1 Ocak 2017 Dergi makalesi Açık Erişim

Unsal-Tan, Oya; Ozadali-Sari, Keriman; Ayazgok, Beyza; Kucukkilinc, Tuba Tuylu; Balkan, Ayla

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    <subfield code="a">This study describes the synthesis, pharmacological evaluation, including acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibition, amyloid beta (A beta) antiaggregation, and neuroprotective effects, as well as molecular modeling of novel 2-(4-substituted phenyl)-1H-benzimidazole derivatives. These derivatives were synthesized by cyclization of o-phenylenediamines with sodium hydroxy(4-substituted phenyl)methanesulfonate salts. In vitro studies indicated that the most of the target compounds showed remarkable inhibitory activity against BChE (IC50: 13.60-95.44 A mu M). Among them, 3d and 3g-i also exhibited high selectivity (SI ae 35.7) for BChE with IC50 values 39.56, 13.60, 14.45, and 15.15 A mu M, respectively. According to the molecular modeling studies, it may be assumed that the compounds are able to reach the catalytic site of BChE but not that of AChE. The compounds showing BChE inhibitory effects were subsequently examined for their A beta-antiaggregating and neuroprotective activities. Among the compounds, 3d inhibited the A beta(1-40) aggregation and demonstrated significant neuroprotection against H2O2-induced and A beta(1-40)-induced cell death. Collectively, compound 3d showed the best multifunctional activity (BChE; IC50 = 39.56 A mu M, SI &amp;gt; 126; A beta self-mediated aggregation; 67.78% at 100 mu M; H2O2-induced cytotoxicity with cell viability of 98% and A beta(1-40)-induced cytotoxicity with cell viability of 127%). All these results suggested that 2-(4-(4-methylpiperidin-1-yl)phenyl)-1H-benzo[d]imidazole (compound 3d) could be a promising multi-target lead candidate against Alzheimer's disease.</subfield>
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    <subfield code="u">Hacettepe Univ, Dept Pharmaceut Chem, Fac Pharm, Ankara, Turkey</subfield>
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