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Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition

  • Piyapan Suwanttananuruk , Jutamas Jiaranaikulwanitch EMAIL logo , Pornthip Waiwut and Opa Vajragupta
Published/Copyright: June 9, 2020
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Open Chemistry
From the journal Open Chemistry Volume 18 Issue 1

Abstract

Amyloid cascade, one of pathogenic pathways of Alzheimer’s disease (AD), was focused as one of drug discovery targets. In this study, β-secretase (BACE1) inhibitors were designed aiming at the development of multifunctional compounds targeting amyloid pathogenic cascade. Tryptophan was used as a core structure due to its properties of the central nervous system (CNS) penetration and BACE1 inhibition activity. Three amino acid residues and guanidine were selected as linkers to connect the tryptophan core structure and the extended aromatic moieties. The distance between the aromatic systems of the core structure and the extended moieties was kept at the optimal length for amyloid-β (Aβ) peptide binding to inhibit its fibrillation and aggregation. Sixteen designed compounds were evaluated in silico. Eight hit compounds of TSR and TGN series containing serine and guanidine linkers, respectively, were identified and synthesized based on docking results. TSR2 and TGN2 were found to exert strong actions as BACE1 (IC50 24.18 µM and 22.35 µM) and amyloid aggregation inhibitors (IC50 37.06 µM and 36.12 µM). Only TGN2 demonstrated a neuroprotective effect in SH-SY5Y cells by significantly reducing Aβ-induced cell death at a concentration of 2.62 µM. These results support the validity of multifunctional approaches to inhibition of the β-amyloid cascade.

Keywords: tryptophan; multifunction activities; beta-secretase inhibitor; amyloid aggregation inhibition; neuroprotection

1 Introduction

Alzheimer’s disease (AD) is currently the most common neurodegenerative disorder, particularly affecting aged members of society and causing impairments of cognition and memory. Two pathological features, amyloid-β (Aβ) plaques and neurofibrillary tangles, have been found in the brains of patients with AD. The observation of these proteins led to the development of drugs for AD, which obstruct the production of Aβ and neurofibrillary tangles and their neurotoxic cascades [1,2]. In the etiology of Aβ, the β-secretase enzyme (BACE1) is an attractive drug target as it generates Aβ peptide, the main constituent of toxic Aβ oligomers and plaques [3,4,5]. Decreased Aβ production would obstruct Aβ oligomerization and consequently reduce Aβ aggregation. A number of BACE1 inhibitors and amyloid aggregation inhibitors have been developed as single target drugs but more than half have apparently failed in clinical trials. Only two BACE1 inhibitors are currently in phase III clinical trials and three compounds in phase II clinical trials [6]. The use of a multitarget single ligand is one of the most challenging approaches to AD drug discovery, aiming to reduce the late-stage clinical attrition. This new paradigm has gained popularity because it suits the complex etiology and multiple pathogenic mechanisms involved in AD [7,8,9].

However, ligand developed to be AD drug should be considered about the possibility to enter the CNS. Three methods of molecule entering to brain are passive diffusion, active transport via solute carrier (SLC) superfamily, and endocyctosis [10]. Thus, the objective of this research was to design and synthesize novel BACE1 inhibitors with multifunctional actions including anti-amyloid aggregation and antioxidant properties by using in silico hit screening and finding. Tryptophan was used as a core structure to make a molecule to transport into CNS.

2 Materials and methods

2.1 In silico study

Molecular dockings were performed to determine the binding mode of compounds to BACE1 and Aβ using the AutoDock program suite, version 4.2. The Pymol program was used to visualize the generated docking graphics objects. The 3D-structures of the compounds were generated and optimized with ChemDraw Ultra 12.0 and Chem3D Ultra 12.0.

The protein template preparation and docking parameters using in this research were the same as in previous study [11]. Briefly, the BACE1 template 2IRZ-F constructed from the crystal structures of 2IRZ [12] and 1FKN [13] was used as a BACE1 macromolecule. The docking parameters in the in silico studies for BACE1 were as follows: 100 runs of the genetic algorithm (GA), a population size of 150, 1,50,00,000 energy evaluations per run, and a maximum number of generations of 27,000.

Aβ template, 1Z0Q-1, was constructed from X-ray crystal structures of inhibitor-bound Aβ (PDB code: 1Z0Q) [14]. Docking parameters in the in silico studies for Aβ binding were as follows: 100 runs of the GA, a population size of 150, 50,00,000 energy evaluations per run, and a maximum number of generations of 27,000.

2.2 Synthesis part

Chemical reagents were purchased from Acros, Aldrich, or AK Science. Melting points were determined on a Model 9100 melting point apparatus (Electrothermal, UK). IR spectra were recorded using a Nicolet FTIR Instruments machine (ThermoFisher, USA). Nuclear magnetic resonance (NMR) spectra were recorded using Bruker Fourier 300 MHz spectrometers (Bruker, Switzerland) with tetramethylsilane as an internal standard. Mass spectra (MS) were obtained in positive ESI mode (Bruker, Switzerland). The 1H and 13C-NMR spectra of synthesized compounds were shown in the supplemental materials (Figures S1–S20).

2.2.1 General synthesis procedure of TSR1–TSR4

A solution of compound T2 (1 mmol), NH2–R2 (1 mmol), HBTU (1.5 mmol), and DIPEA (3 mmol) in 5 mL of DMF was stirred at room temperature. After 18 h stirring, water was added. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined and dried. The obtained residue was purified by column chromatography on silica gel to yield compound Boc-TSR1 to Boc-TSR4. The protecting group of the obtained compound was removed by 50% of TFA in ethyl acetate at room temperature for 3 h. The reaction mixture was adjusted to pH 7 by saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried. The residue was purified by column chromatography on silica gel to yield TSR1–TSR4 (Scheme 1).

Scheme 1 The scheme of synthesis of compounds in the TSR and TGN series: (a) Boc2O, NaOH, THF/H2O (1:1), rt, 18 h; (b) (i) l-serine methyl ester hydrochloride, HBTU, DIPEA, DMF, rt, 18 h, (ii) MeOH, KOH, rt, 3 h; (c) (i) NH2-R2, HBTU, DIPEA, DMF, rt, 18 h, (ii) TFA:EtOAc (1:1), rt, 3 h; (d) N-tert-butoxycarbonyl (Boc)-protected 2-methyl-2-thiopseudourea (1a), HATU, NMM, DMF, rt, 18 h; and (e) (i) NH2-R2, HATU, NMM, DMF, rt, 18 h, (ii) TFA:EtOAc (1:1), rt, 1.5 h.
Scheme 1

The scheme of synthesis of compounds in the TSR and TGN series: (a) Boc2O, NaOH, THF/H2O (1:1), rt, 18 h; (b) (i) l-serine methyl ester hydrochloride, HBTU, DIPEA, DMF, rt, 18 h, (ii) MeOH, KOH, rt, 3 h; (c) (i) NH2-R2, HBTU, DIPEA, DMF, rt, 18 h, (ii) TFA:EtOAc (1:1), rt, 3 h; (d) N-tert-butoxycarbonyl (Boc)-protected 2-methyl-2-thiopseudourea (1a), HATU, NMM, DMF, rt, 18 h; and (e) (i) NH2-R2, HATU, NMM, DMF, rt, 18 h, (ii) TFA:EtOAc (1:1), rt, 1.5 h.

