An Efficient and Sustainable Synthesis of the Antimalarial Drug Tafenoquine
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PROVIDER: S-EPMC9768812 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Project description:The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei.
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Project description:A 6-step synthesis of the antimalarial drug candidate MMV688533 is reported. Key transformations carried out under aqueous micellar conditions include two Sonogashira couplings and amide bond formation. Compared with the first-generation manufacturing process reported by Sanofi, the current route features ppm levels of palladium loading, less material input, less organic solvent, and no traditional amide coupling reagents. The overall yield is improved ten-fold, from 6.4% to 67%.
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Project description:Tafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acute Plasmodium vivax malaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/F and Q/F, respectively), apparent volume of distribution for central and peripheral compartments (V2/F and V3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka ), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/F and 915 liters for V2/F in P. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.
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Project description:Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.
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Project description:Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield. Comparisons to existing literature performed exclusively in organic solvents reveal a 5-fold decrease in environmental impact as measured by E Factors.
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Project description:BackgroundThe long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals.MethodsHealthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population.ResultsTwelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult.ConclusionsAlthough a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).
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