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)-4H-chromen-4-one (7).

Chromone Scaffolds in the Treatment of Alzheimer's and Parkinson's Disease: An Overview

“…In 2019, Lemke et al [66] reported a series of chromones as multi-target small molecules. Among all the derivatives, chromenone 41 (Figure 32) revealed as a potent dual-target agent with potency against AChE and MAOÀ B.…”

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

“…Further, Lemke et al 93 synthesized a library of substituted chromen-4-ones as multi-target-directed ligands for neurodegenerative therapy. The results highlighted the compound 6-(4-(piperidin-1-yl)butoxy)-4 H -chromen-4-one 26 as the dual-target most potent inhibitor against AChE and MAO-B with IC 50 values of 5.58 and 7.20 μM, respectively.…”

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer’s Disease Therapy

“…Thus, this simple design and recent communication on related chromenones [16] led us to select "quinolinones" (I, QN) and "dihydroquinolinones" (II, DQN) (Figure 1) as the MSM of choice, on the basis of the availability of the starting materials, as well as the simple synthetic schemes to However, in our current research project, one of the main concerns was the irreversible MAO inhibition shown by contilisant (Figure 1). Although this could be a point of debate [12], we decided to design new ligands behaving pharmacologically like contilisant, but acting as MAO-reversible inhibitors.…”

“…Thus, this simple design and recent communication on related chromenones [16] led us to select "quinolinones" (I, QN) and "dihydroquinolinones" (II, DQN) (Figure 1) as the MSM of choice, on the basis of the availability of the starting materials, as well as the simple synthetic schemes to synthesize them. Quinolinones have been previously described, with the antipsychotic drug "brexpiprazole" [17] (Figure 1) being one of the best known examples.…”