostability than the parent drugs, and (ii) display remarkable in vitro activity against liver-stage malaria parasites.