Pharmacophore Directed Retrosynthesis Applied to Waixenicin A: Synthesis and Bioactivity of Derivatives Bearing a Minimal Proposed Pharmacophore

Waixenicin A (WaixA) is a marine natural product that has emerged as a potential drug lead for the treatment of hypoxic ischemic brain injury. WaixA specifically blocks the divalent ion channel transient receptor potential melastatin 7 (TRPM7), preventing the influx of calcium into the cell and triggering apoptotic pathways. We applied pharmacophore-directed retrosynthesis to this natural product, leading us to prepare a series of highly simplified derivatives bearing our proposed minimal pharmacophore, namely, the pyranyl vinylogous acetal. The synthesis of these derivatives and their ability to inhibit TRPM7 is described. Inhibition in the 9-57% range was found for these simplified structures in patch-clamp experiments; however, the ability of these highly simplified derivatives to exhibit inhibition provides information regarding minimal structural requirements for bioactivity.