4-Acyl-3,4-dihydropyrrolo[1,2-a]pyrazine Derivative Rescued the Hippocampal-Dependent Cognitive Decline of 5XFAD Transgenic Mice by Dissociating Soluble and Insoluble Aβ Aggregates

Abstract

Cerebral amyloid-β (Aβ) deposition is a representative hallmark of Alzheimer's disease (AD). Development of Aβclearing small molecules could be an advantageous therapeutic strategy for Aβ clearance considering the advantages in terms of side effects, cost-effectiveness, stability, and oral bioavailability. Here, we report an Aβ-dissociating small molecule, YIAD-0121, a derivative of 4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazine. Through a series of anti-Aβ screening assays, YIAD-0121 was identified to inhibit Aβ aggregation and dissociate preformed Aβ fibrils in vitro. Furthermore, the administration of YIAD-0121 in 5XFAD transgenic AD mice inhibited the increase of cerebral Aβ aggregation and progression of hippocampus-dependent cognitive decline, with ameliorated neuroinflammation.

Anticancer Evaluation of Novel Benzofuran–Indole Hybrids as Epidermal Growth Factor Receptor Inhibitors against Non-Small-Cell Lung Cancer Cells

“…2-Hydroxy-2-(6-hydroxybenzo[ d ][ 1 , 3 ]dioxol-5-yl)-1-phenylethan-1-one (7n). Ivory solid, mp: 139.2–139.9 °C (72 mg, 80%); 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 6.48 (s, 1H), 6.44 (s, 1H), 6.31 (s, 1H), 6.21 (d, J = 4.4 Hz, 1H), 5.82 (d, J = 4.0 Hz, 2H), 4.55 (d, J = 4.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.0, 149.3, 148.6, 141.8, 134.1, 133.3, 129.0, 128.7, 116.7, 107.4, 101.3, 99.6, 71.7; HRMS (ESI-QTOF) m / z [M+Na] + calcd for C 15 H 12 NaO 5 295.0577, found 295.0592.…”

“…1-(4-Bromophenyl)-2-hydroxy-2-(6-hydroxybenzo[ d ][ 1 , 3 ]dioxol-5-yl)ethan-1-one (7o). Ivory solid, mp: 108.1–108.8 °C (81 mg, 70%); 1 H NMR (400 MHz, (CD 3 ) 2 SO) δ 9.62 (s, 1H), 7.87 (d, J = 6.8 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H), 6.40 (s, 1H), 6.12 (s, 1H), 5.88 (s, 1H), 5.84 (s, 1H), 5.68 (s, 1H); 13 C NMR (100 MHz, (CD 3 ) 2 SO) δ 198.6, 149.4, 147.7, 140.4, 134.4, 132.1, 130.6, 127.7, 118.0, 107.5, 101.3, 98.1, 69.7; HRMS (ESI-QTOF) m / z [M+Na] + calcd for C 15 H 11 BrNaO 5 372.9682, found 372.9685.…”

“…3-(6-(4-Bromophenyl)-[ 1 , 3 ]dioxolo[4,5- f ]benzofuran-7-yl)-5-methyl-1 H -indole (8w). Brown solid, mp: 205.4–206.0 °C (32 mg, 89%); 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.13–7.09 (m, 2H), 7.06 (s, 1H), 6.78 (s, 1H), 5.99 (s, 2H), 2.36 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 149.5, 149.2, 146.6, 144.6, 134.6, 131.4, 130.2, 129.6, 127.3, 126.7, 124.7, 124.3, 123.5, 121.3, 119.9, 111.5, 111.0, 106.9, 101.3, 99.1, 93.3, 21.5; HRMS (ESI-QTOF) m / z [M+H] + calcd for C 24 H 16 BrNO 3 445.0314, found 445.0315.…”

“…Accordingly, the generation of new drug-like chemical scaffolds and their derivatives for biological screening is highly desired. Against this backdrop, we were able to find several chemical motifs (I–VI) with significant pharmacological functions through the synthesis and biological evaluation of novel heterocycles ( Figure 1 ) [ 1 , 2 , 3 ].…”

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…Using the ThT assay, Kim et al initially screened various derivatives of a small molecule that they have synthesized. 26 Sulfate−polyacrylamide gel electrophoresis (SDS−PAGE) analysis coupled with photoinduced cross-linking of unmodified proteins (PICUPs) was used to assess the distribution of Aβ species in the ThT assay. Then, blood brain barrier (BBB)specific parallel artificial membrane permeability assay (PAMPA) was used to screen brain penetration in vitro.…”