Efficacy, Structure-Activity Relationship, and Mode of Action Studies of a New Generation of Acridine/Acridone-Based Antimalarials.

Malaria continues to devastate humanity with significant global morbidity and mortality. The emerging resistance to antimalarials suggests artemisinin and its derivatives will encounter the same challenges as other antimalarial drugs. Strategies to accelerate developing new antimalarials include utilizing known scaffolds and making structural modifications to enhance properties and elucidate their mode of action. We have focused on acridine derivatives and describe 18 acridine/acridone analogs based on pyronaridine or quinacrine cores. Several molecules demonstrated potent in vitro activity against both chloroquine-sensitive strains ofPlasmodium falciparum, with either no observed or low cytotoxicity. Additionally, we investigated the mode of action of these derivatives, their combination with other antimalarials, and their inhibitory activity against multidrug-resistant strains ofP. falciparum. Compound 5a, an acridone-based derivative, demonstrated lower potency against the atovaquone-resistant strain (IC50PfTM90C6B > 12.5 μM) and exhibited a slow-acting mechanism, along with inhibition of the mitochondrial bc1 complex (IC50bc1 = 2 μM). In contrast, compound 2d (IC50Pf3D7 = 0.02 μM), an acridine-based derivative, showed fast-acting inhibition, localized near the parasite's digestive vacuole, and inhibited hemozoin formation (IC50 = 5 μM). Acridine-based derivatives 2d showed potent nanomolar inhibitory activity against P. falciparum and P. vivax field isolates and improved survival in mice infected with P. berghei, achieving a 100% survival rate at 30 days. These findings suggest that acridone- and acridine-based derivatives likely act through distinct modes of action, providing valuable insights for developing new antimalarials active against resistant strains of P. falciparum and demonstrating efficacy in both ex vivo and in vivo models.