A Class of Potent Antimalarials and Their Specific Accumulation in Infected Erythrocytes

Abstract

During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and P. cynomolgi.

Prodrugs of bisthiazolium salts are orally potent antimalarials

“…Oral dosages (27,9, and 3 mg͞kg once a day for 4 consecutive days) were based on ED 50 values obtained in mice (5 mg͞kg). Parasite development (an initial increase in parasite numbers followed by a decrease and subsequent recrudescence) was similar to that previously reported (10). All doses were rapidly and completely curative (P ϭ 0.001); recrudescence occurred in all untreated animals but was absent in all TE3-treated animals (Fig.…”

“…PC, the major lipid, is mainly synthesized endogenously (24). Bisquaternary ammonium compounds such as G25, which mimic choline structure (7) and lead to subsequent inhibition of de novo PC synthesis, have received recent attention due to their potent antimalarial activity (10,11). However, intrinsic low oral permeability has been a major, seemingly insurmountable barrier to their oral use.…”

“…Cells were suspended in RPMI medium 1640 supplemented with 0.5% albumax containing 50 nM T4. After 2 h at 37°C, cells were washed and isolated by passage through a dibutyl phtalate cushion (10). The cellular accumulation ratio is defined as the ratio of the amount of T4 in the same volume of suspending solution.…”

“…We subsequently tested TE3 against P. cynomolgi in the rhesus monkey (10). Oral dosages (27,9, and 3 mg͞kg once a day for 4 consecutive days) were based on ED 50 values obtained in mice (5 mg͞kg).…”

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

“…These recent advances have allowed development of bioassays based upon validated targets for drug screening, or targets still in the process of validation (for review see , Prabhu & Patravale, 2011, Sahu et al, 2008) : haem polymerization (O'Neill et al, 2006), pyrimidine, purine, folate (Hyde, 2007), lipid (Wengelnik et al, 2002), shikimate (McRobert et al, 2005), non-mevalonate (Wiesner & Jomaa, 2007) and other apicoplast metabolisms (Sato & Wilson, 2005), mitochondrial electron transport (Mather et al, 2007), redox homeostasis (Bauer et al, 2006), protein prenylation (Van Voorhis et al, 2007), proteases (Wegscheid-Gerlach et al, 2010), kinases (Doerig & Meijer, 2007)... Some of them are detailed below.…”