Discovery of novel melatonin–mydroxyquinoline hybrids as multitarget strategies for Alzheimer’s disease therapy

Alzheimer’s disease (AD) is a neurodegenerative disease that seriously affects human health, and current treatment strategies are far from meeting clinical needs. Inspired by multi-target drug design strategies, a series of novel natural products-based melatonin–hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal-chelating at the same time. Most of the compounds showed significant oxygen radical absorbance capacity and Aβ_1–42 aggregation inhibition. Moreover, the compounds possess good blood-brain barrier permeability. 6b and 6c have a good ability to alleviate oxidative stress induced by hydrogen peroxide. 6b and 6c possess metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal-induced Aβ aggregation. This work may provide a new multi-target treatment strategy for Alzheimer’s disease.

1 Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment, whose impact will be even more profound as the global population continues to age (Scheltens et al., 2021; Author Anonymous, 2023). The number of people affected by AD worldwide is estimated to rise from 55 million in 2020 to 135 million by 2050 (Author Anonymous, 2023). The global cost of treating AD is estimated at approximately 2.8 trillion dollars, which will create a huge social burden. The development of safe and effective anti-AD drugs has always been the hot spot in medical chemistry.

The pathogenesis of AD is complex, and many hypotheses were proposed, including the cholinergic hypothesis, the beta-amyloid cascade hypothesis, the oxidative stress hypothesis, the metal ion disorder hypothesis, etc. In the past years, major research institutions and pharmaceutical companies have invested hundreds of billions of dollars in AD. At present, the drugs that have been approved, such as AChE inhibitors and NMDAR inhibitors, only alleviate the symptoms or make them slightly better, and there is no specific drug that can completely cure AD (Cerejeira et al., 2012; Marcinkowska et al., 2021). Therefore, more and more researchers have turned their attention to the multi-target design strategy. Multi-target drugs are expected to become a breakthrough in the treatment of AD (Rossi et al., 2021; Babaei et al., 2022; Turgutalp et al., 2022).

Melatonin (MT) is a neurohormone secreted by the pineal gland (Somalo-Barranco et al., 2022). As an endogenous natural active substance of the human body, accumulating reports suggest that melatonin has excellent antioxidant activity and a protective effect on nerve cells (He et al., 2022). Besides, MT can also chelate heavy metals, including lead, cadmium, and aluminum, while chelating iron and copper can reduce oxidative stress in the body (Reiter et al., 2016). Furthermore, clinical studies have shown that melatonin can improve cognition and mood in Alzheimer’s patients (Dowling et al., 2008). In the meantime, the imbalance of metal ions in the brain will accelerate the aggregation of Aβ and Tau proteins resulting in cognitive decline. Hence, metal ion chelators, such as hydroxyquinoline derivative clioquinol (CQ) are considered potential drugs for the treatment of AD (Adlard et al., 2008; Faux et al., 2010). From this, a hypothesis can be proposed that simultaneously targeting oxidative stress and metal ion disorder may be an effective strategy for treating AD.

In this study, a series of novel melatonin–hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal ion chelation at the same time. In detail, melatonin and hydroxyquinoline were coupled by amide or amine linkage, and the connecting linker’s length and the hydroxyquinoline’s link location were investigated for their impact on bioactivity (Figure 1).

Figure 1

Figure 1. The design strategy of melatonin–hydroxyquinoline hybrids.

2 Results and discussion

2.1 Synthesis

Routes for synthesizing the target compounds (3a-d, 4, 6a-d, 11a-b and 13a-c) are demonstrated in Schemes 1–4. Commercially available 2-methyl-8-hydroxyquinoline (1) was reacted with SeO₂ in the presence of 1,4-dioxane to produce compound 2. Dissolving different amines, compound 2 and isopropanol, they were reacted at room temperature for 3 h, then NaBH₄ was added and kept stirring for 12 h to obtain 3a-d. Target compound 4 was obtained by the N-methylationst of 3a.

Scheme 1

Scheme 1. Synthesis of 3a-d and 4. Reagent and conditions: (a) SeO₂/1,4-dioxane, 60°C to reflux; 86%. (b) NaBH₄, isopropanol, room temperature, overnight, 62%–67%; (c) CH₃I, K₂CO₃, acetone, 60%.

Scheme 2

Scheme 2. Synthesis of 6a-d. Reagent and conditions: (a) SeO₂, pyridine, 120°C, 12 h, 50%; (b) HATU, DIPEA, anhydrous CH₂Cl₂, room temperature, overnight, 60%–70%.

