Page - (000333) - in Biomedical Chemistry: Current Trends and Developments

which the Germans synthesized and screened thousands of compounds for anti-malarial activity. Among these were several 8-aminoquinolines, atabrine (quinacrine), and a drug they discarded for toxicity called Resochin (chloroquine) (Coates, 1963; Vale, 2009). After access to quinine from Indonesia was cut to Allied forces by the entry of Japan into WWII, US and British chemists began a similar push resulting in the adoption of atabrine as the drug of choice for malaria treatment and prophylaxis during the later years of the war. Post-war, powerful new anti-malarial drugs began to emerge as the culmination of follow-on efforts by US and British chemists to exploit the original efforts by Germany. Many of these drugs are still in use today, with robust analog efforts being employed around them to overcome developing resistance. 3.4.4 Modern Efforts in Antimalarial Drug Development Modern efforts in anti-malarial drug discovery in general follow six separate approaches including optimization of therapy with existing agents, development of analogs of existing agents, natural products, repurposing of drugs from other therapeutic areas, reversal of resistance, and discovery of compounds active against novel targets (Rosenthal, 2003). Table 3.4.1 illustrates examples from current literature from each approach. It is interesting to note that many of these approaches revolve around existing agents and their analogs, many of which were known since the 1920s, 30s, or 40s. For the purposes of this discussion, we will focus on ongoing work in existing classes and development of novel classes of anti-malarials, as discussions of combinations of existing drugs can become lengthy and are better suited in a clinical pharmacology text. 3.4.4.1 Quinine, 4-Aminoquinolines, and Quinoline Methanols For natural products, quinine is a success story that has endured for centuries. Quinine is an aryl amino alchohol derived from the bark of the cinchona tree (Fig. 3.4.1). Despite its discovery over 400 years ago, it remains an enormously important drug in the treatment of malaria in the developing world. Quinine is rapidly absorbed, both orally and