Synthesis, docking study and β-adrenoceptor activity of some new oxime ether derivatives

Abstract

A new series of oxime ethers 4a-z was designed and synthesized to test the blocking activity against β₁ and β₂-adrenergic receptors. Docking of these ether derivatives into the active site of the identified 3D structures of β₁ and β₂-adrenergic receptors showed MolDock scores comparable to those of reference compounds. Biological results revealed that the inhibition effects on the heart rate and contractility are less than those of propranolol. Nevertheless, the two compounds 4p and 4q that displayed the highest negative MolDock score with β₂-adrenergic receptors showed β₂-antagonistic activity by decreasing salbutamol relaxation of precontracted tracheal strips, which indicates the importance of a chlorothiophene moiety in the hydrophobic region for best complementarity with β₂ receptors. On other hand, the presence of a homoveratryl moiety increases the MolDock score of the tested compounds with the β₁ receptor.

Figure 1

Chemical structures of IPS 339 and falintolol.

Scheme 1

Synthesis of the oxime ethers 4a–z.

Figure 2

Chemical structures of propranolol and cyanopindolol.

Figure 3

(a) Docking snapshot of compound 4o with β₁ receptor. (b) Docking snapshot of compound 4q with β₂ receptor. Compounds are represented as stick (thick lines) while the amino acids of the active site of the β2-adrenoreceptor appear as (light) lines. Hydrogen atoms in both ligands and receptors have been omitted for clarity. Blue dashed lines indicate the hydrogen bonds.