Pyrazine Side Chain Modifications Reversed Amides

Compounds were made with the amide "reversed", i.e. the N atom attached to the pyrazine ring. The acetamide (OSM-W-6) demonstrated marginal activity, but incurred an approximate order of magnitude loss in potency as compared to amide MMV669543. The one carbon homolog OSM-W-7 was found to be inactive for both lines evaluated (Dd2 and 3D7). OSM-S-272 (MMV639565) (resynthesised) was used as a positive control in the assay. OSM-W-9 was synthesized to provide a compound that could serve as a bridge in the SAR between analogs containing the para-Cyano moiety versus the para-Difluoromethoxy.

Additionally, when OSM-W-7 was evaluated in the aldehyde oxidase assay, the compound displayed moderate clearance, meaning the amide reversal did not prevent the molecule being a substrate for that enzyme (which was the original intent). Furthermore, OSM-W-7 also showed rapid clearance in a generalized HLM stability assay.