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Summary of the ArylPyrrole Data
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Here is a summary of the biological data obtained for the aryl pyrroles to date:
The team have been looking for patterns in the data ahead of the next consultation. The scheme below concisely displays the patterns that have been identified at this stage of the project. More detailed analysis including the structures and activities of all compounds that have been biologically evaluated can be found on the OSDD Malaria G+ page.
- The activity of the original GSK hit (OSM-S-5, 404 nM) has only been matched by (OSM-S-6, 345 nM), which features an extension of the terminal amide into a pyrazolone. The COOCH2CONH2 head group seems to be integral to activity.
- Replacement of the primary ester linkage (tertiary ester OSM-S-68, amine or amide) significantly reduces or kills activity.
- Substitution of the terminal amide with methyl groups, sequentially reduces activity (OSM-S-82 and 91), however substitution with the pyrazolone enhances activity (OSM-S-6).
- A number of 'pro-drugs' were also investigated and found to be in-active (OSM-S-4 is a representative example).
- Replacing the aryl pyrrole core with a pyrazole also kills the activity (OSM-S-92).
The active compounds have been shown to possess zero oral efficacy in mice, so in addition to finding active compounds, this issue needs to be addressed.