2.2.2 (S)-2-Amino-N-((S)-3-hydroxy-1-((4-hydroxyphenyl)amino)-1-oxopropan-2-yl)-3-(1H-indol-3-yl)propanamide (TSR1)

Compound Boc-TSR1 was purified by column chromatography on silica gel (CHCl3/EtOAc/NH4OH 7:3:0.01) to yield white powder. Compound TSR1 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 4:5:1) to yield yellow solid (hygroscopic). Yield 261.45 mg (68.37%). FTIR (ATR, υ, cm−1): 3,392–3,155 (O–H, N–H), 3,110 (sp2 C–H), 2,927 (sp3 C–H), 1,674, 1,514 (C═O, C═C) 1,457, 1,444 (C–C), 1,368 (C–O), 1,201, 1,146 (C–N, C–O). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.88 (s, 1H, indole-NH), 9.73 (s, 1H, OH), 8.20 (s, 1H, NHa), 7.38 (s, 1H, NHb), 7.57 (d, 1H, J 8.0 Hz, 1H, H9′), 7.34 (d, 1H, J 8.1 Hz, H6′), 7.38 (d, 2H, J 8.9 Hz, H2″, 6″), 7.20 (s, 1H, H4′), 7.05 (t, 1H, J 8.1 Hz, H7′), 6.96 (t, 1H, J 7.9 Hz, H8′), 6.69 (d, 2H, J 8.8 Hz, H3″, H5″), 3.88 (dd, 1H, J1 6.0 Hz, J2 7.3 Hz, H1′), 3.64 (m, 3H, H2, H4a, H4b), 3.19 (dd, 1H, J1 5.8 Hz, J2 14.6, H2b′), 3.02 (dd, 1H, J1 7.2 Hz, J2 14.6 Hz, H2a′). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 174.9 (C1), 168.7 (C3), 153.9 (C4″), 136.7 (C5′), 130.9 (C1″), 130.9 (C2″, C6″), 127.9 (C10′), 124.3 (C4′), 121.6 (C7′), 118.9 (C9′), 118.7 (C8′), 115.4 (C3″, C5″), 111.8 (C6′), 110.9 (C3′), 62.4 (C1′), 55.6 (C4), 55.6 (C2), 31.1 (C2′). HRMS (ESI) m/z: 405.1532 [M + Na].

2.2.3 (S)-2-Amino-N-((S)-3-hydroxy-1-((4-hydroxybenzyl)amino)-1-oxopro pan-2-yl)-3-(1H-indol-3-yl)propanamide (TSR2)

Compound Boc-TSR2 was purified by column chromatography on silica gel (CHCl3/EtOAc/Hex 4:5:1) to yield white powder. Compound TSR2 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH/4:4:1) to yield white solid (hygroscopic). Yield 216.25 mg (54.55%). FTIR (ATR, υ, cm−1): 3,419–3,184 (O–H, N–H), 3,110 (sp2 C–H), 2,925 (sp3 C–H), 1,667, 1,516 (C═O, C═C) 1,455, 1,435 (C–C), 1,361, 1,337 (C–O), 1,228, 1,192, 1,131 (C–N, C–O). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.96 (s, 1H, indole-NH), 8.45 (s, 1H, OH), 8.26 (t, 1H, J 5.9 Hz, NH), 7.98 (t, 1H, J 5.9 Hz, NH), 7.62 (d, 1H, J 7.8 Hz, H9′), 7.35 (d, 1H, J 7.7 Hz, H6′), 7.20 (s, 1H, H4′), 7.07 (t, 1H, J 7.8 Hz, H7′), 7.05 (d, 2H, J 8.5 Hz, H2″, H6″), 6.97 (t, 1H, J 7.6 Hz, H8′), 6.70 (dd, 2H, J1 8.4 Hz, J2 8.4 Hz, H3″, H5″), 4.18 (d, 2H, J 5.6 Hz, H7″), 3.80 (dd, 1H, J1 5.1 Hz, J2 7.6 Hz, H1′), 3.72 (dd, 1H, J1 4.9 Hz, J2 5.6 Hz, H2), 3.63 (dd, 1H, J1 5.5 Hz, J2 10.9 Hz, H4b), 3.51 (dd, 1H, J1 5.0 Hz, J2 10.9 Hz, H4a), 3.17 (dd, 1H, J1 5.1 Hz, J2 14.1 Hz, H2b′), 2.94 (dd, 1H, J1 7.7 Hz, J2 14.0 Hz, H2a′). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 175.5 (C1), 170.2 (C3), 156.7 (C4″), 136.7 (C5′), 129.7 (C1″), 128.7 (C2″, C6″), 127.8 (C10′), 124.9 (C4′), 121.4 (C7′), 118.9 (C9′), 118.8 (C8′), 115.4 (C3″, C5″), 111.9 (C6′), 109.3 (C3′), 62.1 (C1′), 55.6 (C4), 54.5 (C2), 42.1 (C7″), 29.6 (C2′). HRMS (ESI) m/z: 419.1687 [M + Na].

2.2.4 (S)-2-Amino-N-((S)-3-hydroxy-1-((4-hydroxyphenethyl)amino)-1-oxopropan-2-yl)-3-(1H-indol-3-yl)propanamide (TSR3)

Compound Boc-TSR3 was purified by column chromatography on silica gel (CHCl3/EtOAc/Hex 4:5:1) to yield white powder. Compound TSR3 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 4:4:1) to yield yellow solid (hygroscopic). Yield 170.09 mg (41.14%). FTIR (ATR, υ, cm−1): 3,413–3,184 (O–H, N–H), 3,116 (sp2 C–H), 2,927 (sp3 C–H), 1,667, 1,515 (C═O, C═C) 1,454, 1,435 (C–C), 1,361, 1,340 (C–O), 1,227, 1,202, 1,136 (C–N, C–O). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.90 (s, 1H, indole-NH), 9.18 (s, 1H, OH), 8.17 (s, 1H, NH), 7.83 (t, 1H, J 7.56 Hz, NH), 7.58 (d, 1H, J 7.4 Hz, H9′), 7.35 (d, 1H, J 7.3 Hz, H6′), 7.21 (d, 1H, J 2.2 Hz, H4′), 6.99 (d, 2H, J 8.3 Hz, H2″, H6″), 7.07 (t, 1H, J 7.0 Hz, H7′), 6.98 (t, 1H, J 7.0 Hz, H8′), 6.67 (d, 2H, J 8.4 Hz, H3″, H5″), 3.64 (dd, 1H, J1 5.2 Hz, J2 7.7 Hz, H1′), 3.55 (dd, 1H, J1 5.4 Hz, J2 10.9 Hz, H4b), 3.40 (dd, 1H, J1 4.8 Hz, J2 10.9 Hz, H4a), 3.12 (m, 4H, H2b′, H2, H8″), 2.85 (dd, 1H, J1 7.9 Hz, J2 14.4 Hz, H2a′), 2.57 (t, 2H, J 7.9 Hz, H7″). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 174.4 (C1), 170.2 (C3), 156.1 (C4″), 136.7 (C5′), 129.9 (C2″, C6″), 129.9 (C1″), 127.8 (C10′), 124.5 (C4′), 121.4 (C7′), 118.9 (C9′), 118.7 (C8′), 115.6 (C3″, C5″), 111.8 (C6′), 110.6 (C3′), 62.2 (C1′), 55.4 (C4), 55.3 (C2), 41.2 (C8″), 34.8 (C7″), 30.7 (C2′). HRMS (ESI) m/z: 433.1840 [M + Na].

2.2.5 (S)-N-(2-(1H-Indol-2-yl)ethyl)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-hydroxypropanamide (TSR4)

Compound Boc-TSR4 was purified by column chromatography on silica gel (CHCl3/EtOAc/Hex 4:5:1) to yield white powder. Compound TSR4 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 4:4:1) to yield yellow solid (hygroscopic). Yield 260.36 mg (60.06%). FTIR (ATR, υ, cm−1): 3,392–3,216 (O–H, N–H), 3,113 (sp2 C–H), 2,919 (sp3 C–H), 1,659, 1,516 (C═O, C═C) 1,457, 1,433 (C–C), 1,363, 1,336 (C–O), 1,229, 1,202, 1,180 (C–N, C–O). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.81 (s, 2H, indole-NH), 7.87 (m, 2H, NH, NH), 7.60 (d, 1H, J 7.6 Hz, H7″), 7.53 (d, 1H, J 7.7 Hz, H9′), 7.32 (d, 1H, J 8.0 Hz, H6′, H4″), 7.15 (m, 2H, H4′, H2″), 7.05 (t, 2H, J 7.4 Hz, H8′, H6″), 6.97 (t, 2H, J 7.3 Hz, H7′, H5″), 4.24 (m, 2H, H1′, H2), 3.60 (dd, 1H, J 9.9 Hz, H4b), 3.50 (dd, 1H, J1 5.7 Hz, J2 10.8 Hz, H4a), 3.09 (dd, 1H, J1 4.7 Hz, J2 14.2 Hz, H2b′), 2.94 (m, 1H, H2a′), 2.76 (m, 4H, H9″, H10″). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 175.1 (C1), 170.3 (C3), 136.9 (C3″), 136.7 (C5′), 127.9 (C8″), 127.6 (C10′), 123.2 (C2″), 123.0 (C4′), 121.6 (C5″), 121.4 (C7′), 118.9 (C9′, C7″), 118.7 (C8′, C6″), 112.0 (C4″), 111.8 (C6′), 111.0 (C1″), 110.8 (C3′), 62.3 (C1′), 55.7 (C4), 55.1 (C2), 44.9 (C10″), 31.2 (C9″), 26.1 (C2′). HRMS (ESI) m/z 434.2193 [M + H].

