Aims and Current Interest in Series 3
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Lead optimisation, to improve solubility and metabolic stability while maintaining potency.
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Validation of PfAsnRS activity as a mechanism of action via experimental and computational means.
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To source more chemical and biological inputs from the widest possible community (cross-screening).
Edited by Yinuo, currently PhD student working on OSM-S3
Based on the current SAR understanding, any small change in geometry will cause a loss in IC50 potency. For more information 2024 OSMS3 paper and All Analogs Evaluated to Date.
Making single atom replacements (such as adding pyridine or replacing H with F) is a good start for further modifications. Sulfamate analogues are thermally unstable, so they are a lower priority for synthesis.
- Rationale 1: There is no interaction with the sulfonamide aromatic ring from docking studies, so we wonder if adding pyridine will lead to new interactions.
- Rationale 2: 106 showed a very high clearance rate in a mouse model, and one of our collaborators wonders if the metabolic point of 106 is at the 3-position of the aromatic ring. Replacing H with F might affect the metabolism rate.
The current issues with these analogues are mentioned in this issue. The challenge of achieving super low yields in direct borylation on the thienopyrimidine core 4 has received a lot of support from passionate organic chemists on online platforms. See the LinkedIn Post . Exploring these ideas and reaction parameters will be carried out using the automated chemistry platform (CAR) at XChem, Diamond Light Source.
We naturally wondered about the activity of the other 106-aa derivatives of the molecule because we expect all the 106-aa adducts to show activity. The 106-aa adduct will not easily cross membranes, but the schizont stage is quite permeable, so we expect activity in a 72-hour assay. For example, the synthetic 106-Asn adduct was tested against 3D7 and showed an IC value of 120 nM.
OSM-LO-91 (OSM-S-106-Proline adduct, YNW69) showed great inhibition against Pf3D7 and no cytotoxicity against HepG2. The idea to start with Proline came from Leann's group; AMS could generate an AMS-Pro adduct LCMS peak in E. coli. AMS is an adenosine sulfamate that inhibits Pf aa-tRNA synthetase.