Scheme 3

Scheme 3. Synthesis of 11a-b. Reagent and conditions: (a) ZnCl₂, HCl, formaldehyde, room temperature, 12 h, 85%; (b) DMF, reflux, 8 h, 50%; (c) HCl, reflux, 9 h, 75%; (d) HATU, DIPEA, anhydrous CH₂Cl₂, room temperature, overnight, 58%–60%.

Scheme 4

Scheme 4. Synthesis of 13a-c. Reagent and conditions: (a) HATU, DIPEA, anhydrous CH₂Cl₂, room temperature, overnight, 40%–55%.

The synthetic route of 6a-d via a tow-step produce is shown in Scheme 2. Commercially available 2-methyl-8-hydroxyquinoline was reacted with SeO₂ in pyridine to produce compound 5, followed by treatment with amines, HATU and DIPEA to mediate amine formation, so 6a-d were obtained.

The synthesis of the target compounds 11a-b is summarized in Scheme 3. Using ZnCl₂ as a catalyst, 8-hydroxyquinoline was reacted with formaldehyde and hydrochloric acid to produce 8. Compound 8 was refluxed in DMF for 8 h. Then refluxed in hydrochloric acid for 9 h to obtain compound 10. Followed by treatment with different substituted carboxylic acids, HATU and DIPEA to produce target 11a-b.

As showed in Scheme 4, treatment of the commercially available 8-hydroxyquinoline-7-carboxylic acid and different amines in the presence of HATU and DIPEA afforded the target compounds 13a-b.

2.2 Activity evaluation and structure-activity relationships

2.2.1 The oxygen radical absorbance capacity (ORAC)

Oxidative stress is involved in various pathological processes of AD and is one of the crucial adjective pathogeneses of AD. Therefore, it is essential to test the scavenging ability of target compounds. The oxygen radical absorbance capacity (ORAC) (Wang et al., 2014; Wang et al., 2015) was tested to evaluate the effects of compounds on oxidative stress. As shown in Table 1, MT has a satisfactory antioxidant effect, with the ORAC values of 2.38, whereas CQ had almost no antioxidant effect. Compared with the melatonin, most of the target compounds, such as 3a∼3d, 4, 6a∼6d, and 11a∼11b, which ORAC values were greater than 2.3. while compound 13a∼13c, which is linked at position 7 of hydroxyquinoline, have weaker oxygen radical scavenging ability. This suggests that the position of the junction on CQ has a large effect on the activity. Furthermore, the change in the connecting linker’s length has a slight effect on the ORAC, just as 3a and 3d have different lengths while having similar antioxidant activity.

Table 1

Table 1. Oxygen radical absorbance capacity, PAMPA assay and inhibition of Aβ_1-42 self-aggregation for target compounds.

2.2.2 Inhibition of Aβ_1–42 aggregation

Self-mediated Aβ1–42 aggregation inhibition was assessed via thioflavin T (ThT) fluorescence assay (Rosini et al., 2008; Wang et al., 2018; Babaei et al., 2022). As shown in Table 1, both CQ and MT showed good anti-aggregation effect. Most of the target compounds showed good inhibition of Aβ_1-42 aggregation. Among them, 3c, 4, 6a, 6b, 6c, 11a, and 13a showed better activity than melatonin (38.96 ± 9.35) and CQ (30.76 ± 1.08). When the connection is amine, compounds with -OH substituents on the indole ring have the highest inhibitory activity against Aβ_1–42 aggregation. Compound 3c containing hydroxyl-substituted indole ring fragments has the highest inhibitory rate against Aβ_1-42 self-aggregation (40.23%), which is much higher than the inhibition rate of methoxy-substituted and unsubstituted indole ring fragment compounds (18.23% and 27.10% respectively). When the connection mode is an amide, compound 6b with a methoxy group on the indole ring has the highest inhibition rate (63.24%). This shows that the different substituents at position 5 on the indole ring and the different link methods between melatonin and hydroxyquinoline play an important role in inhibiting the self-aggregation of Aβ_1-42. Compared 3a (27.10%) with 4 (52.54%), it can be found that methylation of nitrogen atoms leads to increased activity. On the whole when the connection mode is amide, the inhibitory activity is better. The length of the connected chain is shortened, and the activity decreases to different degrees. In addition, the compounds obtained at positions 2, 5 and 7 of the quinoline ring had no significant effect on the self-aggregation of Aβ_1-42 such as 6a (45.45%), 11a (44.74%) and 13a (46.98%).