2.2.6 General synthesis procedure of TGN1–TGN4

A solution of compound T3 (1 mmol), NH2–R2 (1 mmol), HATU (1.5 mmol), and N-methylmorpholine (NMM) (3 mmol) in 5 mL of DMF was stirred at room temperature. After 18 h stirring, water was added. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried. The obtained residue was purified by column chromatography on silica gel to yield compound Boc-TGN1 to Boc-TGN4. The protecting group of the obtained compound was removed by 50% of TFA in ethyl acetate at room temperature for 1.5 h. The reaction mixture was adjusted to pH 7 by saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried. The residue was purified by column chromatography on silica gel to yield TGN1–TGN4 (Scheme 1).

2.2.7 (S)-2-Amino-N-(N-(4-hydroxyphenyl)carbamimid oyl)-3-(1H-indol-3-yl)propanamide (TGN1)

Compound Boc-TGN1 was purified by column chromatography on silica gel (EtOAc/CHCl3/Hex 2:7:1) to yield white powder. Compound TGN1 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 6:3:1) to yield white powder. Yield 190.75 mg (56.54%); m.p. = 208 (d) °C. FTIR (ATR, υ, cm−1): 3,417–3,018 (O–H, N–H), 3,080 (sp2 C–H), 2,923 (sp3 C–H), 1,678, 1,588, 1,511 (C═O, C═C, C═N), 1,456, 1,432 (C–C), 1,366, 1,341 (C–O st), 1,204, 1,139 (C–N). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.85 (s, 1H, indole-NH), 9.36 (s, 1H, OH), 8.26 (s, 1H, NH), 7.57 (d, 1H, J 7.6 Hz, H9′), 7.52 (s, 1H, NH), 7.34 (s, 1H, NH), 7.34 (d, 1H, J 7.7 Hz, H6′), 7.35 (d, 2H, J 8.9 Hz, H2″, H6″), 7.21 (d, 1H, J 2.2 Hz, H4′), 7.06 (t, 1H, J 7.5 Hz, H7′), 6.97 (t, 1H, J 7.4 Hz, H8′), 6.70 (dd, 2H, J 8.8 Hz, H3″, H5″), 4.05 (m, 1H, H1′), 3.16 (dd, 1H, J1 4.1 Hz, J2 14.6 Hz, H2b′), 2.93 (dd, 1H, J1 6.1 Hz, J2 14.6 Hz, H2a′). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 171.8 (C1), 158.5 (C2), 154.5 (C4″), 136.4 (C5′), 129.9 (C1″), 128.1 (C2″, C6″), 127.9 (C10′), 123.9 (C4′), 121.2 (C7′), 119.1 (C9′), 118.6 (C8′), 115.8 (C3″, C5″), 111.7 (C6′), 110.0 (C3′), 60.8 (C1′), 27.4 (C2′). HRMS (ESI) m/z: 360.1426 [M + Na].

2.2.8 (S)-2-Amino-N-(N-(4-hydroxybenzyl)carbamimid oyl)-3-(1H-indol-3-yl)propanamide (TGN2)

Compound Boc-TGN2 was purified by column chromatography on silica gel (EtOAc/CHCl3/Hex 2:7:1) to yield white powder. Compound TGN2 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 2:7:1) to yield brown viscous (hygroscopic). Yield 487.40 mg (53.33%). FTIR (ATR, υ, cm−1): 3,394–3,111 (O–H, N–H), 3,065 (sp2 C–H), 2,925 (sp3 C–H), 1,674, 1,611, 1,515 (C═O, C═C, C═N) 1,456, 1,431 (C–C), 1,357, 1,338 (C–O), 1,201, 1,136 (C–N). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.87 (s, 1H, indole-NH), 9.32 (s, 1H, OH), 8.10 (s, 1H, NH), 7.55 (s, 1H, NH), 7.55 (d, 1H, J 7.7 Hz, H9′), 7.34 (s, 1H, NH), 7.34 (d, 1H, J 7.6 Hz, H6′), 7.13 (s, 1H, H4′), 6.93 (d, 2H, J 8.4 Hz, H2″, H6″), 7.06 (t, 1H, J 7.5 Hz, H7′), 6.97 (t, 1H, J 7.5 Hz, H8′), 6.67 (d, 2H, J 8.4 Hz, H3″, H5″), 4.24 (m, 2H, H7″), 4.06 (m, 1H, H1′), 3.14 (dd, 1H, J1 4.0 Hz, J2 14.6 Hz, H2b′), 2.83 (dd, 1H, J1 6.9 Hz, J2 14.6 Hz H2a′). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 171.9 (C1), 156.9 (C4″), 156.8 (C2), 136.5 (C5′), 129.1 (C1″), 128.9 (C2″, C6″), 127.9 (C10′), 123.9 (C4′), 121.2 (C7′), 119.0 (C9′), 118.7 (C8′), 115.5 (C3″, C5″), 111.7 (C6′), 110.3 (C3′), 61.4 (C1′), 45.0 (C7″), 27.9 (C2′). HRMS (ESI) m/z: 374.1590 [M + Na].

2.2.9 (S)-2-Amino-N-(N-(4-hydroxyphenethyl)carbamimid oyl)-3-(1H-indol-3-yl)propanamide (TGN3)

Compound Boc-TGN3 was purified by column chromatography on silica gel (EtOAc/CHCl3/EtOAc 2:7:1) to yield white powder. Compound TGN3 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 3:6:1) to yield yellow viscous (hygroscopic). Yield 266.68 mg (62.03%). FTIR (ATR, υ, cm−1): 3,387–3,120 (O–H, N–H), 3,056 (sp2 C–H), 2,925 (sp3 C–H), 1,694, 1,612, 1,514 (C═O, C═C, C═N) 1,455, 1,434 (C–C), 1,362, 1,338 (C–O), 1,230, 1,131 (C–N). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 11.01 (s, 1H, indole-NH), 9.22 (s, 1H, OH), 7.96 (t, 1H, J 5.6 Hz, NH), 7.68 (s, 2H, NH, NH), 7.68 (d, 1H, J 7.8 Hz, H9′), 7.37 (d, 1H, J 7.8 Hz, H6′), 7.23 (d, 1H, J 2.3 Hz, H4′), 7.09 (t, 1H, J 7.8 Hz, H7′), 7.00 (d, 2H, J 8.4 Hz, H2″, H6″) 7.02 (t, 1H, J 7.5 Hz, H8′), 6.68 (d, 2H, J 8.5 Hz, H3″, H5″), 4.03 (m, 1H, H1′), 3.22 (m, 3H, H2b′, H8″), 3.05 (dd, 1H, J1 8.2 Hz, J2 14.7 Hz, H2a′) 2.58 (t, 2H, J 7.5 Hz, H7″). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 172.6 (C1), 156.3 (C2), 156.2 (C4″), 136.5 (C5′), 129.9 (C1″), 129.9 (C2″, C6″), 127.9 (C10′), 123.7 (C4′), 121.3 (C7′), 118.9 (C9′), 118.7 (C8′), 115.6 (C3″, C5″), 111.7 (C6′), 110.6 (C3′), 66.8 (C8″), 61.4 (C1′), 28.8 (C7″), 27.9 (C2′). HRMS (ESI) m/z: 388.1737 [M + Na].

