C3 amino-substituted chalcone derivative with selective adenosine r A1 receptor affinity in the micromolar range

Helena D Janse van Rensburg; Lesetja J Legoabe; Gisella Terre'Blanche

doi:10.1007/s11696-020-01414-9

C3 amino-substituted chalcone derivative with selective adenosine r A₁ receptor affinity in the micromolar range

Chem Zvesti. 2021;75(4):1581-1605. doi: 10.1007/s11696-020-01414-9. Epub 2020 Nov 17.

Authors

Helena D Janse van Rensburg¹, Lesetja J Legoabe¹, Gisella Terre'Blanche^{1

2}

Affiliations

¹ Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.
² Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.

Abstract

Abstract: To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synthesis, characterization and in vitro and in silico evaluation of 33 chalcones (15-36 and 37-41) and structurally related compounds (42-47) are reported. These compounds were characterized by radioligand binding and GTP shift assays to determine the degree and type of binding affinity, respectively, against rat (r) A₁ and A_2A ARs. The chalcone derivatives 24, 29, 37 and 38 possessed selective A₁ affinity below 10 µM, and thus, are the most active compounds of the present series; compound 38 was the most potent selective A₁ AR antagonist (K _i (r) = 1.6 µM). The structure-affinity relationships (SAR) revealed that the NH₂-group at position C3 of ring A of the chalcone scaffold played a key role in affinity, and also, the Br-atom at position C3' on benzylidene ring B. Upon in vitro and in silico evaluation, the novel C3 amino-substituted chalcone derivative 38-that contains an α,ß-unsaturated carbonyl system and easily allows structural modification-may possibly be a synthon in future drug discovery.

Graphic abstract: C3 amino-substituted chalcone derivative (38) with C3' Br substitution on benzylidene ring B possesses selective adenosine rA₁ receptor affinity in micromolar range.

Keywords: Base- and acid-catalysed Claisen–Schmidt condensation reactions; Chalcone; Neurological conditions; Schiff base; Selective adenosine A1 receptor antagonist.