2.2.3 Blood–brain barrier permeability assay

The blood-brain barrier permeability of central nervous drugs is a crucial drug-like property. In this work, the parallel artificial membrane permeability assay (PAMPA) (Di et al., 2003; Wang et al., 2014) was used to evaluate the ability of compounds to cross the blood-brain barrier. 13 commercial drugs were chosen to establish the evaluation system (Supplementary Table S1). Most of the target compounds can cross the blood-brain barrier with the P_e > 4.7, such as 3a, 3b, 3c, 3d, 4, 6a, 6b and 6d. The compounds with hydroxyl groups exhibit poor BBB permeability, possibly due to increased hydrophilia.

2.2.4 Cytotoxicity assay

To further investigate the bioactivity of the compounds, cytotoxicity was evaluated on SH-SY5Y and BV2 cell lines (Figures 2A, B). The results showed that 6b and 6c exhibit no cytotoxicity at 5 μM in SH-SY5H cell lines while showing slight toxicity at concentrations of 10 μM. As for BV2 cells, 6b and 6c also showed no significant cytotoxicity at 20 μM concentration.

Figure 2

Figure 2. Cytotoxicity assay of 6b and 6c on SH-SY5Y (A) and BV2 (B). Protective effect of 6b and 6c against H₂O₂ induced SH-SY5Y oxidative stress (C).

2.2.5 Alleviating oxidative stress induced by hydrogen peroxide

The effect of 6b and 6c on the oxidative stress of SH-SY5H cells induced by hydrogen peroxide was investigated using DCFH-DA as the fluorescent probe (Xu et al., 2021). The results showed that the ROS increased sharply in SH-SY5H cells treated with 400 μM hydrogen peroxide for 12 h. Pretreatment with 6b or 6c reduced ROS production in a dose-dependent manner, suggesting that 6b and 6c have a good ability to alleviate oxidative stress (Figure 2C).

2.2.6 Metal-chelating property

To further evaluate multi-target anti-AD potential, the metal-chelating properties of 6b and 6c were determined by UV spectrophotometry (Geng et al., 2012; Lu et al., 2013; Hu et al., 2019). As shown in Figures 3A, C, 6b exhibited a maximum absorption peak at 255 nm, and the maximum absorption peak showed a significant redshift and the intensity decreased when 6b co-incubated with Cu²⁺ or Zn²⁺. While co-incubated with Fe³⁺ or Fe²⁺, the intensity at 255 nm was in different degrees decreased. The same result occurred for 6c. Those results suggested that 6b and 6c possess metal-chelating properties. Next, the chelation ratios of 6b and 6c to Cu²⁺ were measured and calculated using the inflection point method (Figures 3B, D). The inflection point appears when the concentration ratio of compound Cu²⁺ to 6b or 6c is 0.5, so it can be inferred that the chelation ratio of compound 6b and 6c to Cu²⁺ is 2:1.

Figure 3

Figure 3. UV-vis absorption spectra of compounds 6b, 6c with Cu²⁺, Zn²⁺, Fe²⁺, and Fe³⁺ (A, C). The chelation ratios of 6b and 6c to Cu²⁺ (B, D).

2.2.7 Effect of Cu²⁺-induced Aβ aggregation

To further detect the ability of compounds 6b, CQ and MT to disaggregate or inhibit the Cu²⁺-induced Aβ_1-42 aggregation, we conducted thioflavin T fluorometric detection (Hu et al., 2019). The results showed that compounds 6b and CQ both significantly disaggregated Cu²⁺-induced Aβ_1-42 aggregation, also with the mild disaggregated effect of MT (Figure 4A). As shown in Figure 4B, 6b exhibited a distinct inhibitory effect on Cu²⁺-induced Aβ_1-42 aggregation, which was superior to the reference compound CQ, while MT exhibited weak inhibitory activity. Those results suggest that 6b can significantly mitigate metal ion induced Aβ aggregation.

Figure 4

Figure 4. Thioflavin T fluorometric detection. Compounds were incubated before (A) or after (B) the pre-fibrillation of Aβ_1-42 and Cu²⁺ at 37°C for 24 h.

