4-Aminoquinolines: Chloroquine, amodiaquine and next-generation analogues: Chloroquine, amodiaquine and next-generation analogues

For several decades, the 4-aminoquinolines chloroquine (CQ) and amodiaquine (AQ) were considered the most important drugs for the control and eradication of malaria. The success of this class has been based on excellent clinical efficacy, limited host toxicity, ease of use and simple, cost-effective synthesis. Importantly, chloroquine therapy is affordable enough for use in the developing world. However, its value has seriously diminished since the emergence of widespread parasite resistance in every region where P. falciparum is prevalent. Recent medicinal chemistry campaigns have resulted in the development of short-chain chloroquine analogues (AQ-13), organometallic antimalarials (ferroquine) and the "fusion" antimalarial trioxaquine (SAR116242). Projects to reduce the toxicity of AQ have resulted in the development of metabolically stable AQ analogues (isoquine/N-tert-butyl isoquine). In addition to these developments, older 4-aminoquinolines such as piperaquine and the related aza-acridine derivative pyronaridine continue to be developed. It is the aim of this chapter to review 4-aminoquinoline structure-activity relationships and medicinal chemistry developments in the field and consider the future therapeutic value of CQ and AQ.