4-Aminoquinolines--past, present, and future: a chemical perspective.

The 4-aminoquinoline chloroquine (1) can be considered to be one of the most important synthetic chemotherapeutic agents in history. Since its discovery, chloroquine has proved to be a highly effective, safe, and well-tolerated drug for the treatment and prophylaxis of malaria. However, the emergence of chloroquine-resistant strains of the malarial parasite has underlined the requirement for a synthetic alternative to chloroquine. This review describes structure-activity relationships for the 4-aminoquinolines, along with views on the mechanism of action and parasite resistance. A description of drug metabolism and toxicity also is included, with a brief description of potential approaches to the design of new synthetic derivatives.