Synthesis and evaluation of chalcones and structurally related compounds as adenosine A₁ and/or A₂ᴀ receptor antagonists for the potential treatment of neurological conditions
Janse van Rensburg, H.D.
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"Abstract not copied"Parkinson’s disease (PD) is now the fastest growing neurological condition worldwide, and regrettably, no drug stops, or at least, slows the neurodegeneration underlying this disease. Fortunately, coffee intake is associated with lower incidence of PD. Caffeine’s mechanism of action is non-selective adenosine receptor (AR) blockade, and as such; A₁ and/or A₂ᴀ AR antagonists hold promise for the potential treatment of PD. The flavonoids are a family of phytochemicals which are even more widespread in the human diet than the xanthine derivative caffeine. There is growing interest in this family of phytochemicals based on their health-related benefits. Notably, many flavonoids possess inhibition constant (Ki) values against ARs in the micromolar-range. As such, extended family members of the flavonoids, namely chalcones and the structurally related benzylidene indanones, -tetralones and benzoyl benzofurans may be a starting point for the design of non-xanthine based A₁ and A₂ᴀ AR antagonists. In order to identify novel AR ligands based on the chalcone scaffold; herein the synthesis, characterization and evaluation of almost 100 chalcones and structurally related compounds are reported. The degree and type of binding affinity that the test compounds showed toward rat (r) A₁ and/or A₂ᴀ ARs were determined via radioligand binding assays and GTP shift assays, respectively. The effect of selected test compounds on the viability of cultured Vero cells were assessed by means of an AlamarBlue®/resazurin assay. The pharmacokinetics, drug-likeness and medicinal chemistry friendliness of the selected test compounds were computed with SwissADME, a free web tool used to evaluate the key parameters of small molecules.
- Health Sciences