4-Aminoquinolines: Chloroquine, Amodiaquine and Next-Generation Analogues Paul M. O’Neill, Victoria E. Barton, Stephen A. Ward, and James Chadwick Abstract 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 wide- spread 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 develop- ments in the field and consider the future therapeutic value of CQ and AQ. P.M. O’Neill (*) Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK Department of Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK e-mail: pmoneill@liverpool.ac.uk V.E. Barton • J. Chadwick Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK S.A. Ward Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK H.M. Staines and S. Krishna (eds.), Treatment and Prevention of Malaria, DOI 10.1007/978-3-0346-0480-2_2, # Springer Basel AG 2012 19