2.2.10 (S)-N-(N-(2-(1H-Indol-2-yl)ethyl)carbamimidoyl)-2-amino-3-(1H-indol-3-yl))propanamide (TGN4)

Compound Boc-TGN4 was purified by column chromatography on silica gel (EtOAc/CHCl3/EtOAc 2:7:1) to yield white powder. Compound TGN4 was purified by column chromatography on silica gel (CHCl3/EtOAc/MeOH 3:6:1) to yield white viscous (hygroscopic). Yield 154.22 mg (39.70%). FTIR (ATR, υ, cm−1): 3298.97 (N–H), 3,084 (sp2 C–H), 2,924 (sp3 C–H), 1,670, 1,612, 1,494 (C═O, C═C, C═N) 1,455, 1,431 (C–C), 1,359, 1,339 (C–O), 1,201, 1,135 (C–N). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.98, 10.91 (s, 2H, indole-NH), 7.88 (s, 3H, NH, NH, NH), 7.54 (d, 1H, J 7.6 Hz, H7″), 7.53 (d, 1H, J 7.5 Hz, H9′), 7.36 (d, 1H, J 7.6 Hz, H4″), 7.32 (d, 1H, J 7.6 Hz, H6′), 7.23 (d, 1H, J 2.3 Hz, H4′), 7.13 (d, 1H, J 2.3 Hz, H2″), 7.02 (m, 4H, H7′, H8′, H5″, H6″), 4.15 (m, 1H, H1′), 3.14 (dd, 1H, J1 4.0 Hz, J2 15.0 Hz H2b′), 3.07 (m, 2H, H10″), 2.98 (m, 2H, H9″), 2.87 (dd, 1H, J1 7.3 Hz, J2 14.9 Hz H2a′). 13C-NMR spectrum in DMSO-d6 (δ, ppm): 185.2 (C1), 168.2 (C2), 136.8 (C3″), 136.5 (C5′), 127.8 (C8″), 127.3 (C10′), 124.1 (C2″), 123.9 (C4′), 121.6 (C5″), 121.3 (C7′), 118.9 (C7″), 118.8 (C9′), 118.7 (C6″), 118.5 (C8′), 112.0 (C4″), 111.7 (C6′), 109.8 (C1″), 109.6 (C3′), 61.0 (C1′), 31.1 (C10″), 27.4 (C2′), 23.6 (C9″). HRMS (ESI) m/z: 411.1907 [M + Na].

2.2.11 (S)-2-(tert-Butoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (T1)

A solution mixture of l-tryptophan (20.45 g, 0.10 mol), sodium hydroxide pellets (8.80 g, 0.22 mol), and di-tert-butyl dicarbonate (24.01 g, 0.11 mol) in THF/H2O (1:1) 100 mL was stirred at room temperature for 18 h. After the reaction was complete, water was added to dissolve the precipitate. Then, THF was removed under reduced pressure, and aqueous layer was extracted with dichloromethane. The aqueous layer was acidified by 1 N HCl to pH 4 and extracted with ethyl acetate. The organic phase was dried to yield white solid of compound T1. Yield 24.05 g (79%); m.p. 141–143 °C. 1H-NMR spectrum in DMSO-d6 (δ, ppm): 12.55 (s, 1H, COOH), 10.84 (s, 1H, indole NH), 7.53 (d, 1H, J 7.7 Hz, H9′), 7.34 (d, 1H, J 8.0 Hz, H6′), 7.15 (d, 1H, J1 1.5 Hz, H4′), 7.07 (t, 1H, J 7.4 Hz, H7′), 6.99 (t, 1H, J 7.14 Hz, H8′), 4.16 (m, 1H, H1′), 3.14 (dd, 1H, J1 4.5 Hz, J2 14.5 Hz, H2b′), 2.98 (dd, 1H, J1 9.4 Hz, J2 14.5 Hz, H2a′), 1.33 (s, 9 H, CH3).

2.2.12 (S)-Methyl 2-((S)-2-amino-3-(1H-indol-3-yl)propan amido)-3-hydroxy propanoate (T2)

A solution of compound T1 (304 mg, 1 mmol), l-serine methyl ester hydrochloride (155 mg, 1 mmol) HBTU (568.86 mg, 1.5 mmol), and DIPEA (0.42 mL, 3 mmol) in 5 mL of DMF was stirred at room temperature for 18 h. After the reaction was complete, water was added. The aqueous phase was extracted with ethyl acetate. The organic solution was dried over sodium sulphate, concentrated and purified by column chromatography on silica gel (EtOAc/hexane 4:1) to yield intermediated compound. Then, 10 mL of 1 N KOH in methanol was added to the obtained compound, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was adjusted to pH 7 by 1 N HCl and extracted with ethyl acetate. The combined organic layers were dried to yield compound T2 as white solid. Yield 267.05 mg (68.23%); m.p. 75–76 °C. 1H-NMR spectrum in DMSO-d6 (δ, ppm): 10.81 (s, 1H, indole NH), 8.20 (d, 1H, J 7.4 Hz, NH), 7.62 (d, 1H, J 7.7 Hz, H9′), 7.33 (d, 1H. J 7.8 Hz, H6′), 7.15 (s,1H, H4′), 7.06 (t, 1H, J 7.5 Hz, H7′), 6.98 (t, 1H, J 7.4 Hz, H8′), 4.40 (m, 1H, H2), 4.28 (m, 1H, H1′), 3.75 (dd, 2H, J1 4.5 Hz, J2 10.8 Hz, H4), 3.11 (dd, 1H, J1 3.8 Hz, J2 14.6 Hz, 1H, H2b′), 2.91 (dd, 1H, J1 9.7 Hz, J2 14.7 Hz, H2a′), 1.30 (s, 9H, CH3).

2.2.13 (S,Z)-tert-Butyl(6-((1H-indol-3-yl)methyl)-10,10-dimethyl-5,8-dioxo-9-oxa-2-thia-4,7-diazaundecan-3-ylidene)carbamate (T3)

A solution of compound T1 (304 mg, 1 mmol), compound 1a (160.22 mg, 1 mmol), HATU (570 mg, 1.5 mmol), and N-methylmorpholine (NMM) (0.22 mL, 2 mmol) in 5 mL of DMF was stirred at room temperature for 18 h. After the reaction was complete, water was added and extracted with ethyl acetate. The organic solution was dried. The obtained residue was purified by column chromatography on silica gel (EtOAc/Hex 1:4) to yield compound 5 as white powder. Yield 324.77 mg (68.20%); m.p. 80–81 °C. 1H-NMR spectrum in DMSO-d6 (δ, ppm): 12.17 (s, 1H, NH), 10.85 (s, 1H, indole-NH), 7.49 (s, 1H, NH), 7.57 (d, 1H, J 7.75 Hz, H9′), 7.33 (d, 1H, J 8.0 Hz, H6′), 7.19 (d, 1H, J 1.7 Hz, H4′), 7.07 (t, 2H, J 7.0 Hz, H7′), 6.99 (t, 1H, J 7.0 Hz, H8′), 4.27 (m, 1H, H1′), 3.19 (dd, 1H, J1 4.8 Hz, J2 14.7 Hz, H2b′), 2.97 (dd, 1H, J1 9.8 Hz, J2 14.6 Hz, H2a′), 2.30 (s, 3 H, CH3), 1.45 (s, 9 H, CH3), 1.33 (s, 9 H, CH3).

2.2.14 N-tert-Butoxycarbonyl (Boc)-protected 2-methyl-2-thiopseudourea (1a)

A solution of methylisothiourea hemisulfate salt (198 mg, 1 mmol) in THF/H2O (1:1) 30 mL was added with sodium bicarbonate (168 mg, 1 mmol), di-tert-butyl dicarbonate (218 mg, 1 mmol), and stirred at room temperature for 18 h. After the reaction was complete, THF was removed under reduced pressure, and aqueous layer was extracted with dichloromethane. The organic phase was dried to yield compound 1a as colorless viscous liquid. Yield 195.71 mg (76.62%). 1H-NMR spectrum in DMSO-d6 (δ, ppm): 8.54 (s, 1H, NH), 2.31 (s, 3H, CH3), 1.40 (s, 9H, CH3).

2.3 Biological experiment part

BACE1 enzyme and the BACE1 substrate were purchased from Sino Biological® and Calbiochem®, respectively. Aβ (1–42) from Anaspec® was used in the ThT assay. IC50 values were calculated using GraphPad Prism 4 with nonlinear regression curve fit. Statistics were determined by ANOVA, calculated using IBM SPSS statistics version 24.