3 Experimental

3.1 Chemistry

3.1.1 8-hydroxyquinoline-2-carbaldehyde (2)

At 60°C, 10 mL dioxane solution of 2-methyl-8-hydroxyquinoline (10 mmol) was added to 50 mL dioxane solution of SeO₂ (20 mmol). After half an hour of drip adding, the reaction reflux for 4 h. Yield 86%. ¹H NMR (400 MHz, Acetone-d₆) δ 10.16 (s, 1H), 9.22 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.2, 0.9 Hz, 1H), 7.28 (dd, J = 7.7, 1.0 Hz, 1H).

3.1.2 8-hydroxyquinoline-2-carboxylic acid (5)

1 (20 mmol) was dissolved in pyridine (50 mL), and SeO₂ (20 mmol) was added followed by stirring at 120°C for 12 h, after the completion of the reaction (monitored by TLC). The reaction mixture was filtered off first. The solvent was distilled off and the residue was dissolved in an aqueous KOH solution (10%), Then filtered and the filtered liquid was acidified with hydrochloric acid (10%). Last the filtered crude product was purified by silica-column chromatography. yellow solid, yield 50%.¹H NMR (400 MHz, Acetone-d₆) δ 9.68 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H).

3.1.3 5-(Chloromethyl)quinolin-8-ol hydrochloride (8·HCl)

Compound 8 was synthesized according to the literature. Pale yellow solid, yield 98%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (d, J = 7.9 Hz, 1H), 9.13 (dd, J = 5.0, 1.1 Hz, 1H), 8.12 (dd, J = 8.6, 5.1 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 5.33 (s, 2H).

3.1.4 2-(hydroxyquinoline-5-yl-methyl)-isoquinoline-1,3-diketone (9)

Under the nitrogen atmosphere. A mixture of phthalimide potassium (4.5 mmol), 5-(Chloromethyl)quinolin-8-ol Hydrochloride (3 mmol) and DMF (10 mL) was heated to 150°C, and refluxed for 8 h. After cooling to room temperature, the white potassium chloride residue was formed at the bottom of the flask, which was filtered. The filtrate was poured into water (400 mL), and filtered to obtain compound 9. White solid, yields 73%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.88 (dd, J = 4.1, 1.2 Hz, 1H), 8.73 (dd, J = 8.6, 1.3 Hz, 1H), 7.92–7.87 (m, 2H), 7.87–7.82 (m, 2H), 7.65 (dd, J = 8.6, 4.1 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.14 (s, 2H).

3.1.5 5-aminomethyl-8-hydroxyquinoline (10)

To a stirred concentrated hydrochloric acid (20 mL), compound 9 (2.19 mmol) was added, refluxed for 9 h until the mixture became transparent after cooling to room temperature. The solvent was distilled off and the residue was dissolved in water, then the solution pH to produce a solid. Greenish solid, yield 75%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (dd, J = 4.1, 1.4 Hz, 1H), 8.56 (dd, J = 8.5, 1.4 Hz, 1H), 7.57 (dd, J = 8.5, 4.1 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 4.08 (s, 2H).

3.1.5.1 General method for the preparation of compounds 3a-3d

To a solution of 2 (1 mmol) and different indole (1 mmol) in isopropyl alcohol. After stirring at room temperature for 3 h, the NaBH₄ (2 mmol) was added and kept stirring for 12 h. Quenched with water, extracted with ethyl acetate, the organic layer was dried with Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 3a-3d (CH₂Cl₂/CH₃OH = 50:1).

3.1.6 2-(((2-(1H-indol-3-yl)ethyl)amino)methyl)quinolin-8-ol (3a)

Yellow solid, yield 65%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.42–7.37 (m, 1H), 7.37–7.33 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.09–7.06 (m, 1H), 7.06–7.01 (m, 1H), 6.94 (t, J = 7.4 Hz, 1H), 4.07 (s, 2H), 2.91 (s, 2H), 2.90 (s, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 159.23, 153.23, 137.91, 136.69, 136.66, 128.05, 127.75, 127.23, 122.96, 121.45, 121.28, 118.76, 118.58, 117.98, 113.10, 111.79, 111.46, 55.13, 50.53, 26.04. HRMS (ESI) m/z calcd for C₂₀H₁₉N₃O [M + H]⁺, 318.1562; found, 318.1562. HPLC purity: 99.6%, retention time: 8.8 min.

