Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer’s Disease

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu­(II)-induced Aβ_1–42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds <b>5d</b> and <b>10d</b> are potential lead compounds for AD therapy (<b>5d</b>, IC₅₀ = 7.56 μM and <b>10d</b>, IC₅₀ = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu­(II)-induced Aβ aggregation. Furthermore, <b>5d</b> crossed the blood–brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that <b>5d</b> is a very promising lead compound for AD

Multitarget-Directed Benzylideneindanone Derivatives: Anti-β-Amyloid (Aβ) Aggregation, Antioxidant, Metal Chelation, and Monoamine Oxidase B (MAO-B) Inhibition Properties against Alzheimer’s Disease

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer’s disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ_1–42) aggregation (10.5–80.1%, 20 μM) and MAO-B activity (IC₅₀ of 7.5–40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75–9.37), and to function as metal chelators. In particular, compound <b>41</b> had the greatest ability to inhibit Aβ_1–42 aggregation (80.1%), and MAO-B (IC₅₀ = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu­(II)-induced Aβ_1–42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound <b>41</b> is an excellent multifunctional agent for the treatment of AD

Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimer’s Disease Based on the Fusion of Donepezil and Ebselen

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer’s disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound <b>7d</b>, one of the most potent acetylcholinesterase inhibitors (IC₅₀ values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC₅₀ = 1.586 μM), to possess rapid H₂O₂ and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν₀ = 123.5 μM min^–1), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood–brain barrier model, <b>7d</b> is able to penetrate the central nervous system

Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract

<div><p>As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound <b>14f</b>) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds <b>4</b>, <b>5</b>, <b>8</b>, <b>14a-e</b>), substitute the phenyl ring with a larger steric hindrance ring (compounds <b>10</b>, <b>17c</b>) or modify the carbon chain (compounds <b>17a</b>, <b>17b</b>, <b>21</b>, <b>23</b>, <b>25</b>). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds <b>5</b>, <b>10</b>, <b>14a</b>, <b>14b</b>, <b>14d</b>, <b>14e</b>, <b>14f</b>, <b>17b</b>, <b>17c</b>, <b>23</b>, and <b>25</b> inhibited AR activity, with IC₅₀ values ranging from 5.02 to 288.8 μM. Compounds <b>5</b>, <b>10</b>, <b>14b</b>, and <b>14f</b> inhibited iNOS activity with IC₅₀ ranging from 432.6 to 1188.7 μM. Compounds <b>5</b>, <b>8</b>, <b>10</b>, <b>14b</b>, <b>14f</b>, and <b>17c</b> protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound <b>10</b> showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts.</p></div

Synthesis of 17, 21, 23, and 25.

<p>Reagents and conditions: a. TsOH, ethanol; 0°C, NaBH₄; b. K₂CO₃, ethanol; c. Pd/C, H₂, RT, 12 h; d. BBr₃, CH₂Cl₂, -20°C, 2 h; RT, 4 h. e. Et₃N, CH₂Cl₂; f. 180°C, neat, N₂.</p

Inhibitory effect of gigantol and its analogs on AR activity¹.

<p>¹The results are expressed as mean ± SD (n = 3).</p><p>Abbreviation: NA, no activity</p><p>*<i>P</i> < 0.01, vs. Extractive gigantol.</p><p>Inhibitory effect of gigantol and its analogs on AR activity<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141092#t001fn001" target="_blank">¹</a>.</p

Gigantol analogs at 0.1, 0.5, and 1.0 μg·mL^-1 on viability of HLECs treated with 250 mmol·L^-1 D-galactose for 72 h.

<p>Cell viability was determined by the MTT assay in the absence (Con) and presence (all other groups) of D-galactose. Ext-G refers to gigantol extracted from dendrobii. Viability (mean ± SD, n = 3) is expressed as the percentage of viable cells in the treatment to those of the Con. ^#<i>P</i> < 0.01 vs. Con, *<i>P</i> < 0.05 vs. D-galactose.</p

Synthesis of 4, 5, 8, 10, 14, and gigantol.

<p>Reagents and conditions: a. NaBH₄, MeOH; b. PBr₃, pyridine, 0°C; c. P(OEt)₃, 120°C; d. different aldehydes, CH₃ONa, 0°C to room temperature (RT), 12 h; e. Pd/C, H₂, RT, 12 h; f. BBr₃, CH₂Cl₂, -20°C, 2 h; RT, 4 h; g. NaH, ethanethiol, DMF, N₂, reflux; h. MOMCl, <i>i</i>-Pr₂NEt, CH₂Cl₂, 0°C, 1 h; RT, 12 h; i. diethyl naphthalen-1-ylmethylphosphonate, CH₃ONa, 0°C, 1 h; rt, 12 h; j. 2 M HCl, methanol, 50°C, 1 h; k. BnBr, 18-crown-6, K₂CO₃, reflux, 9 h.</p

Inhibitory effect of gigantol and its analogs on iNOS activity¹.

<p>¹The results are expressed as mean ± SD (n = 3). Abbreviation: NA, no activity.</p><p>Inhibitory effect of gigantol and its analogs on iNOS activity<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141092#t002fn001" target="_blank">¹</a>.</p