TY - JOUR
T1 - Design, Synthesis and Biological Evaluation of Potent Antioxidant 1-(2,5-Dimethoxybenzyl)-4-arylpiperazines and N-Azolyl Substituted 2-(4-Arylpiperazin-1-yl)
AU - Saadeh, Haythem A.
AU - Khasawneh, Mohammad A.
AU - Samadi, Abdelouahid
AU - El-Haty, Ismail A.
AU - Satała, Grzegorz
AU - Bojarski, Andrzej J.
AU - Ismaili, Lhassane
AU - Bautista-Aguilera, Óscar M.
AU - Yañez, Matilde
AU - Mestres, Jordi
AU - Marco-Contelles, José
N1 - Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2017/5/2
Y1 - 2017/5/2
N2 - 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-1-yl) 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 μM, whereas the most potent interaction with a GPCR was 1-(2,5-dimethoxybenzyl)-4-(4-trifluoromethylphenyl) (5) for the 5-HT6 serotonin receptor, with a Ki value of 0.7 μM. 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.
AB - 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-1-yl) 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 μM, whereas the most potent interaction with a GPCR was 1-(2,5-dimethoxybenzyl)-4-(4-trifluoromethylphenyl) (5) for the 5-HT6 serotonin receptor, with a Ki value of 0.7 μM. 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.
KW - 1-(2,5-dimethoxybenzyl)-4-arylpiperazines
KW - Antioxidants
KW - MAO/5-HT6 modulators
KW - N-azolyl substituted 2-(4-arylpiperazin-1-yl)
KW - coupled G-receptors
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U2 - 10.1002/slct.201700397
DO - 10.1002/slct.201700397
M3 - Article
AN - SCOPUS:85041554865
SN - 2365-6549
VL - 2
SP - 3854
EP - 3859
JO - ChemistrySelect
JF - ChemistrySelect
IS - 13
ER -