2.3.1 BACE1 inhibition assay

The test compound, prepared at various concentrations in 5% DMSO, was added to black 96 well plates followed by 30 µl of enzyme working solution (0.01 unit/µl) and 20 µl of substrate solution (125 µM). The final volume was adjusted to 100 µl with 100 mM sodium acetate buffer (pH 4.5), and the reaction plate was incubated at 37°C for 30 min. The emitted fluorescence (Em) was measured at 510 nm after excitation (Ex) at 380 nm [15]. Compound 12c, previously synthesized and described in [16], was used as an in house BACE1 inhibitor positive control at a final concentration of 100 µM. The resulting data were analyzed, and compounds showing greater than 70% inhibition were evaluated at concentrations of 5–25 µM to determine their IC50 values. The IC50 values were calculated using GraphPad Prism 4 with a nonlinear regression curve fit.

2.3.2 Aβ aggregation inhibition assay

Amyloid solution in 50 mM Tris buffer (pH 7.4) at a concentration of 25 µM (9 µL) was added to transparent 96 well plate followed by test compounds (1 µL) at various concentrations prepared in DMSO. The reaction was mixed gently by tapping and incubated in dark at 37°C for 48 h. After incubation, 200 µL of 5 µM thioflavin-T (Sigma®) in 50 mM Tris buffer (pH 7.4) was added to each well. The emitted fluorescence (Em) was measured at 490 nm after excitation (Ex) at 446 nm [17]. Curcumin was included in the assay as a positive control. The resulting data were analyzed and compounds showing more than 70% inhibition were evaluated to determine their IC50 values. The data were analyzed using GraphPad Prism 4 with a nonlinear regression curve fit.

2.3.3 Antioxidant assay

The test compounds were prepared at a concentration of 500 µM in 50% DMSO. DPPH, prepared at a concentration of 500 µM in methanol, was added to transparent 96 well plates in a volume of 70 µL per well. Methanol was used to adjust the volume to 80 µL. After adjusting the volume, 20 µL of test compound was added to each well. The reaction plate was incubated at room temperature in dark for 30 min. The absorption was measured at wavelength 517 nm [18]. Ascorbic acid was used as a positive control. The percent inhibition was calculated. Compounds showing inhibition greater than 70% were evaluated to determine their IC50 values.

2.3.4 Neuroprotective effect on β-amyloid-induced cell damage

Protective effect on β-amyloid-induced cell damage was evaluated in human neuroblastoma cell (SH-SY5Y) cells. SH-SY5Y cells were cultured in Ham’s F12:Dulbecco’s modified Eagle’s medium (DMEM) containing 50 IU/mL penicillin, 50 g/mL streptomycin, 2 mM l-glutamine, and 10% fetal bovine serum. Cell cultures were maintained at 37°C in an atmosphere of 95% humidified air and 5% CO2. For the assays, SH-SY5Y cells were sub-cultured into a 96-well plate for 24 h. The cells were then incubated with Aβ1–42 (25 µM) with or without various concentrations of the test compounds for 24 h. Curcumin at a concentration of 10 µM was used as positive control. Cell viability was determined by staining the cells using water-soluble tetrazolium salt (WST-8) assay. The absorption was measured using a well plate reader at 450 nm [19].

  1. Ethical approval: The conducted research is not related to either human or animal use.

3 Results and discussion

3.1 Design and docking study

Trytophan was designed to be the core structure due to its properties in blood brain penetration via the large neutral amino acid transporter 1 or LAT1 transporter [20,21] and the BACE1 inhibitory activity [11]. The modification of the tryptophan was designed by including aromatic systems substituted with nucleophilic groups, such as hydroxyl groups, into the moieties based on reported pharmacophore models of anti-amyloid aggregation, antioxidant and metal chelating properties [22,23]. The proposed of extended part is to enhance the binding affinity for BACE1 in order to access the S3 pocket and also to contribute to multifunctional properties.

The expanded moiety was composed of two parts: R1 and R2. The amino acid (R1) was designed as a linker which contained a hydrogen bond acceptor to enable additional hydrogen bonding with Asp32 or Asp228, the key catalytic residues in BACE1 (Figure 1). Thus, amino acids with side chains bearing hydrogen bond donor such as –OH and –NH–, serine, tyrosine, threonine, and guanidine were selected as R1 linkers. The R2 terminal of the expanded moiety was designed to be an aromatic system with a nucleophilic motif to provide antioxidant activity. Moreover, the number of carbon atoms between the amino acid linker, R1, and the aromatic terminal R2 was varied between 7 and 10 Å, considering the optimal 8–9 Å distance when binding to Aβ (Figure 1) [22]. All 16 designed compounds were screened in silico with the main target BACE1, 2IRZ-F template, using the AutoDock program suite, version 4.2, to identify hit compounds for synthesis. The docking results were showed in Table 1.

Figure 1 The proposed designed compounds (X = O or N atom).
Figure 1

The proposed designed compounds (X = O or N atom).

Table 1

Docking results of the designed compounds against the BACE1 template

CpdR1R2ΔG (kcal/mol)LEaH-bond numberH-bond interacting residues (distance, A)
TSR1Ser
−11.5−0.416Asp32 (1.8), Gln73 (2.0), Asp228 (1.9, 2.0), Thr231 (1.9, 1.9)
TSR2Ser
−12.5−0.436Asp32 (1.7), Ser36 (1.9), Asn37 (1.9), Thr73 (2.1), Tyr198 (2.2), Asp228 (2.0)
TSR3Ser
−11.8−0.397Asp32 (1.7), Ser35 (2.0), Asn37 (1.9), Gln73 (2.3), Asp228 (1.9, 1.9), Thr231 (2.2)
TSR4Ser
−11.8−0.384Asp32 (1.9), Asp228 (1.8, 1.9), Thr231 (2.1)
TYR1Tyr
−9.1−0.265Gly34 (2.1), Gln73 (2.1), Phe108 (2.5), Thr231 (2.0), Thr232 (2.0)
TYR2Tyr
−10.5−0.304Asp32 (1.8), Ser229 (2.1), Gly230 (2.0), Thr232 (2.1)
TYR3Tyr
−10.3−0.283Phe108 (2.0), Gly230 (2.0), Thr231 (2.5)
TYR4Tyr
−10.0−0.264Gln73 (1.9), Gly230 (2.0), Thr231 (2.2), Thr232 (2.0)
TTH1Thr
−11.6−0.404Asp32 (1.9), Gln73 (1.9), Asp228 (1.8), Thr231 (2.1)
TTH2Thr
−12.5−0.415Asp32 (1.6), Ser35 (2.0), Thr72 (2.3), Asn73 (2.1), Asp228 (1.9)
TTH3Thr
−12.7−0.406Asp32 (1.6), Ser35 (1.7), Thr72 (2.4), Asn73 (2.0), Asp228 (1.8), Thr231 (2.0)
TTH4Thr
−13.0−0.395Asp32 (1.7), Thr72 (2.1), Gln73 (2.0), Asp228 (1.8), Gly230 (2.0)
TGN1Gnd
−11.7−0.475Asp32 (1.9), Asp228 (1.7, 2.2), Thr72 (2.1), Thr232 (2.1)
TGN2Gnd
−12.3−0.475Asp32 (1.7, 2.0), Thr72 (2.2), Asp228 (2.0), Thr232 (1.9)
TGN3Gnd
−12.0−0.446Asp32 (1.8), Thr72 (2.1), Asp228 (1.7, 2.1), Thr231 (1.9), Ser325 (2.0)
TGN4Gnd
−14.0−0.483Asp32 (1.7), Asp228 (1.7), Gly230 (1.9)
  1. a

    LE = ΔG/N, N is number of nonhydrogen atom.

The docking results showed that compounds in the TSR and TGN series generally gave better binding results than those in TYR and TTH series. This was because their binding mode allowed the linker R1 (serine or guanidine) to form extra H-bonds with the catalytic residues, Asp32 or Asp228. Moreover, ligand efficiency (LE) values and free binding energy of the four compounds in the TYR series with tyrosine as the linker (LE: −0.26 to −0.30 and ∆G: −9.1 to −10.0 kcal/mol) were not as favorable as those of the compounds in the TSR (LE: −0.38 to −0.43 and ∆G: −11.5 to −12.5 kcal/mol) or TGN series (LE: −0.44 to −0.48 and ∆G: −11.7 to −14.0 kcal/mol). The inferior binding affinity of the compounds in the TYR series was possibly due to their steric properties and greater flexibility of the tyrosine side chain. Compounds in the TTH series also presented good LE values and binding affinities, however, the linker R1 could not form an extra H-bond with the key residues Asp32 or Asp228. Therefore, compounds in the TYR and TTH series were not included in the synthesis part of the study.

