Seite - (000335) - in Biomedical Chemistry: Current Trends and Developments

action for all 4-aminoquinolines is not exactly known, they are known to be effective in treating only erythrocytic stages of infection. Poor compliance or poor management of care with such drugs can rapidly lead to resistance. This was exactly the case with chloroquine. By the early 1950’s, chloroquine resistance was identified along the Thai- Cambodian border and Colombia. Within two decades it had spread to every malaria endemic region of the world (Farooq & Mahajan, 2004). While the mechanism of action for the 4-aminoquinolines is not completely understood, the most widely cited hypothesis is that accumulation in the digestive vacuole of the parasite interferes with hemoglobin digestion. Resistance is believed to be conferred by the presence of a chloroquine specific P-glycoprotein pump (Foley & Tilley, 1998). Several loci in the P. falciparum genome have been implicated in this resistance (Farooq & Mahajan, 2004). This mechanism, or a variant thereof may well be important in quinine, mefloquine, or other quinoline resistance mechanisms, however, it should be noted that more lipophilic quinolines do not concentrate in the food vacuole to the same extent as chloroquine, and therefore other mechanisms need to be explored (including potential alternative targets of efficacy) when considering these drugs. A considerable effort is still ongoing to circumvent resistance through analog campaigns or co-administration with other drugs (Hanboonkunupakarn, 2014; Le Garlantezec, 2014; I. Opsenica, 2011; I. M. Opsenica, 2013; Thriemer, 2014). While it is tempting to synthesize analogs of a compound with emerging or established resistance, in the author’s opinion, such efforts should be entered into with full knowledge that selection pressures in malaria endemic areas quickly erode the efficacy of new drugs from old classes. It is advisable to pursue a combination approach wherein fast acting short half-life drugs (e.g. artemesinins) are combined with long half-life (longer exposure of parasite to drug) quinolines prone to emergence of resistance. Further, future efforts in this class should pay careful attention to early signs of cross resistance in chloroquine resistant strains. While small jumps in IC50 in a resistant strain may not raise alarms if those IC50s are still significantly less than the anticipated maximum concentrations achieved in plasma post-exposure, they could be indicative of shared