3.1.7 2-(((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)methyl)quinolin-8-ol (3b)

Yellow solid, yield 67%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.42–7.37 (m, 1H), 7.37–7.31 (m, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 7.0, 1.6 Hz, 1H), 6.94 (d, J = 2.2 Hz, 1H), 6.68 (dd, J = 8.7, 2.3 Hz, 1H), 4.08 (s, 2H), 3.68 (s, 3H), 2.88 (s, 4H). ¹³C NMR (126 MHz, DMSO-d₆) δ 159.19, 153.34, 153.24, 137.91, 136.66, 131.83, 128.05, 128.01, 127.24, 123.67, 121.45, 117.97, 112.85, 112.45, 111.48, 111.46, 100.47, 55.70, 55.06, 50.38, 26.05. HRMS (ESI) m/z calcd for C₂₁H₂₁N₃O₂ [M + H]⁺, 348.1678; found,348.1667. HPLC purity: 98.6%. Retention time: 8.7 min.

3.1.8 2-(((2-(5-hydroxy-1H-indol-3-yl)ethyl)amino)methyl)quinolin-8-ol (3c)

Yellow solid, yield 62%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.45–7.38 (m, 1H), 7.38–7.33 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.08 (dd, J = 7.0, 1.4 Hz, 1H), 7.04 (d, J = 1.7 Hz, 1H), 6.83 (d, J = 1.9 Hz, 1H), 6.58 (dd, J = 8.6, 2.1 Hz, 1H), 4.10 (s, 2H), 3.00 (d, J = 6.8 Hz, s), 2.85 (d, J = 6.6 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 158.84, 153.22, 150.59, 137.88, 136.73, 131.29, 128.42, 128.06, 127.29, 123.46, 121.40, 118.00, 112.11, 111.96, 111.68, 111.51, 102.73, 55.01, 50.37, 26.01. HRMS (ESI) m/z calcd for C₂₀H₁₉N₃O₂ [M + H]⁺, 348.1678; found,348.1667. HPLC purity: 98.1%. Retention time: 8.4 min.

3.1.9 2-((((1H-indol-3-yl)methyl)amino)methyl)quinolin-8-ol (3d)

Yellow solid, yield 64%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.41–7.38 (m, 1H), 7.38–7.36 (m, 1H), 7.36–7.34 (m, 1H), 7.30 (s, 1H), 7.10–7.08 (m, 1H), 7.08–7.06 (m, 1H), 6.97 (t, J = 7.2 Hz, 1H), 4.07 (s, 2H), 3.99 (s, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 158.77, 153.24, 137.89, 136.82, 136.68, 128.06, 127.52, 127.26, 124.32, 121.49, 121.43, 119.34, 118.79, 117.98, 113.49, 111.80, 111.50, 54.35, 44.43. HRMS (ESI) m/z calcd for C₁₉H₁₇N₃O [M + H]⁺, 304.1423; found,304.1405. HPLC purity: 98. Retention time: 13.7 min.

3.1.10 2-(((2-(1H-indol-3-yl)ethyl)(methyl)amino)methyl)quinolin-8-ol (4)

To a solution of 3a (0.5 mmol) and K₂CO₃ (1 mmol) in acetone, CH₃I (0.5 mmol) was added slowly. After being stirred at room temperature overnight, the solvent was evaporated, followed by extraction with CH₂Cl₂. The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford yellow oil (CH₂Cl₂/CH₃OH = 30: 1). Yellow solid, yield 66%. ¹H NMR (400 MHz, MeOD) δ 8.16 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 6.88 (t, J = 7.5 Hz, 1H), 4.00 (s, 2H), 3.06 (dd, J = 9.8, 6.4 Hz, 2H), 2.87 (dd, J = 9.7, 6.4 Hz, 2H), 2.50 (s, 3H).¹³C NMR (126 MHz, MeOD) δ 156.15, 153.00, 138.01, 136.73, 136.46, 128.00, 127.22, 127.04, 121.74, 121.40, 120.87, 118.10, 117.80, 117.40, 112.18, 110.83, 110.66, 62.75, 58.27, 41.63, 22.31. HRMS (ESI) m/z calcd for C₂₁H₂₁N₃O [M + H]⁺, 332.1732; found, 332.1718. HPLC purity: 97.8%. Retention time: 11.6 min.

