Page - (000336) - in Biomedical Chemistry: Current Trends and Developments

mechanisms of resistance that might worsen over time with large exposures in environments with poorly controlled administration or where monotherapy is used. Mefloquine, a quinoline methanol, was developed by the US Army in the 1970s, and was considered very desirable for both treatment and prophylaxis due to its long half-life (Croft, 2007). In recent years mefloquine usage has decreased due to emerging resistance, and more significantly, poor tolerance (Farooq & Mahajan, 2004; Milner, 2010). Mefloquine has been linked to neurological side-effects including vertigo, loss of balance, and polyneuropathy, which have recently been labeled as potentially irreversible by the FDA (Nevin, 2014). Extensive efforts have shown promise in improving the therapeutic index of mefloquine by opening or removing the piperadine side-chain (Dow, 2006; 2011; Milner, 2011). With the notoriously poor predictive power of models of CNS toxicity and the stigma attached to the quinoline methanol class, these efforts have largely been abandoned. Further, recent trials with enantiomerically pure mefloquine (currently marketed as a racemic mixture) have shown little promise in improving tolerability (Nevin, 2014). 3.4.4.2 8-Aminoquinolines Another powerful class of anti-malarial drugs to emerge from war efforts is the 8-aminoquinolines. Although still quinoline based, this class has several key features which make it unique. One primary feature of this class is its ability to act as a causal prophylactic, or to prevent the initial infection of parasites in the liver. Further, the class has powerful anti- hypnozoite activity. Hypnozoites being the dormant liver stage of P. vivax and P. ovale, this imparts a separate prophylactic use, namely presumptive anti-relapse therapy or PART. Combined with this unique exoerythrocytic activity is the gametocytocidal activity, whereby 8- aminoquinolines kill the sexual stages of the parasite blocking further transmission of infection. This combination of activities makes this class highly attractive for prophylaxis, treatment of relapsing strains of malaria, and/or elimination efforts. The class has also shown in vitro anti-leishmanicidal activity and has clinical utility in the treatment of