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 GABA_B 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 GABA_B receptor agonists.