Synthesis and Structure Activity Relationships of Chalcone based Benzocycloalkanone Derivatives as Adenosine A1 and/or A2A Receptor Antagonists

Abstract

Adenosine A1 and/or A2A receptor antagonists hold promise for the potential treatment of neurological conditions, such as Parkinson’s disease. Herein, a total of seventeen benzocycloalkanone derivatives were synthesised and evaluated for affinity towards adenosine receptors (A1 and A2A AR). The obtained results allowed for the conclusion that affinity and/or selectivity of the 2-benzylidene-1-indanone and -tetralone derivatives toward A1 and/or A2A ARs may be modulated by the nature of the substituents (either -OH, -OCH3 or morpholine) attached at position C4 of the 1-indanone core and C5 of the 1-tetralone core as well as the meta (C3’) and/or para (C4’) position(s) on ring B. Several compounds (2a–b, 3b–c and 4a–b) possessed affinity for the A1 and/or A2A AR below 10 µM. Additionally, compounds 2a, 3b and 4a were A1 AR antagonists. These results, once again, confirmed the importance of C4 methoxy-group substitution on ring A in combination with meta (C3’) and/or para (C4’) hydroxyl-group substitution ring B of the 2-benzylidene-1-indanone scaffold leading to drug-like compounds 1h and 1j with affinity in the nanomolar-range.

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

“…Van Rensburg et al in two other works described 2-benzylidene-1-indanone derivatives as A 1 R and/or A 2A R ligands [ 68 , 69 ]. The effect of substituents (-OH, -OCH 3 , or -N(CH 3 ) 2 ) and their position on the A and/or B ring of the chalcone moiety was investigated.…”

“…The effect of substituents (-OH, -OCH 3 , or -N(CH 3 ) 2 ) and their position on the A and/or B ring of the chalcone moiety was investigated. In the first work, 12 compounds [ 68 ] were described whereas in the second work 14 compounds were described [ 69 ]. First, authors changed the position of substituents in both A (only methoxy group) and B rings whereas in the second study they further investigated these changes with substituents in the best position from the first studies.…”

“…In the case of a methoxy group, it causes a decrease in affinity for A 1 R and A 2A R when located on the B ring. The most active compound of this series turned out to be compound 40 ( Figure 30 ), which showed affinities for both adenosine receptors in submicromolar ranges (A 1 R rat K i = 0.79 µM; A 2A R rat K i = 0.44 µM) [ 69 ]. Intrinsic activity profile studies were performed only for compound 40 and interactions with the A 1 R. The GTP shift test confirmed the activity of 40 as an A 1 R antagonist.…”

“… 2-Benzylidene-1-indanone as adenosine A 1 and A 2A receptor ligands and the most potent compounds in this series [ 68 , 69 ]. …”

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

“…Continuing this concept, the same scientists designed and synthesized another series of benzocycloalkanone analogs by exchanging substituents in benzene rings. Among others, compound 2a ( 5 in Figure 2 ) with improved A 2A /A 1 receptor affinity ratio ( Table 1 ) was reported [ 80 ]. An interesting approach consisting in dual-targeting of adenosine A 2A and dopamine D 2 receptor was exploited by Shao et al, resulting in discovery of indolylpiperazinylpyrimidine derivatives as novel potential antiparkinsonian agents.…”