3.2 Multifunctional assay

The compounds in the TSR and TGN series were initially screened for their inhibitory actions against BACE1, anti-amyloid aggregation effects, and antioxidant properties at a concentration of 100 µM, and the screening results are shown in Table 2. Compounds that demonstrated a percentage inhibition greater than 70% were further evaluated to determine their IC50 values. Positive controls for each assay were performed at the same concentration.

Table 2

Multifunctional activity of TSR and TGN compounds

CompoundsBACE1 inhibitionAnti-amyloid aggregationAntioxidant
% inhibition at 100 µM (± SD)IC50 (µM)% inhibition at 100 µM (± SD)IC50 (µM)% inhibition at 100 µM (± SD)IC50 (µM)
TSR150.64 (±0.72)*—88.06 (±1.22)*38.5515.36 (±0.66)*—
TSR288.07 (±2.87)24.1873.15 (±0.50)*37.064.28 (±1.02)*—
TSR346.72 (±2.12)*—53.33 (±1.85)*—3.47 (±0.81)*—
TSR496.98 (±1.62)*21.3846.32 (±1.23)*—9.78 (±0.66)*—
TGN149.60 (±2.33)*—36.12 (±0.51)*—81.88 (±0.45)*36.14
TGN294.35 (±1.86)22.3586.96 (±0.82)36.1213.05 (±1.45)*—
TGN399.68 (±1.02)31.0354.32 (±2.35)*—16.38 (±0.67)*—
TGN485.65 (±0.15)35.3549.78 (±1.54)*—8.19 (±1.39)*—
BACE1 inhibitor (12c)92.64 (±1.72)20.89————
Curcumin——84.02 (±1.07)0.63——
Ascorbic acid————54.16 (±0.77)94.92

Data are mean ± SD (n = 3), *p value < 0.001 compared with the positive control of each group (paired t- test statistic from Microsoft Excel). Structure of positive control compounds was shown in the supplemental information (Figures S21 and S22).

3.2.1 BACE1 inhibition assay

TSR2, TSR4, and TGN2 were found to be the potent inhibitors of BACE1. The IC50 values of these compounds were in the range of 21.38–24.18 µM. The binding modes of the three compounds are shown in Figure 2. The amino group in the tryptophan core structure of these three compounds provided H-bonds with the catalytic residues Asp32 and Asp228, and the compounds were well accommodated in binding pockets to form 5–6 hydrogen bonds. The OH of the serine and the NH of the guanidine linker did not form hydrogen bonds with the catalytic amino acids as expected, instead the NH of the amide backbone of both TSR4 and TGN2 formed additional H-bonds with Asp32 and Asp228. Moreover, the OH of the serine linker in compound TSR4 formed an H-bond with Thr231. The indole in the tryptophan core of compounds TSR2 and TSR4 was anchored to the S1 binding pocket whereas the middle part of TSR2 binding pose was aligned in the same orientation as TGN2. However, the tryptophan cores of TSR2 and TGN2 flipped into the opposite direction, the phenolic end (R2) of TSR2 directed to the S2′/S3′ pocket, providing H-bonding and hydrophobic interactions with residues in these pockets. The access to the S2′/S3′ pocket accommodated the phenolic OH and the NH between the middle serine and the phenolic group of TSR2 to form three hydrogen bonds with Ser36, Asn37, and Tyr198 (Figure 2b). Moreover, the insertion of the phenolic moiety of TSR2 contributed to interactions with the residues in the S3′ pocket, especially with Arg128, the amino acid reported to affect the binding conformation of a potent inhibitor (Figure 2b) [13]. These interactions enabled TSR2 to achieve the same level of inhibition as TSR4 and TGN2, although it was inaccessible to the S3 pocket.

Figure 2 The binding modes of TSR2 (yellow), TSR4 (green), and TGN2 (magenta) in the active binding site of BACE1, overlay of docked poses (a); and the interacting residues, showing hydrogen bonds as green dotted lines (b–d).
Figure 2

The binding modes of TSR2 (yellow), TSR4 (green), and TGN2 (magenta) in the active binding site of BACE1, overlay of docked poses (a); and the interacting residues, showing hydrogen bonds as green dotted lines (b–d).

3.2.2 Aβ aggregation inhibition assay

The anti-Aβ aggregation screening results obtained at a concentration of 100 µM showed that compounds TSR1, TSR2, and TGN2 inhibited amyloid aggregation by more than 70% (Table 2), and the IC50 values of these compounds were 38.55 µM, 37.06 µM, and 36.12 µM, respectively. The distances between aromatic terminals in the docked poses of compounds TSR1, TSR2, and TGN2 were measured and found to be 8.50 Å, 9.88 Å, and 8.00 Å, respectively, which are within the theoretical optimal distance (8–9 Å) [22]. The binding mode of the lead compounds with Aβ template revealed that TSR1-formed H-bonds with Glu11 (1.78 Å), Gln15 (2.09 Å), Glu22 (1.86 Å) and Asp23 (2.01 Å), while TSR2 provided H-bonds with Glu22 (1.92, 1.94 and 2.11 Å) and Asp23 (1.86 Å) (Figure 3a). The potent inhibitory activity of TSR1 and TSR2 against amyloid aggregation was possibly a result of two crucial types of interactions, H-bond interactions and hydrophobic interactions, with the key residues responsible for self-binding and the oligomer formation leading to aggregation.

Figure 3 The binding modes of the lead compounds with Aβ peptide: (a) TSR1 (cyan) and TSR2 (yellow); (b) TGN2 (magenta).
Figure 3

The binding modes of the lead compounds with Aβ peptide: (a) TSR1 (cyan) and TSR2 (yellow); (b) TGN2 (magenta).

H-bond interactions have been detected, particularly with Asp23, which is the key amino acid for intermolecular salt bridge formation of Aβ peptides in protein aggregation [24,25]. Hydrophobic interactions have been found with the key residue Phe19, the amino acid in the hydrophobic interaction region [25] that connects two β-strands of Aβ monomers, in the initiation of oligomer and fibril formation [26]. Thus, ligand binding with these amino acid residues (Phe19 and Asp23) was a contributing factor to the blocking of Aβ oligomer formation and hence to anti-aggregation activity. Besides Phe19 and Asp23, TSR1 and TSR2 were found to interact with His13 and His14, in the metal-binding site [27]. The metal-binding site (His6, His13, and His14) has been reported as the part of two monomers that coordinate with a metal ion (Cu2+ or Zn2+) [28,29]. This metal binding stabilizes and increases amyloid oligomerization [28,30]. Compound TGN2 formed H-bond interactions with Ala2 (1.74 Å), Glu3 (1.94 Å), and Glu11 (1.85 Å) (Figure 3b). Hydrophobic interactions of TGN2 were also found with all key amino acid residues in the metal-binding site, His6, His13, and His14 [31]. Moreover, all three compounds also had hydrophobic interactions with Gln15 and Val18, which are self-recognition residues in the aggregation process [32]. Taken together, binding at the important regions responsible for Aβ aggregation, namely, the hydrophobic region, the intermolecular salt bridge, and the metal-binding site resulted in the enhancement of anti-amyloid aggregation activity in the tested compounds.

3.2.3 Antioxidant assay

The antioxidant activity of the hit compounds was evaluated at concentrations of 100 µM using the DPPH scavenging method [18]. TGN1 was the only compound that showed high inhibition, with IC50 values of 36.14 µM, approximately three times better than that of ascorbic acid (IC50 94.92 µM). The direct guanidine substitution at the para-position of the phenol group in TGN1 might be the reason for its antioxidant properties, because of its strong electron-donating group via the π-bond and increased number of conjugated double bonds in the TGN1 molecule [33,34].

