Overcoming Chloroquine Resistance in Malaria: Design, Synthesis and Structure-Activity Relationships of Novel Hybrid Compounds

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents which resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) which resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency towards a range of resistant malaria parasites. A preferred compound, 35: , showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability and in vitro toxicity, in a hepatocyte and a cardiomyocyte cell line, indicates that 35: has a good therapeutic window and favourable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.