Novel Pyridine-Containing Sultones: Structure-Activity Relationship and Biological Evaluation as Selective AChE Inhibitors for the Treatment of Alzheimer's disease |
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Authors: | Hong Zhang Chengyao Wu Xing Chen Ziwen Zhang Xia Jiang Dr. Hua-Li Qin Dr. Wenjian Tang |
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Affiliation: | 1. Department of Pharmacy, Fuyang People's Hospital of AHMU, Anhui Medical University, Fuyang, 236000 China These authors contributed equally to this work.;2. School of Pharmacy, Anhui Medical University, Hefei, 230032 China These authors contributed equally to this work.;3. School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070 China;4. School of Pharmacy, Anhui Medical University, Hefei, 230032 China |
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Abstract: | Novel pyridine-containing sultones were synthesized and evaluated for their cholinesterase (ChE) inhibitory activity. Most of compounds showed selective acetylcholinesterase (AChE) inhibitory activity. The structure-activity relationship (SAR) showed: (i) the fused pyridine-containing sultones increase AChE inhibition, series B >series A ; (ii) for series A , the effect of the 4-substituent on AChE activity, p->m- or o-; (iii) for series B , a halophenyl group increase activity. Compound B4 (4-(4-chlorophenyl)-2,2-dioxide-3,4,5,6-tetrahydro-1,2-oxathiino[5,6-h]quinoline) was identified as a selective AChE inhibitor (IC50=8.93 μM), and molecular docking studies revealed a good fit into TcAChE via hydrogen interactions between the δ-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive (Ki=7.67 μM) AChE inhibition, nontoxicity and neuroprotective activity. In vivo studies confirmed that compound B4 could ameliorate the cognitive performance of scopolamine-treated C57BL/6 J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD. |
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Keywords: | Acetylcholinesterase pyridine sultone SuFEx Alzheimer's disease |
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