N8‐Modified Quino[4,3,2‐Kl]acridines as Promising Antimalarial G‐Quadruplex Ligands
Abstract
To face the increasing multidrug resistance of the malaria parasite Plasmodium falciparum, the development of new compounds that act in novel ways is urgent. G-quadruplexes (G4), Guanine-rich secondary structures of DNA and RNA sequences, have an essential role in cell survival and cell metabolism regulation, including in Plasmodium. We have recently demonstrated that the G-quadruplex ligand RHPS4, an acridine derivative, displays strong antiplasmodial activity by disrupting P. falciparum through G4 stabilization, leading to parasite death. Based on this original mode of action, we propose here a series of new RHPS4 analogues. These derivatives were then tested against P. falciparum and on human cells to evaluate their selectivity index. They exhibited IC 50 values ranging from 70 nM to up to 10 μM with cationic analogues more active than neutral ones. Their ability to interact and stabilize G-quadruplex DNA structures was also evaluated. Among all RHPS4 analogues, the compound 8b (N8-ethyl) exhibited the best activity (70 nM), a high selectivity index (143), and a significant capacity to stabilize the G4 structures.
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BibTeX
@article{saulnier2026n8modified,
title = {{N8‐Modified Quino[4,3,2‐Kl]acridines as Promising Antimalarial G‐Quadruplex Ligands}},
author = {Steve Saulnier and Marco Antônio G B Gomes and Mariam Salim and Maxime Guichonnet and Michel Nguyen and Laure Vendier and Flore Nardella and Jean‐michel Augereau and Dennis Gomez and Anne Robert and Françoise Benoit‐vical},
journal = {ChemBioChem},
year = {2026},
month = sep,
doi = {10.1002/cbic.70516},
url = {https://hal.science/hal-05748475v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - N8‐Modified Quino[4,3,2‐Kl]acridines as Promising Antimalarial G‐Quadruplex Ligands
AU - Steve Saulnier
AU - Marco Antônio G B Gomes
AU - Mariam Salim
AU - Maxime Guichonnet
AU - Michel Nguyen
AU - Laure Vendier
AU - Flore Nardella
AU - Jean‐michel Augereau
AU - Dennis Gomez
AU - Anne Robert
AU - Françoise Benoit‐vical
PY - 2026
DA - 2026/09/10
JO - ChemBioChem
DO - 10.1002/cbic.70516
UR - https://hal.science/hal-05748475v1
AB - To face the increasing multidrug resistance of the malaria parasite Plasmodium falciparum, the development of new compounds that act in novel ways is urgent. G-quadruplexes (G4), Guanine-rich secondary structures of DNA and RNA sequences, have an essential role in cell survival and cell metabolism regulation, including in Plasmodium. We have recently demonstrated that the G-quadruplex ligand RHPS4, an acridine derivative, displays strong antiplasmodial activity by disrupting P. falciparum through G4 stabilization, leading to parasite death. Based on this original mode of action, we propose here a series of new RHPS4 analogues. These derivatives were then tested against P. falciparum and on human cells to evaluate their selectivity index. They exhibited IC 50 values ranging from 70 nM to up to 10 μM with cationic analogues more active than neutral ones. Their ability to interact and stabilize G-quadruplex DNA structures was also evaluated. Among all RHPS4 analogues, the compound 8b (N8-ethyl) exhibited the best activity (70 nM), a high selectivity index (143), and a significant capacity to stabilize the G4 structures.
SN - 1439-4227
SN - 1439-7633
ER -