by Keyword: Acridine
Fonte, M, Rôla, C, Santana, S, Avalos-Padilla, Y, Fernàndez-Busquets, X, Prudèncio, M, Gomes, P, Teixeira, C, (2024). Disclosure of cinnamic acid/4,9-diaminoacridine conjugates as multi-stage antiplasmodial hits Bioorganic & Medicinal Chemistry 104, 117714 
4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans-cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei, although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 mu M. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates.
JTD Keywords: Acid-derivatives, Analogs, Antimalarial, Artemisinin, Bearing, Cinnamic acid, Covalent bitherapy, Diaminoacridine, Good health and well-being, Malaria, Multi-target, N-cinnamoylation, Plasmodium-falciparum, Primaquine, Quinacrine, Resistance
Fonte, M, Fontinha, D, Moita, D, Caño-Prades, O, Avalos-Padilla, Y, Fernàndez-Busquets, X, Prudencio, M, Gomes, P, Teixeira, C, (2023). New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial leads European Journal Of Medicinal Chemistry 258, 115575
A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans-cinnamic acids. The 4-(N-cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei, (ii) erythrocytic forms of Plasmodium falciparum, and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta-fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
JTD Keywords: agents, analogs, antimalarial, artemisinin, blood-stage, cinnamic acid, gametocyte, hybrid, liver-stage, malaria, multi-target, plasmodium-falciparum, primaquine, quinacrine, resistance, Acridine, Antimalarial, Blood-stage, Cinnamic acid, Cinnamic acid-derivatives, Gametocyte, Hybrid, Liver-stage, Multi-target
Fonte, M, Tassi, N, Fontinha, D, Bouzón-Arnáiz, I, Ferraz, R, Araújo, MJ, Fernàndez-Busquets, X, Prudêncio, M, Gomes, P, Teixeira, C, (2021). 4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial Hits Chemmedchem 16, 788-792
© 2020 Wiley-VCH GmbH Multi-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.
JTD Keywords: acridines, antimalarial activity, blood-stage, liver-stage, malaria, plasmodium, Acridines, Antimalarial activity, Blood-stage, Liver-stage, Malaria, Plasmodium, Synthesis