3.2.4 Neuroprotective effect on β-amyloid-induced cell damage

Among the eight compounds, two compounds, TSR2 and TGN2, possessed dual activities. TSR2 and TGN2 were evaluated for their neuroprotective effects on Aβ-induced cytotoxicity in SH-SY5Y neuroblastoma cells. The cytotoxicity of TSR2 and TGN2 was initially tested at 1, 10, and 100 µg/mL by the MTT assay. No significant reduction in cell viability was found at any of the tested concentrations, which indicated nontoxicity at the highest concentration (100 µg/mL). TSR2 and TGN2 were then screened at the highest concentration (100 µg/mL) for neuroprotective effects with the WST-8 assay, in which Aβ1–42 (25 µM) was used to induce cytotoxicity in SH-SY5Y cells. Cell viability was determined by measuring the absorption of the WST-8 at 450 nm [19]. The screening results are shown in Figure 4a. Neither compound showed neuroprotection at 100 µg/mL as anticipated, instead they presented lower percentage viability than the Aβ-treated group. Although TSR2 and TGN2 alone were nontoxic at 100 µM, it is likely that a synergistic effect occurred with the combination of Aβ and the test compounds at this concentration. As the percentage viability of TGN2 treated cells was slightly lower than that of Aβ treated cells, TGN2 was tested at lower doses (1 µg/mL and 10 µg/mL) to avoid the synergistic effect. TGN2 at lower concentrations appeared to reduce the cytotoxicity of Aβ (Figure 4b). However, a significant neuroprotective effect was observed only at 10 µg/mL or 2.62 µM.

Figure 4 Neuroprotective effects of dual activity compound against Aβ induced cytotoxicity: (a) the screening results at the nontoxic concentration of 100 µg/mL; (b) neuroprotective effects of TGN2. Data are mean ± SD (n = 3), #p < 0.01 compared with the control group and *p < 0.01 compared with the Aβ-treated group (paired t-test statistic from Microsoft Excel).
Figure 4

Neuroprotective effects of dual activity compound against Aβ induced cytotoxicity: (a) the screening results at the nontoxic concentration of 100 µg/mL; (b) neuroprotective effects of TGN2. Data are mean ± SD (n = 3), #p < 0.01 compared with the control group and *p < 0.01 compared with the Aβ-treated group (paired t-test statistic from Microsoft Excel).

4 Conclusion

Among the developed compounds, TGN2 was found to exhibit multifunctionality, with potent actions as a BACE1 inhibitor and against amyloid aggregation. TGN1 was found as a potent antioxidant with greater activity than ascorbic acid. Moreover, based on its multifunctional activity on the Aβ cascade, TGN2 at a concentration of 2.62 µM showed a significant neuroprotective effect against Aβ-induced cytotoxicity.

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  1. Conflict of interest: The authors have declared no conflict of interest.

Acknowledgments

The authors would like to acknowledge the financial support from the Office of the High Education Commission and Mahidol University under the National Research Universities and the Commission on Higher Education (grant number CHE-RG-2551-53). This research work was partially supported by Chiang Mai University.

References

[1] Barage SH, Sonawane KD. Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides. 2015;52:1–18. 10.1016/j.npep.2015.06.008Search in Google Scholar PubMed

[2] Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer’s disease. Brain. 2006;129(11):2840–55. 10.1093/brain/awl280Search in Google Scholar PubMed

[3] Ghosh AK, Osswald HL. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem Soc Rev. 2014;43(19):6765–813. 10.1039/c3cs60460hSearch in Google Scholar PubMed PubMed Central

[4] Nie Q, Du XG, Geng MY. Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer’s disease. Acta Pharm Sin. 2011;32(5):545–51. 10.1038/aps.2011.14Search in Google Scholar PubMed PubMed Central

[5] Imbimbo BP. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem. 2008;8(1):54–61. 10.2174/156802608783334015Search in Google Scholar PubMed

[6] Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement. 2017;3(3):367–84. 10.1016/j.trci.2017.05.002Search in Google Scholar PubMed PubMed Central

[7] Luo XT, Wang CM, Liu Y, Huang ZG. New multifunctional melatonin derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur J Med Chem. 2015;103:302–11. 10.1016/j.ejmech.2015.08.052Search in Google Scholar PubMed

[8] Xie SS, Wang X, Jiang N, Yu W, Wang KDG, Lan JS, et al. Multi-target tacrine–coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur J Med Chem. 2015;95:153–65. 10.1016/j.ejmech.2015.03.040Search in Google Scholar PubMed

[9] Estrada M, Herrera-Arozamena C, Pérez C, Viña D, Romero A, Morales-García JA, et al. New cinnamic − N-benzylpiperidine and cinnamic – N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties. Eur J Med Chem. 2016;121:376–86. 10.1016/j.ejmech.2016.05.055Search in Google Scholar PubMed

[10] Barar J, Rafi MA, Pourseif MM, Omidi Y. Blood–brain barrier transport machineries and targeted therapy of brain diseases. Bioimpacts. 2016;6(4):225–48. 10.15171/bi.2016.30Search in Google Scholar PubMed PubMed Central

[11] Jiaranaikulwanitch J, Boonyarat C, Fokin VV, Vajragupta O. Triazolyl tryptoline derivatives as β-secretase inhibitors. Bioorg Med Chem Lett. 2010;20(22):6572–6. 10.1016/j.bmcl.2010.09.043Search in Google Scholar PubMed PubMed Central

[12] Rajapakse HA, Nantermet PG, Selnick HG, Munshi S, McGaughey GB, Lindsley SR, et al. Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1). J Med Chem. 2006;49(25):7270–3. 10.1021/jm061046rSearch in Google Scholar PubMed

[13] Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000;290(5489):150–3. 10.1126/science.290.5489.150Search in Google Scholar PubMed

[14] Tomaselli S, Esposito V, Vangone P, van Nuland NAJ, Bonvin AM, Guerrini R, et al. The α-to-β conformational transition of Alzheimer’s Aβ-(1–42) peptide in aqueous media is reversible: a step by step conformational analysis suggests the location of β conformation seeding. ChemBioChem. 2006;7(2):257–67. 10.1002/cbic.200500223Search in Google Scholar PubMed

[15] Ermolieff J, Loy JA, Koelsch G, Tang J. Proteolytic activation of recombinant Pro-memapsin 2 (Pro-β-secretase) studied with new fluorogenic substrates. Biochemistry. 2000;39(40):12450–6. 10.1021/bi001494fSearch in Google Scholar PubMed

[16] Jiaranaikulwanitch J, Govitrapong P, Fokin VV, Vajragupta O. From BACE1 inhibitor to multifunctionality of tryptoline and tryptamine triazole derivatives for Alzheimer’s disease. Molecules. 2012;17(7):8312–33. 10.3390/molecules17078312Search in Google Scholar PubMed PubMed Central

[17] LeVine 3rd H. Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 1993;2(3):404–10. 10.1002/pro.5560020312Search in Google Scholar PubMed PubMed Central

[18] Sharma OP, Bhat TK. DPPH antioxidant assay revisited. Food Chem. 2009;113(4):1202–5. j.foodchem.2008.08.008.Search in Google Scholar

[19] Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M, et al. Synthesis, biological evaluation and molecular modeling study of novel tacrinecarbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem. 2014;75:21–30. 10.1016/j.ejmech.2014.01.020Search in Google Scholar PubMed

[20] Tarlungeanu DC, Deliu E, Dotter CP, Kara M, Janiesch PC, Scalise M, et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 2016;167(6):1481–94. 10.1016/j.cell.2016.11.013Search in Google Scholar PubMed PubMed Central

[21] Rautio J, Gynther M, Laine K. LAT1-mediated prodrug uptake: a way to breach the blood–brain barrier? Ther Deliv. 2013;4(3):281–4. 10.4155/tde.12.165Search in Google Scholar PubMed

[22] Reinke AA, Gestwicki JE. Structure–activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des. 2007;70(3):206–15. 10.1111/j.1747-0285.2007.00557.xSearch in Google Scholar PubMed

[23] Geldenhuys WJ, Youdim MB, Carroll RT, Van, der Schyf CJ. The emergence of designed multiple ligands for neurodegenerative disorders. Prog Neurobiol. 2011;94(4):347–59. 10.1016/j.pneurobio.2011.04.010Search in Google Scholar PubMed

[24] Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, et al. 3D structure of Alzheimer’s amyloid-β(1–42) fibrils. Proc Natl Acad Sci U S A. 2005;102(48):17342–7. 10.1073/pnas.0506723102Search in Google Scholar PubMed PubMed Central

