Synthesis and Structure Activity Relationships of Chalcone based Benzocycloalkanone Derivatives as Adenosine A₁ and/or A_2A Receptor Antagonists

Abstract

Adenosine A₁ and/or A_2A 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 A_2A 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 A_2A 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 A_2A 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.

Key words

2-Benzylidene-1-tetralone derivatives - 2-Benzylidene-1-indanone derivatives - acid catalysed aldol condensation reaction - neurological conditions

• References

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