4-Aminoquinolines: 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. 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: [email protected] 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 1 History and Development Quinine 1, a member of the cinchona alkaloid family, is one of the oldest antimalarial agents and was first extracted from cinchona tree bark in the late 1600s. The cinchona species is native to the Andean region of South America, but when its therapeutic potential was realised, Dutch and British colonialists quickly established plantations in their south-east Asian colonies. These plantations were lost to the Japanese during World War II, stimulating research for synthetic analogues based on the quinine template, such as the 4-aminoquinoline chloroquine (CQ 2, Fig. 1) [1]. A thorough historical review of CQ (in honour of chloroquine’s 75th birthday) is available elsewhere [2]. In short, CQ was first synthesized in 1934 and became the most widely used antimalarial drug by the 1940s [3]. The success of this class has been based on excellent clinical efficacy, limited host toxicity, ease of use and simple, cost-effective synthesis. Importantly, CQ treatment has always been affordable – as little as USD 0.10 in Africa [4]. However, the value of quinoline-based antimalarials has been seriously eroded in recent years, mainly as a result of the development and spread of parasite resistance [5]. Although much of the current research effort is directed towards the identification of novel chemotherapeutic targets, we still do not fully understand the mode of action and the complete mechanism of resistance to the quinoline compounds, knowledge that would greatly assist the design of novel, potent and inexpensive alternative quinoline antimalarials. The search for novel quinoline-based antimalarials with pharmacological benefits superseding those provided by CQ has continued throughout the later part of the twentieth century and the early part of this century since the emergence of CQ resistance. Comprehensive reviews on the pharmacology [6] and structure activity relationships [7] have been published previously, so will be only mentioned briefly. It is the aim of this chapter to review developments in the field that have led to the next-generation 4-aminoquinolines in the development “pipeline”, in addition to discussion of the future therapeutic value of CQ and amodiaquine (AQ). We will begin with studies directed towards an understanding of the molecular mechanism of action of this important class of drug.