3.1.10.1 General method for the preparation of compounds 6a-6d, 11a-11b and 13a-13c

To a solution of quinoline acid or quinoline amine (1 mmol) and indole amine or indole acid (1.3 mmol) in anhydrous CH₂Cl_2, HATU (1 mmol) and DIPEA (2 mmol) were added. After stirred at room temperature overnight, the reaction was extracted with CH₂Cl₂. The combined organic phase was dried and evaporated, the target compounds were purified by column chromatography via CH₂Cl₂/MeOH mixture. (CH₂Cl₂: MeOH = 50:1.)

3.1.11 N-(2-(1H-indol-3-yl) ethyl)-8-hydroxyquinoline-2-carboxamide (6a)

Pale yellow solid, yield 60%. ¹H NMR (500 MHz, DMSO-d₆) δ 10.85 (s, 1H), 10.13 (s, 1H), 9.82 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.52–7.45 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.18 (dd, J = 7.6, 0.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 3.69 (dd, J = 14.7, 6.6 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 164.11, 154.08, 148.09, 138.19, 136.88, 136.72, 129.92, 129.81, 127.70, 123.15, 121.44, 119.29, 118.75, 118.64, 118.01, 112.22, 111.99, 111.89, 25.90. HRMS (ESI) m/z calcd for C₂₀H₁₇N₃O₂ [M + H]⁺, 332.1732; found,332.1354. HPLC purity: 98.3%. Retention time: 15.4 min.

3.1.12 8-hydroxy-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)quinoline-2-carboxamide (6b)

Pale yellow solid, yield 62%. ¹H NMR (500 MHz, DMSO-d₆) δ 10.69 (s, 1H), 10.15 (s, 1H), 9.83 (s, 1H), 8.50 (d, J = 8.3 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 7.12 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H), 3.04 (s, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 164.12, 154.08, 153.48, 148.11, 138.17, 136.89, 131.84, 129.91, 129.81, 128.05, 123.83, 119.29, 118.00, 112.52, 112.12, 111.99, 111.63, 100.56, 55.71, 25.90. HRMS (ESI) m/z calcd for C₂₁H₁₉N₃O₃ [M + H]⁺, 362.1471; found, 362.1460. HPLC purity: 99.6%. Retention time: 13.4 min.

3.1.13 8-hydroxy-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)quinoline-2-carboxamide (6c)

Pale yellow solid, yield 60%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 10.11 (s, 1H), 9.78 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.61 (dd, J = 8.6, 2.1 Hz, 1H), 3.65 (dd, J = 14.8, 6.6 Hz, 2H), 2.99–2.93 (m, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 164.09, 154.07, 150.72, 148.12, 138.18, 136.89, 131.30, 129.92, 129.81, 128.37, 123.57, 119.29, 118.01, 112.18, 111.99, 111.82, 111.24, 102.70, 26.03. HRMS (ESI) m/z calcd for C₂₀H₁₇N₃O₃ [M + H]⁺, 348.1313; found, 348.1303. HPLC purity: 99.5%. Retention time: 8.0 min.

3.1.14 N-((1H-indol-3-yl)methyl)-8 -hydroxyquinoline-2-carboxamide (6d)

Pink solid, yield 60%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 10.14 (s, 1H), 9.89 (t, J = 5.9 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.23 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.39–7.37 (m, 1H), 7.37–7.35 (m, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 4.77 (d, J = 5.9 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 163.90, 154.13, 148.13, 138.16, 136.91, 136.87, 129.91, 129.80, 126.96, 124.49, 121.67, 119.47, 119.23, 119.07, 117.96, 112.77, 112.01, 111.98, 34.80. HRMS (ESI) m/z calcd for C₁₉H₁₅N₃O₂ [M + H]⁺, 318.1573; found, 318.1198. HPLC purity: 97.9%. Retention time: 16.5 min.

3.1.15 N-((8-hydroxyquinolin-5-yl)methyl)-2-(1H-indol-3-yl)acetamide (11a)

Pale white solid, yield 58%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 9.72 (s, 1H), 8.85 (d, J = 3.8 Hz, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.35 (t, J = 5.1 Hz, 1H), 7.53–7.48 (m, 1H), 7.48–7.43 (m, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 4.62 (d, J = 5.5 Hz, 2H), 3.54 (s, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 170.93, 153.21, 148.24, 139.12, 136.56, 133.23, 128.21, 127.66, 127.30, 125.53, 124.24, 122.14, 121.38, 119.19, 118.65, 111.74, 110.66, 109.32, 54.05, 33.16. HRMS (ESI) m/z calcd for C₂₀H₁₇N₃O₂ [M + H]⁺, 332.1364; found, 332.1354. HPLC purity: 95.2%. Retention time: 8.2 min.

