Development of a synthetic route towards N4 ,N9 -disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarial

Malaria is one of the deadliest infectious diseases in the world and was responsible for 435 000 deaths in 2017, namely by Plasmodium falciparum species.1 Antimalarial drugs are the unique weapon to fight this disease once there is no vaccine yet. Generally antimalarial chemotherapy targets mainly the pathogenic blood stage in humans. However, there is an urgent need of new, economic and safe drugs in order to: (i) block parasite transmission to the vectors, (ii) target parasite forms that, for some species, remain transiently dormant in the liver, and (iii) overcome the resistance against artemisinin-based treatments emerging in some vulnerable population in Africa. Consequently, malaria eradication is only possible with the discovery of new multi-targets drugs.2 Mepacrine (MP, Scheme 1), the first synthetic antimalarial drug, was widely employed but it was rapidly superseded by chloroquine (CQ, Scheme 1), whose efficiency, bioavailability, and safety were far superior. By “dissecting” the chemical structure of QN, the acridine moiety of MP can be seen as the fusion between CQ and the heterocycle core of primaquine (PQ, Scheme 1), another emblematic antimalarial, active against all liver forms of the parasite, and gametocytes. In this context, and based on the fact that one fast and low-cost strategy to accelerate antimalarials development is to recycle classical pharmacophores, the aim of this work is the development a yet unexplored multi-step synthetic route towards 4,9-diaminoacridines (Scheme 1). 2 These can be regarded as respectively corresponding to the fusion between CQ and PQ derivatives. As expected, the preliminary in vitro results showed that the new compounds preserved the activity of the parent drugs, with activity against blood-stage, as in CQ, as well as against all liver forms and gametocytes, similarly to PQ.info:eu-repo/semantics/publishedVersio

Development of a synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarials

A multi-step synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines that, to the best of our knowledge, has no precedence in the literature, has been developed. The target structures are likely to reveal interesting biological activities in the near future, not only due to their mepacrine-like core, but also because they embed simultaneously the pharmacophores of chloroquine and primaquine, antimalarial drugs that act at different stages of malaria infection.info:eu-repo/semantics/publishedVersio

New 4-(N-cinnamoylbutyl)aminoacridines as potential multi-stage antiplasmodial leads

© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).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.This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through the project CIRCNA/BRB/0281/2019. The authors further thank FCT/MCTES for supporting Research Units LAQV-REQUIMTE (UIDB/50006/2020) and for the Doctoral Grant to MF (SRFH/BD/147354/2019). MP further acknowledges the “la Caixa” Foundation for Grant HR21-848. ISGlobal and IBEC are members of the CERCA Programme, Generalitat de Catalunya. We acknowledge support from the Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación (MCIN/AEI/ 10.13039/501100011033) through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S). This research is part of ISGlobal's Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundación Ramón Areces.info:eu-repo/semantics/publishedVersio

4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial Hits

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.info:eu-repo/semantics/publishedVersio