DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF POTENT 1-(2,5-DIMETHOXY-BENZYL)-4-ARYLPIPERAZINES

Haythem A. Saadeh, Mohammad A. Khasawneh, Abdelouahid Samadi and Ismail A. El-Haty

Department of Chemistry, United Arab Emirates University, Al Ain, United Arab Emirates

Abstract

Design, Synthesis and Biological Evaluation of Potent 1-(2,5-Dimethoxybenzyl)-4-arylpiperazines Haythem A. Saadeh, Mohammad A. Khasawneh*, Abdelouahid Samadi, Ismail A. El-Haty, Grzegorz Satala, Andrzej J. Bojarski, Lhassane Ismaili, Óscar M. Bautista-Aguilera, Matilde Yañez, Jordi Mestres, and José Marco-Contelles* We describe here the synthesis, antioxidant capacity, and biological activitiy on MAO, ChE, and selected GPCRs, of several novel 1-(2,5-dimethoxybenzyl)-4-arylpiperazines that have a variety of substituents on the phenyl ring including electron withdrawing and electron donating substituents. The synthesis of these compounds was carried out using easily available precursors and following well known synthetic procedures. Reduction of commercial 2,5-dimethoxybenzaldehyde with NaHB4 at 0°C to the corresponding alcohol followed by bromination with hydrobromic acid at 0°C, gave 2-(bromomethyl)-1,4-dimethoxybenzene in good yield. In a final step, the reaction of intermediate with a series of commercial piperazines afforded the desired products, in moderate to good yields. Some of the new 4-arylpiperazines were found to have low-micromolar affinities for the proteins tested. The most potent interaction with a GPCR was 1-(2,5-Dimethoxybenzyl)-4-(4-trifluoromethylphenyl) piperazine for the 5-HT6 serotonin receptor, with a Ki value of 0.7 M. Interestingly, some of the compounds described here showed impressive antioxidant potential. Of mention, 4-Phenyl piperazine, 4-chlorophenyl piperazine and 4-fluorophenyl piperazine had trolox/equivalent ORAC values of 9.10, 8.80, and 8.82, respectively, all of them being significantly higher than the TE determined for ferulic acid (3.74), a standard antioxidant.

Keywords: 1-(2,5-Dimethoxybenzyl)-4-arylpiperazines, MAO/ChE inhibition, coupled G-receptors, antioxidants.