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

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 ) A 1 and A 2A ARs. The chalcone derivatives 24 , 29 , 37 and 38 possessed selective A 1 affinity below 10 µM, and thus, are the most active compounds of the present series; compound 38 was the most potent selective A 1 AR antagonist ( K i ( r ) = 1.6 µM). The structure–affinity relationships (SAR) revealed that the NH 2 -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 r A 1 receptor affinity in micromolar range. Electronic supplementary material The online version of this article (10.1007/s11696-020-01414-9) contains supplementary material, which is available to authorized users.

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

“…The structure, molecular mass and purity of these compounds were verified by hydrogen-1 / protium ( 1 H) and carbon-13 ( 13 C) nuclear magnetic resonance (NMR) spectra, mass spectroscopy and HPLC (see supplementary material). It should be noted that, protons on the NH 2 -group (e.g., 6l ) and the OH-group (e.g., 6k ) are not always visible on a 1 H NMR spectrum as protons attached to a N-atom (or O-atom) are acidic, and thus, exchangeable [ 50 ]. Halogen-carbon bonds tend to cause splitting of 13 C NMR chemical shifts (e.g., 6p and 7a ) due to deshielding by the F-atom on the directly bonded carbon nucleus [ 51 ] which results in multiple carbon peaks.…”

“…The potential interaction of compounds 6c , 6d , 6m , 6o , 6q and 7c with cytochromes P450 (CYP) isoenzymes was also evaluated. This is important for determination of drug-drug interactions and adverse effects due to low drug clearance leading to accumulation of the drug [ 50 , 51 ]. Generally, all the compounds are inhibitors of CYP isoforms (CYP1A2, CYP2C19, CYP2C9, CYP3A4) with a few exceptions, but they did not affect CYP2D6 except compound 6q .…”

Chalcones as Potential Ligands for the Treatment of Parkinson’s Disease

“…A series of 27 amino-substituted chalcones was synthesised by van Rensburg et al [ 66 ] and the effect of the substituent (e.g., halogen) and the position of this substituent on the B ring of the chalcone on the affinity for the rat A 1 R (rat whole membranes) and rat A 2A R (rat striatal membranes) was investigated. The degree and type of binding affinity to these receptors was determined in a radioligand binding and a guanosine triphosphate (GTP) shift assays.…”

“…This compound had a low relative affinity for A 2A R rat (specific binding [ 3 H] NECA of 75% at 100 µM). Structure-activity relationship analysis showed that the amino group in the meta position of the A ring of chalcone and the bromine atom in the meta position of the B ring of chalcone played key roles in the affinity for A 1 R [66]. AR ligands have attracted increasing interest in drug design and development for the treatment of neurodegenerative diseases.…”

Chalcone‐inspired rA1/A2A adenosine receptor ligands: Ring closure as an alternative to a reactive substructure

“…Reaction intermediates (1 and 2) and lead compounds (3, 8 and 9) were synthesised using previously described methods (see Supplementary Material). Lead compounds 4-7 were obtained from a recent study where they were synthesised and reported (Janse van Rensburg et al, 2021).…”