Abstract
Chemical decomposition of DMSO stock solutions is a common incident that can mislead biological screening campaigns. Here, we share our case study of 2‐aminothiazole 1, originating from an antimalarial class that undergoes chemical decomposition in DMSO at room temperature. As previously measured biological activities observed against Plasmodium falciparum NF54 and for the target enzyme PfIspE were not reproducible for a fresh batch, we tackled the challenge to understand where the activity originated from. Solvent‐ and temperature‐dependent studies using HRMS and NMR spectroscopy to monitor the decomposition led to the isolation and in vitro evaluation of several fractions against PfIspE. After four days of decomposition, we successfully isolated the oxygenated and dimerised compounds using SFC purification and correlated the observed activities to them. Due to the unstable nature of the two isolates, it is likely that they undergo further decomposition contributing to the overall instability of the compound.
Highlights
Chemical decomposition of DMSO stock solutions is a common incident that can mislead biological screening campaigns
In the search for novel antimalarial compounds targeting the kinase IspE of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, we identified a new 2-aminothiazole class via an enzymatic high-throughput screening (HTS) campaign
For a newly synthesised batch and the corresponding freshly prepared stock solution of compound 1, no activity against Plasmodium falciparum (Pf) IspE was detected and cellbased activity against the plasmodial strain PfNF54 resulted in an 17-fold reduction in activity (Table 1)
Summary
Henni-Karoliina; Bader, Chantal D; Diamanti, Eleonora; Illarionov, Boris; Rottmann, Matthias; Fischer, Markus; Witschel, Matthias; Müller, Rolf; Hirsch, Anna K H. Bader,[a] Eleonora Diamanti,[a, b] Boris Illarionov,[c] Matthias Rottmann,[d, e] Markus Fischer,[c] Matthias Witschel,[f] Rolf Müller,[a, b] and Anna K. Chemical decomposition of DMSO stock solutions is a common incident that can mislead biological screening campaigns. We share our case study of 2-aminothiazole 1, originating from an antimalarial class that undergoes chemical decomposition in DMSO at room temperature. First evidence of the decomposition was visually observed due to a change in colour of the compound’s stock solution from clear to dark This colour change would only be obvious to someone familiar with the original colour of the parent compound. Stability issues of chemical compounds kept as stock solutions in DMSO are acknowledged and spontaneous reactions, such as oxidation, cyclisation and hydrolysis, in stock solutions may affect the biological
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