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作者

M.C. Casanova Y. Zhao S. Hutter M. Fil M.H. Do A. Benech T.-B. Muller C. Curti M. Médebielle P. Vanelle N. Azas J. Broggi

作者单位

⁴Assistance Publique – Hôpitaux de Marseille (AP-HM), Service central de la qualité et de l'information pharmaceutiques (SCQIP), Pôle pharmacie, Hôpital de la Conception, 13005 Marseille, France ⁵Univ Lyon 1, CNRS, Institut de Chimie et de Biochimie Moléculaires et Supramoléculaires ICBMS-UMR 5246, 69622 Villeurbanne, France ²Aix Marseille Univ, IHU Méditerran ¹Aix Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR - UMR 7273, Faculté de Pharmacie, 13005 Marseille, France Infection, UMR VITROME, 13005 Marseille, France ³Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, China

刊名

European Journal of Medicinal Chemistry

年份

2025

页码

117633

ISSN

0223-5234

关键词

N-heterocyclic iminium salts bis-aminopyridinium salts K1 multi-resistant Plasmodium falciparum strain (PfK1) in vitro antimalarial activity bivalent interactions

摘要

The emergence of Plasmodium resistance to past and newly introduced antimalarial drugs reinforces the need for new antimalarial agents with innovative mechanisms of action. In this regard, the search for new redox-cycling compounds might offer an interesting approach to treat malaria since P. falciparum is sensitive to oxidative stress. Based on our experience in the design of powerful organic reducers, we undertook here the synthesis and evaluation of different families of N-heterocyclic iminiu...更多

The emergence of Plasmodium resistance to past and newly introduced antimalarial drugs reinforces the need for new antimalarial agents with innovative mechanisms of action. In this regard, the search for new redox-cycling compounds might offer an interesting approach to treat malaria since P. falciparum is sensitive to oxidative stress. Based on our experience in the design of powerful organic reducers, we undertook here the synthesis and evaluation of different families of N-heterocyclic iminium salts that could provide more selective redox-cycling candidates against the K1 multi-resistant Plasmodium falciparum strain . Bis-aminopyridinium salts emerged as the most promising candidates, exhibiting nanomolar antiplasmodial activity comparable to that of methylene blue. The biological study also underlined the positive impact on the in vitro activity of electron-donating groups and bis-salt forms, likely due to simultaneous bivalent interactions with the target. Our investigations revealed differences in the mechanism of action according to the heterocycle nature, highlighting an original mechanism for bis-aminopyridinium derivatives, different from that of chloroquine.收起

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