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<p>A group of sixteen symmetric (1,4-diazepane-1,4-diyl)bis(phenylmethanone) derivatives (<b>3a–p</b>) containing a 1,4-diazepane scaffold were designed, synthesized, and evaluated as potential inhibitors of Aβ42 and Aβ40 aggregation. In the in vitro fluorescence aggregation kinetics compounds <b>3k</b> (R = naphthalen-1-yl) and <b>3o</b> (R = benzo[<i>d</i>][1,3]dioxole) exhibited concentration-dependent inhibition of Aβ42 aggregation, with compound <b>3k</b> demonstrating 50% inhibition of aggregation whereas compound <b>3o</b> exhibited 33% inhibition at 25 µM. In the Aβ40 aggregation assay, compounds <b>3c</b> and <b>3o</b> demonstrated superior inhibitory activity, with inhibition ranging from 60–63%. These findings were corroborated by transmission electron microscopy, which confirmed reductions in both Aβ42 and Aβ40 fibril load in the presence of 1,4-diazepane derivatives <b>3c</b>, <b>3k</b> and <b>3o</b>. The dual Aβ42 and Aβ40 aggregation inhibitor <b>3o</b> identified from this study was not toxic to mouse hippocampal HT22 cells (cell viability ⁓96% at 25 µM) and demonstrated significant reductions in Aβ42-induced cytotoxicity at 25 µM (⁓48% cell viability) compared to Aβ42-alone treated group (37% cell viability). Furthermore, <b>3o</b> demonstrated neuroprotective effects in hydrogen peroxide-induced cytotoxicity and ability to get into the brain in the in vitro blood-brain barrier permeation assay. Computational studies showed that compound <b>3o</b> binds within the narrow channel formed by the N- and C-terminal residues of Aβ42 pentamer and Aβ40 dimer models, potentially stabilizing the peptide assemblies and inhibiting further aggregation. These results highlight the application of conformationally flexible sp3 hybridized 1,4-diazepane scaffold as a promising and novel template to design novel dual inhibitors of both Aβ42 and Aβ40 aggregation.</p><p></p>

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Synthesis and evaluation of symmetric (1,4-diazepane-1,4-diyl)bis(phenylmethanone) derivatives as amyloid-beta aggregation inhibitors

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Rahul C. Karuturi,
  • Ahmed A. Hefny,
  • Yusheng Zhao,
  • Arash Shakeri,
  • Samala Venkateswarlu,
  • Praveen P. N. Rao

摘要

A group of sixteen symmetric (1,4-diazepane-1,4-diyl)bis(phenylmethanone) derivatives (3a–p) containing a 1,4-diazepane scaffold were designed, synthesized, and evaluated as potential inhibitors of Aβ42 and Aβ40 aggregation. In the in vitro fluorescence aggregation kinetics compounds 3k (R = naphthalen-1-yl) and 3o (R = benzo[d][1,3]dioxole) exhibited concentration-dependent inhibition of Aβ42 aggregation, with compound 3k demonstrating 50% inhibition of aggregation whereas compound 3o exhibited 33% inhibition at 25 µM. In the Aβ40 aggregation assay, compounds 3c and 3o demonstrated superior inhibitory activity, with inhibition ranging from 60–63%. These findings were corroborated by transmission electron microscopy, which confirmed reductions in both Aβ42 and Aβ40 fibril load in the presence of 1,4-diazepane derivatives 3c, 3k and 3o. The dual Aβ42 and Aβ40 aggregation inhibitor 3o identified from this study was not toxic to mouse hippocampal HT22 cells (cell viability ⁓96% at 25 µM) and demonstrated significant reductions in Aβ42-induced cytotoxicity at 25 µM (⁓48% cell viability) compared to Aβ42-alone treated group (37% cell viability). Furthermore, 3o demonstrated neuroprotective effects in hydrogen peroxide-induced cytotoxicity and ability to get into the brain in the in vitro blood-brain barrier permeation assay. Computational studies showed that compound 3o binds within the narrow channel formed by the N- and C-terminal residues of Aβ42 pentamer and Aβ40 dimer models, potentially stabilizing the peptide assemblies and inhibiting further aggregation. These results highlight the application of conformationally flexible sp3 hybridized 1,4-diazepane scaffold as a promising and novel template to design novel dual inhibitors of both Aβ42 and Aβ40 aggregation.