Pharmacokinetic and Pharmacodynamic Profiles of Rapid- and Slow-Acting Antimalarial Drugs

Artemisinin and its derivatives are highly effective antimalarial drugs. These compounds combine potent and rapid antimalarial activity with a wide therapeutic index. An initiation of artemisinin resistance, described by a delayed parasite clearance time, is unlikely to cause high-level resistance. Artemisinins as a class demonstrate poor efficacy as monotherapy. This shortcoming can be overcome using oral artemisinin-based combination therapies (ACT) and intravenous-artesunate (IV-AS) in combination with slow-acting partner drugs. Pharmacokinetic and pharmacodynamic (PK/PD) evaluation demonstrates that the rapid efficacy of artemisinins is largely due to drug peak concentrations. Critical evaluation also demonstrates that AS is superior in PK/PD either following oral or intravenous administration when compared to the other rapid-acting artemisinins. This rapid efficacy and decreased mortality demonstrates that currently available artemisinins have a great advantage when combined with slow-acting antimalarial drugs for uncomplicated malaria or in sequential therapy with AS injection initially for severe and complicated malaria. Compared to other ACTs, dihydroartemisinin-piperaquine (DP) demonstrates a superior in PK/PD profile, most likely due to the long half-life of piperaquine. These findings will help us better understand the PK/PD profiles of rapid-acting (artemisinins) and slow-acting (piperaquine) drugs, and suggest how to best use ACTs in the future

Testing Electrostatic Complementarity in Enzyme Catalysis: Hydrogen Bonding in the Ketosteroid Isomerase Oxyanion Hole

A longstanding proposal in enzymology is that enzymes are electrostatically and geometrically complementary to the transition states of the reactions they catalyze and that this complementarity contributes to catalysis. Experimental evaluation of this contribution, however, has been difficult. We have systematically dissected the potential contribution to catalysis from electrostatic complementarity in ketosteroid isomerase. Phenolates, analogs of the transition state and reaction intermediate, bind and accept two hydrogen bonds in an active site oxyanion hole. The binding of substituted phenolates of constant molecular shape but increasing p K (a) models the charge accumulation in the oxyanion hole during the enzymatic reaction. As charge localization increases, the NMR chemical shifts of protons involved in oxyanion hole hydrogen bonds increase by 0.50–0.76 ppm/p K (a) unit, suggesting a bond shortening of ˜0.02 Å/p K (a) unit. Nevertheless, there is little change in binding affinity across a series of substituted phenolates (ΔΔG = −0.2 kcal/mol/p K (a) unit). The small effect of increased charge localization on affinity occurs despite the shortening of the hydrogen bonds and a large favorable change in binding enthalpy (ΔΔH = −2.0 kcal/mol/p K (a) unit). This shallow dependence of binding affinity suggests that electrostatic complementarity in the oxyanion hole makes at most a modest contribution to catalysis of ˜300-fold. We propose that geometrical complementarity between the oxyanion hole hydrogen-bond donors and the transition state oxyanion provides a significant catalytic contribution, and suggest that KSI, like other enzymes, achieves its catalytic prowess through a combination of modest contributions from several mechanisms rather than from a single dominant contribution

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

BACKGROUND: The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug. METHODS: Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MS(E) analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes. RESULTS: The metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. CONCLUSIONS: Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion

Supplementary data for article: Opsenica, I. M.; Verbić, T. Ž.; Tot, M.; Sciotti, R. J.; Pybus, B. S.; Djurković-Djaković, O.; Slavić, K.; Šolaja, B. A. Investigation into Novel Thiophene- and Furan-Based 4-Amino-7-Chloroquinolines Afforded Antimalarials That Cure Mice. Bioorganic and Medicinal Chemistry 2015, 23 (9), 2176–2186. https://doi.org/10.1016/j.bmc.2015.02.061

Supplementary material for: [https://doi.org/10.1016/j.bmc.2015.02.061]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1691

Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

We herein report the design and synthesis of a novel series of thiophene-and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of b-hematin polymerization. Tested compounds were 3-71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40 mg/kg/day, while 5/5 mice survived in Thompson test at 160 mg/kg/day