HPLC-MS with an Ion Trap Mass Spectrometer

Ion traps have become an important and powerful tool in many fields of analytical chemistry. The immanent sensitivity of the device and the ability to perform MSn opens a wide variety of experimental setups even at very low sample concentration levels. Modern and intelligent instrument control is of particular importance. The spread of ion trap mass spectrometry will greatly enhance the amount of data generated by LC-MS laboratories. The ability to handle and screen the flood of information puts high demands on companies and research facilities to keep pace with these developments

The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro

With artemisinin-resistant Plasmodium falciparum parasites emerging in Africa, the need for new antimalarial chemotypes is persistently high. The ideal pharmacodynamic parameters of a candidate drug are a rapid onset of action and a fast rate of parasite killing or clearance. To determine these parameters, it is essential to discriminate viable from nonviable parasites, which is complicated by the fact that viable parasites can be metabolically inactive, whilst dying parasites can still be metabolically active and morphologically unaffected. Standard growth inhibition assays, read out via microscopy or [3H] hypoxanthine incorporation, cannot reliably discriminate between viable and nonviable parasites. Conversely, the in vitro parasite reduction ratio (PRR) assay is able to measure viable parasites with high sensitivity. It provides valuable pharmacodynamic parameters, such as PRR, 99.9% parasite clearance time (PCT99.9%) and lag phase. Here we report the development of the PRR assay version 2 (V2), which comes with a shorter assay duration, optimized quality controls and an objective, automated analysis pipeline that systematically estimates PRR, PCT99.9% and lag time and returns meaningful secondary parameters such as the maximal killing rate of a drug (Emax) at the assayed concentration. These parameters can be fed directly into pharmacokinetic/pharmacodynamic models, hence aiding and standardizing lead selection, optimization, and dose prediction

Blood schizontocidal and gametocytocidal activity of 3-hydroxy-N'-arylidenepropanehydrazonamides

3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a <1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro

Blood Schizontocidal and Gametocytocidal Activity of 3‑Hydroxy‑<i>N</i>′‑arylidenepropane­hydrazonamides: A New Class of Antiplasmodial Compounds

3-Hydroxy-<i>N</i>′-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of <i>Plasmodium falciparum</i> with nanomolar IC₅₀ values in the range of 8–28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a <i>P. berghei</i> malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound <b>29</b> displays selective activity against <i>P. falciparum</i>. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of <i>P. falciparum</i> in vitro