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<p>The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds <b>IM-5</b> and <b>IM-10</b> exhibited the best inhibitory activities with IC<sub>50</sub> value of 12.4&#xa0;μM and 15.6&#xa0;μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5&#xa0;μM, respectively. ThT assay revealed compounds <b>IM-5</b> and <b>IM-10</b> exhibited the optimal Aβ<sub>1-42</sub> self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20&#xa0;μM. In addition, compounds <b>IM-5</b> and <b>IM-10</b> exhibited low cytotoxicities and significant neuroprotective effects on Aβ<sub>1-42</sub>-induced and H<sub>2</sub>O<sub>2</sub>-induced SH-SY5Y cell injury. More importantly, compounds <b>IM-5</b> and <b>IM-10</b> could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds <b>IM-5</b> and <b>IM-10</b> which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds <b>IM-5</b> and <b>IM-10</b> showed high <i>h</i>MAO-B inhibitory potency. In summary, all above results revealed compounds <b>IM-5</b> and <b>IM-10</b> might be promising multifunctional agents for AD treatment.</p>

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Development of novel melatonin-isatin hybrids as multifunctional agents for Alzheimer’s disease

  • 期刊论文

  • 发表日期：

    2025年3月4日

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  • Ying-Ying Zhong,
  • Jun‑Ze Deng,
  • Qin Wang,
  • Li Chen,
  • Zi-Hang Yang,
  • Ya-Mei Zhang,
  • Lu‑Yi Zhou,
  • Yi-Ran Li,
  • Jia-Qiang Wu,
  • Xiao-Qin Wang

摘要

The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC50 value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ1-42-induced and H2O2-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.