3.1.16 N-((8-hydroxyquinolin-5-yl)methyl)-2-(5-methoxy-1H-indol-3-yl)acetamide (11b)

Pale white solid, yield 60%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.71 (s, 1H), 8.84 (dd, J = 4.0, 1.3 Hz, 1H), 8.42 (dd, J = 8.5, 1.2 Hz, 1H), 8.35 (t, J = 5.3 Hz, 1H), 7.47 (dd, J = 8.6, 4.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.99 (d, J = 5.7 Hz, 1H), 6.98 (s, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.62 (s, 3H), 3.51 (s, 2H). ¹³C NMR (126 MHz, MeOD) δ 173.08, 153.64, 152.64, 147.53, 138.78, 132.55, 131.89, 127.87, 127.29, 127.08, 124.42, 124.33, 121.35, 111.63, 111.50, 109.58, 107.81, 99.89, 54.63, 40.20, 32.85. HRMS (ESI) m/z calcd for C₂₁H₁₉N₃O₃ [M + H]⁺, 362.1469; found, 362.1460. HPLC purity: 96.2%. Retention time: 7.5 min.

3.1.17 N-(2-(1H-indol-3-yl)ethyl)-8 -hydroxyquinoline-7-carboxamide (13a)

Orange solid, yield 40%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 9.01 (t, J = 5.2 Hz, 1H), 8.92 (d, J = 3.0 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.67–7.63 (m, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 3.66 (dd, J = 13.4, 6.9 Hz, 2H), 3.03 (t, J = 7.3 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.62, 157.48, 149.58, 139.71, 136.75, 136.45, 131.12, 130.11, 127.68, 125.38, 123.95, 123.27, 121.45, 118.77, 117.35, 112.96, 112.08, 111.89, 40.60, 25.51. HRMS (ESI) m/z calcd for C₂₀H₁₇N₃O₂ [M + H]⁺, 332.1373; found, 332.1354. HPLC purity: 98.9%. Retention time: 5.0 min.

3.1.18 8-hydroxy-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)quinoline-7-carboxamide (13b)

Orange solid, yield 45%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 9.00 (t, J = 5.4 Hz, 1H), 8.92 (dd, J = 4.1, 1.5 Hz, 1H), 8.35 (dd, J = 8.3, 1.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.3, 4.2 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.72 (dd, J = 8.7, 2.3 Hz, 1H), 3.66 (dd, J = 13.2, 7.0 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 168.62, 157.44, 153.48, 149.58, 139.67, 136.47, 131.87, 131.11, 128.03, 125.38, 123.96, 123.93, 117.35, 112.96, 112.53, 111.93, 111.62, 100.58, 55.71, 40.61, 25.48. HRMS (ESI) m/z calcd for C₂₁H₁₉N₃O₃ [M + H]⁺, 362.1466; found, 362.1460. HPLC purity: 97.5%. Retention time: 5.1 min.

3.1.19 N-((1H-indol-3-yl)methyl) -8-hydroxyquinoline-7-carboxamide (13c)

Orange solid, yield 50%. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 9.12 (t, J = 5.2 Hz, 1H), 8.90 (dd, J = 4.1, 1.4 Hz, 1H), 8.34 (dd, J = 8.3, 1.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.70–7.65 (m, 1H), 7.65–7.62 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.41–7.38 (m, 1H), 7.38–7.36 (m, 1H), 4.75 (d, J = 5.4 Hz, 2H). ¹³C NMR (126 MHz, DMSO-d₆) δ 167.89, 157.00, 149.47, 139.58, 136.81, 136.51, 131.06, 126.94, 125.77, 124.75, 123.93, 121.70, 119.17, 119.10, 117.36, 113.23, 112.19, 112.01, 35.04. HRMS (ESI) m/z calcd for C₁₉H₁₅N₃O₂ [M + H]⁺, 318.1219; found, 318.1198. HPLC purity: 99.5%. Retention time: 4.7 min.

