A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

Abstract

cPantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC 50 ], ϳ20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of ␣-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC 50 , 52 ؎ 6 nM), target specificity, and low toxicity.O ne-half of the world's population (ϳ3.4 billion people) is at risk of contracting malaria, with pregnant women and children Ͻ5 years of age being especially vulnerable. In 2013, the WHO estimated that malaria caused ϳ584,000 deaths globally, with the majority occurring in Africa (1). Although efforts to control and to eliminate malaria in the past 15 years have saved an estimated 3.3 million lives (1), drug-resistant parasites continue to emerge (2). This places the progress in the fight against the disease under pressure, especially since there is no effective vaccine against malaria (3). Several new drug targets have been identified in recent years (4); however, these targets now need to be exploited through the development of directed treatments.We are interested in targeting the biosynthesis of the essential cofactor coenzyme A (CoA) from the water-soluble vitamin B 5 (pantothenate, compound 1 in Fig. 1) for antimalarial drug development (5, 6). It has been shown that extracellular pantothenate is essential for intracellular malaria parasites (7), which indicates that Plasmodium falciparum does not utilize exogenous CoA but must synthesize CoA de novo (8).Pantothenate analogues interfere with the ability of P. falciparum to utilize the vitamin, with many analogues being characterized as growth inhibitors of the blood-stage parasites (9-11). Furthermore, a recent study showed that CoA biosynthesis can be targeted by a chemically diverse set of inhibitors that do not resemble pantothenate, the most potent of which had a 50% inhibitory concentration (IC 50 ; the concentration that inhibits parasite proliferation by 50%) of 120 nM against blood-stage parasites (12). These studies support pantothenate utilization (and therefore CoA biosynthesis and CoA-dependent processes) as an antiplasmodial target.Recently we showed that N-substituted pantothenamides (PanAms), a specific class of pantothenate analogues, have excellent antiplasmodial activity. Among these, N-phenethyl-pantothenamide (N-PE-PanAm) (compound 2 in Fig. 1) exhibited an IC 50 of 20 nM (13); this potency is comparable to that of chloroquine (14, 15). In practice, however, the antiplasmodial activity of the PanAms is decreased since they are degraded by pantetheinase (13), a ubiquitous enzyme of the Vanin protein family that is present in serum (16,17). Pantetheinase normally catalyzes the hydrolysis of pantetheine (a CoA-derived metabolite) to for...

Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds

“…Antiplasmodial activity measurement (Table ) revealed IC 50 values above 100 μ m for both 8 e and 8 f , implying that branching of the linker is detrimental to activity, at least with a one‐carbon linker. This contrasts with the beneficial effect reported for alpha‐methylation of the two‐carbon linker in the pantothenamide series …”

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

“…berghei . As a number of inhibitors of this pathway are currently being investigated for asexual inhibition of the malaria parasite [65,66,69–71], these studies should be extended to assess the transmission-blocking capacity of these inhibitors.…”

Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

“…Pantothenamides may be considered promising leads for the development of new antimalarial agents due to their excellent potency against P. falciparum (some with IC 50 s comparable to that of chloroquine against the RBC stage of the parasite), the fact that they act on a pathway not targeted by current drugs (12,17), and their low toxicity against mammalian cells (7,17). Their susceptibility to degradation by serum pantetheinase (12), however, has prevented their further development.…”