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 IC₅₀ 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.