Design, synthesis, and in vitro biological evaluation of 7-chloro-4-quinolylhydrazones as promising anti-malarial agents

Malaria is a disease caused by parasitic protozoa of the genus Plasmodium which afflicts more than 500 million people worldwide, causing approximately 2 million deaths each year. For decades, chloroquine (CQ) provided reliable prophylaxis for travelers and therapy for those with established infection. However, the emergence in the early 1960s and subsequent spread of CQ-resistant parasites created a tremendous therapeutic void. As a result, there is an urgent need for the rapid development of effective, safe and affordable chemotherapeutics. A series of hydrazones based on a 7-chloroquinoline scaffold and characterized by the presence of functionalized aromatic and heteroaromatic rings at the hydrazone moiety, were synthesized and tested for their antiplasmodial properties. These compounds were designed to interact with iron III FPIX (hematin), possibly generating toxic radical species capable of affecting the crucial reducing milieu of the parasite by interfering with Plasmodium falciparum heme detoxification process. They showed remarkable anti-plasmodial activity in vitro against both CQ-S and CQ-R strains. Detailed structure-activity relationships of this class of promising antimalarial agents are discussed (EP06005306.3).