ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

C3 amino-substituted chalcone derivative with selective adenosine rA₁ receptor affinity in the micromolar range

Helena D. Janse van Rensburg, Lesetja J. Legoabe, and Gisella Terre’Blanche

Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa

E-mail: Lesetja.Legoabe@nwu.ac.za

Received: 10 March 2020  Accepted: 3 November 2020

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

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01414-9

Chemical Papers 75 (4) 1581–1605 (2021)