Design and synthesis of 3,5-disubstituted isoxazoles by Cu-mediated 1,3-dipolar cycloaddition and their in silico evaluation as potential GABAB receptor modulators

In this work, we report the synthesis of three series of 3,5-disubstituted isoxazoles (4a-d, 5a-d and 6a-d), as analogues of the clinically important drug baclofen. The isoxazole ring systems were assembled through the key copper-catalyzed 1,3-dipolar cycloaddition reaction between a nitrile oxide (generated in situ from nitro compounds) and an alkyne. An X-ray crystallography study shows that the 1,3-dipolar cycloaddition reactions proceeded with very high regioselectively, leading exclusively to the formation of the 3,5-disubstituted regio isomers. Additionally, it was possible to obtain these compounds in enantiomerically pure form using SuperQuat-type chiral auxiliary. As suggested by our QSAR analysis and docking studies, these analogues have the potential to be biologically active as GABAB receptor modulators. Finally, the absorption, distribution, properties of metabolism and excretion (ADME) of the synthesized molecules was also determined by a computational approach. From this work we obtained five molecules ((S)-4d, (S)-5b, (S)-6b, (S)-6c and (S)-6d) as potential GABAB receptor agonists. [Display omitted]