Design, Synthesis and Biological Evaluation of Potent Antioxidant 1-(2,5-Dimethoxybenzyl)-4-arylpiperazines and N-Azolyl Substituted 2-(4-Arylpiperazin-1-yl)

We describe here the synthesis, antioxidant capacity, and biological activities on MAO, ChE, and selected GPCRs, of novel 1-(2,5-dimethoxybenzyl)-4-arylpiperazines 1-10, as well as known N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl))-2-(4-arylpiperazin- 1-yl) 11-20 and N-(5-nitrothiazol-2-yl)-2-(4-arylpiperazin-1yl) 21-29. Some of the new 4-arylpiperazines were found to have low-micromolar affinities for the proteins tested. The most potent MAO inhibitor identified was compound 2-(4-(3-fluorophenyl)- yl)-N-(5-nitrothiazol-2-yl)(27), with an IC50 value of 4.14 +/- 0.5 mM, whereas the most potent interaction with a GPCR the 5-HT6 serotonin receptor, with a Ki value of 0.7 mu M. Interestingly, some of the compounds described here showed impressive antioxidant potential. Of mention, compounds 1, 6, 7, and 23 had trolox/equivalent ORAC values of 9.10, 8.80, 8.82, and 9.42, respectively, all of them being significantly higher than the TE determined for ferulic acid (3.74), a standard antioxidant. Among all molecules synthesized and tested, compound 23 can be regarded as an interesting low-micromolar MAO B/5-HT6 dual inhibitor lead with potent antioxidant properties.