ELQ-300 Prodrugs for Enhanced Delivery and Single-Dose Cure of Malaria

Abstract

f ; Medicines for Malaria Venture, Geneva, Switzerland g ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3-to 4-fold, reaching a maximum concentration of drug in serum (C max ) of 5.9 M by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures.

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase

“…Pyrimidine biosynthesis is coupled to the respiratory chain by the participation of ubiquinone in the reoxidation of DHODH, and the electrons generated from dihydroorotate oxidation are transferred into the respiratory chain (24). T. gondii and blood stages of malaria parasites both require mitochondrial metabolism, because these parasites are highly susceptible to inhibitors of cytochrome bc 1 (complex III), such as atovaquone (36)(37)(38), that inhibit electron transport through the essential respiratory chain (39)(40)(41). Recent studies on mammalian DHODH have shown that DHODH is physically associated with the respiratory chain complexes III and II (42).…”

Antibiotics in malaria therapy: which antibiotics except tetracyclines and macrolides may be used against malaria?

“…This implies that only low blood concentrations can be achieved following oral dosing. Pro-drug strategy represents a viable approach to improve bio-availability and overcome the physicochemical limitations of quinolone analogues to deliver the active drug at concentrations sufficient for safety, as well as achieving single-dose cures [88]. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300, a endochin analogue from ELQ-337, its O-linked carbonate ester pro-drug, is enhanced by threefold to fourfold, reaching a maximum concentration of drug in serum [88].…”

Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities

“…6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.…”

“…6 The third partner is logically constructed about the 4(1H)-quinolone scaffold. In addition to being used clinically against a variety of infectious diseases including tuberculosis, 7 certain quinolones have acquired lead status for development of drugs for treatment of toxoplasmosis 8,9 and malaria 10,11,12 respectively.Our attention is drawn to decoquinate (DQ, 1) that has been used for many years in veterinary medicine largely coadministered with poultry feed for treatment of coccidiosis wherein it displays negligible toxicity. 13,14 It is also used against other apicomplexan infections in animals 15 and is highly active in a murine model against Toxoplasma gondii.…”