3.2 Thioflavin T fluorometric detection

Detection of the compounds for disaggregated and inhibitory effects on Cu²⁺ induced Aβ_1-42 aggregation. Aβ_1-42 (Sigma-Aldrich A9810, 20 μM) was dissolved in HEPES buffer (pH = 6.6, containing 1% ammonium hydroxide). 10 μL of Aβ_1-42 was previously incubated with or without Cu²⁺ at 37°C for 3 days to pre-fibrillation. 10 μL of 6b, CQ, and MT (150 μM, in DMSO) were incubated before or after the pre-fibrillation of Aβ_1-42 at 37°C for 1 day. After incubation, 170 μL of thioflavin T (5 μM, in 50 mM glycine-NaOH buffer) was added to mix well. After incubation for 5 min, the Aβ_1-42 aggregation was detected by Microplate Reader (HITACHI, F-4700) with excitation/emission at 450/485 nm.

3.2.1 Oxygen radical absorbance capacity (ORAC-FL) assay

The testes compounds and fluorescein (FL) stock solution were diluted with 75 mM phosphate buffer (pH 7.4) to 5 µM and 0.117 µM, respectively (Wang et al., 2018). The solution of Trolox was diluted with 75 mM phosphate buffer to 40, 20, 10, 5, 2.5, and 1.25 µM. The solution of 2,2′-azobis- (amidinopropane) dihydrochloride (AAPH) was prepared to a final concentration of 40 mM. The mixture of the tested compounds (20 µL) and FL (120 μL; 70 nM) was pre-incubated for 10 min at 37°C, 60 µL of the AAPH solution was added. The fluorescence was recorded every minute for 120 min (excitation, 485 nm; emission, 520 nm). The antioxidant curves (fluorescence versus time) were normalized to the curve of the blank. The area under the fluorescence decay curve (AUC) was calculated as the following equation:

$\text{AUC}=1+{\displaystyle {\sum }_{i=1}^{i=120}}fi/f0$

Where f0 is the initial fluorescence reading at 0 min and fi is the fluorescence reading at time i. The net AUC was calculated by the expression: AUC_sample—AUC_blank. Regression equations between net AUC and Trolox concentration were calculated. ORAC-FL value of the tested compound expressed as Trolox equivalents.

3.2.2 Inhibition of Aβ_1–42 aggregation assay

Following the previous literature (Rosini et al., 2008; Wang et al., 2018), Aβ₁₋₄₂ (Sigma-Aldrich) was dissolved in NH₄OH (1% v/v) to get a stock solution, which was aliquoted into small samples and stored at −80°C.

3.2.3 Metal-chelating study

6b and 6c (50 µM) were incubated with CuSO₄, FeSO₄, FeCl₃, or ZnCl₂ (50 µM) in buffer (20 mM HEPES, 150 mM NaCl, pH 7.4) for 30 min, and the absorption spectras were recorded at room temperature. For the stoichiometry of the compound–Cu²⁺ complex, a fixed amount of 6b and 6c (50 µM) was mixed with growing amounts of copper ion (0–100 µM), and the difference UV−vis spectra were examined to investigate the ratio of ligand/metal in the complex.

3.2.4 Statistical analysis

Data were presented as mean ± standard deviation (SD) (represented by error bars). All the experiments had three replicates (n = 3). In vivo anti-tumor Student’s t-test was used for comparing two groups, and significant differences were indicated by *p < 0.05, *p < 0.01, ***p < 0.001. The statistical analysis was performed with GraphPad Prism 8.0.1.

4 Conclusion

In this study, a series of novel melatonin–hydroxyquinoline hybrids were designed and synthesized, simultaneously targeting anti-oxidation and metal-chelating. Most of the compounds possess good blood-brain barrier permeability and showed significant oxygen radical absorbance capacity and Aβ_1–42 aggregation inhibition. Among them, 6b and 6c have a good ability to alleviate oxidative stress (Figure 2C) induced by hydrogen peroxide and exhibit metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal ion induced Aβ aggregation.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Author contributions

WW: Writing–original draft, Investigation, Methodology, Validation. TP: Investigation, Methodology, Writing–original draft. RS: Methodology, Writing–original draft, Formal Analysis. MC: Writing–original draft, Data curation. WX: Writing–original draft, Methodology. CX: Writing–original draft, Conceptualization, Funding acquisition, Writing–review and editing. LH: Conceptualization, Supervision, Writing–review and editing.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (82160653 to LH and 82204193 to CX), Hainan Provincial Natural Science Foundation of China (822MS052 to CX), Natural Science Foundation of Guangdong Province (2022A1515012527 to CX).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2024.1374930/full#supplementary-material

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