Evaluation of chemical constituents of Rooibos (Aspalathus linearis) and Honeybush (Cyclopia intermedia) as adenosine A1/A2A receptor ligands

Abstract

Rooibos (Aspalathus linearis) and Honeybush (Cyclopia intermedia) are popular tisanes in South Africa and are of growing interest due to the wide variety of flavonoids and other phytochemicals they contain. Despite their history as herbal teas and traditional medicines, the chemical constituents of these tisanes have yet to be studied for their effects on adenosine receptors. A series of 30 commercially available chemical constituents of Rooibos and Honeybush were investigated via radioligand binding studies to determine their adenosine A1 and A2A receptor affinity at both rat and human subtypes in order to establish structure-activity relationships and identify novel adenosine receptor ligands. In addition, in silico evaluations of the 30 test compounds were also performed to predict their physiochemical and pharmacokinetic properties. The most promising chemical constituent was kaempferol (28) which showed sub-micromolar affinity towards the rat A1 subtype (rA1Ki = 0.7287 μM; hA1Ki = 9.88 µM) and acted as an antagonist toward adenosine rA1 receptors. Additionally, quercetin (2), chrysoeriol (8), luteolin (9), eriodyctiol (12), and naringenin (27) also showed adenosine A1 and/or A2A receptor affinity. It was observed that a flavonol scaffold is preferred to flavone and flavanone scaffolds, and within the flavonols, C4’-OH substitution on ring B is preferred to C3’,4’-diOH substitution. These phytochemicals, specifically kaempferol (28), may be considered lead-like and valuable in designing novel ligands, based on in vitro and in silico evaluation.