Chromenones as Multineurotargeting Inhibitors of Human Enzymes

Abstract

The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC₅₀ values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4<i>H</i>-chromen-4-one (<b>7</b>).