[25] Hayne DJ, Lim S, Donnelly PS. Metal complexes designed to bind to amyloid-[small beta] for the diagnosis and treatment of Alzheimer’s disease. Chem Soc Rev. 2014;43:6701–15. 10.1039/C4CS00026ASearch in Google Scholar

[26] Alies B, Conte-Daban A, Sayen S, Collin F, Kieffer I, Guillon E, et al. Zinc(II) binding site to the Amyloid-β peptide: insights from spectroscopic studies with a wide series of modified peptides. Inorg Chem. 2016;55(20):10499–509. 10.1021/acs.inorgchem.6b01733Search in Google Scholar PubMed PubMed Central

[27] Rezaei-Ghaleh N, Giller K, Becker S, Zweckstetter M. Effect of zinc binding on β-amyloid structure and dynamics: implications for Aβ aggregation. Biophys J. 2011;101(5):1202–11, 10.1016/j.bpj.2011.06.062Search in Google Scholar PubMed PubMed Central

[28] Miller Y, Ma B, Nussinov R. Metal binding sites in amyloid oligomers: complexes and mechanisms. Coord Chem Rev. 2012;256(19–20):2245–52. 10.1016/j.ccr.2011.12.022Search in Google Scholar

[29] Gaggelli E, Grzonka Z, Kozłowski H, Migliorini C, Molteni E, Valensin D, et al. Structural features of the Cu(II) complex with the rat Aβ(1–28) fragment. Chem Commun. 2008;2008:341–3. 10.1039/b713453cSearch in Google Scholar PubMed

[30] Miura T, Suzuki K, Kohata N, Takeuchi H. Metal binding modes of Alzheimer’s amyloid β-peptide in insoluble aggregates and soluble complexes. Biochemistry. 2000;39(23):7024–31. 10.1021/bi0002479Search in Google Scholar PubMed

[31] Kozin SA, Mezentsev YV, Kulikova AA, Indeykina MI, Golovin AV, Ivanov AS, et al. Zinc-induced dimerization of the amyloid-[small beta] metal-binding domain 1–16 is mediated by residues 11–14. Mol Biosyst. 2011;7(4):1053–5. 10.1039/c0mb00334dSearch in Google Scholar PubMed

[32] Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, et al. Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils. Nat Struct Mol Biol. 2010;17(5):561–7. 10.1038/nsmb.1799Search in Google Scholar PubMed PubMed Central

[33] Ji HF. Insight into the strong antioxidant activity of deinoxanthin, a unique carotenoid in deinococcus radiodurans. Int J Mol Sci. 2010;11(11):4506–10. 10.3390/ijms11114506Search in Google Scholar PubMed PubMed Central

[34] Bendary E, Francis RR, Ali HMG, Sarwat MI, El Hady S. Antioxidant and structure–activity relationships (SARs) of some phenolic and anilines compounds. Ann Agric Sci. 2013;58(2):173–81. 10.1016/j.aoas.2013.07.002Search in Google Scholar

Received: 2020-02-11
Revised: 2020-03-31
Accepted: 2020-04-03
Published Online: 2020-06-09

© 2020 Piyapan Suwanttananuruk et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/chem-2020-0067
Keywords for this article
tryptophan; multifunction activities; beta-secretase inhibitor; amyloid aggregation inhibition; neuroprotection
Creative Commons
BY 4.0

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  11. Design, Synthesis and Characterization of Novel Isoxazole Tagged Indole Hybrid Compounds
  12. Comparison of kinetic and enzymatic properties of intracellular phosphoserine aminotransferases from alkaliphilic and neutralophilic bacteria
  13. Green Organic Solvent-Free Oxidation of Alkylarenes with tert-Butyl Hydroperoxide Catalyzed by Water-Soluble Copper Complex
  14. Ducrosia ismaelis Asch. essential oil: chemical composition profile and anticancer, antimicrobial and antioxidant potential assessment
  15. DFT calculations as an efficient tool for prediction of Raman and infra-red spectra and activities of newly synthesized cathinones
  16. Influence of Chemical Osmosis on Solute Transport and Fluid Velocity in Clay Soils
  17. A New fatty acid and some triterpenoids from propolis of Nkambe (North-West Region, Cameroon) and evaluation of the antiradical scavenging activity of their extracts
  18. Antiplasmodial Activity of Stigmastane Steroids from Dryobalanops oblongifolia Stem Bark
  19. Rapid identification of direct-acting pancreatic protectants from Cyclocarya paliurus leaves tea by the method of serum pharmacochemistry combined with target cell extraction
  20. Immobilization of Pseudomonas aeruginosa static biomass on eggshell powder for on-line preconcentration and determination of Cr (VI)
  21. Assessment of methyl 2-({[(4,6-dimethoxypyrimidin-2-yl)carbamoyl] sulfamoyl}methyl)benzoate through biotic and abiotic degradation modes
  22. Stability of natural polyphenol fisetin in eye drops Stability of fisetin in eye drops
  23. Production of a bioflocculant by using activated sludge and its application in Pb(II) removal from aqueous solution
  24. Molecular Properties of Carbon Crystal Cubic Structures
  25. Synthesis and characterization of calcium carbonate whisker from yellow phosphorus slag
  26. Study on the interaction between catechin and cholesterol by the density functional theory
  27. Analysis of some pharmaceuticals in the presence of their synthetic impurities by applying hybrid micelle liquid chromatography
  28. Two mixed-ligand coordination polymers based on 2,5-thiophenedicarboxylic acid and flexible N-donor ligands: the protective effect on periodontitis via reducing the release of IL-1β and TNF-α
  29. Incorporation of silver stearate nanoparticles in methacrylate polymeric monoliths for hemeprotein isolation
  30. Development of ultrasound-assisted dispersive solid-phase microextraction based on mesoporous carbon coated with silica@iron oxide nanocomposite for preconcentration of Te and Tl in natural water systems
  31. N,N′-Bis[2-hydroxynaphthylidene]/[2-methoxybenzylidene]amino]oxamides and their divalent manganese complexes: Isolation, spectral characterization, morphology, antibacterial and cytotoxicity against leukemia cells
  32. Determination of the content of selected trace elements in Polish commercial fruit juices and health risk assessment
  33. Diorganotin(iv) benzyldithiocarbamate complexes: synthesis, characterization, and thermal and cytotoxicity study
  34. Keratin 17 is induced in prurigo nodularis lesions
  35. Anticancer, antioxidant, and acute toxicity studies of a Saudi polyherbal formulation, PHF5
  36. LaCoO3 perovskite-type catalysts in syngas conversion
  37. Comparative studies of two vegetal extracts from Stokesia laevis and Geranium pratense: polyphenol profile, cytotoxic effect and antiproliferative activity
  38. Fragmentation pattern of certain isatin–indole antiproliferative conjugates with application to identify their in vitro metabolic profiles in rat liver microsomes by liquid chromatography tandem mass spectrometry
  39. Investigation of polyphenol profile, antioxidant activity and hepatoprotective potential of Aconogonon alpinum (All.) Schur roots
  40. Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
  41. Physicochemical evaluation of the fruit pulp of Opuntia spp growing in the Mediterranean area under hard climate conditions
  42. Electronic structural properties of amino/hydroxyl functionalized imidazolium-based bromide ionic liquids
  43. New Schiff bases of 2-(quinolin-8-yloxy)acetohydrazide and their Cu(ii), and Zn(ii) metal complexes: their in vitro antimicrobial potentials and in silico physicochemical and pharmacokinetics properties
  44. Treatment of adhesions after Achilles tendon injury using focused ultrasound with targeted bFGF plasmid-loaded cationic microbubbles
  45. Synthesis of orotic acid derivatives and their effects on stem cell proliferation
  46. Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis
  47. Fe3O4@urea/HITh-SO3H as an efficient and reusable catalyst for the solvent-free synthesis of 7-aryl-8H-benzo[h]indeno[1,2-b]quinoline-8-one and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives
  48. Adsorption kinetic characteristics of molybdenum in yellow-brown soil in response to pH and phosphate
  49. Enhancement of thermal properties of bio-based microcapsules intended for textile applications
  50. Exploring the effect of khat (Catha edulis) chewing on the pharmacokinetics of the antiplatelet drug clopidogrel in rats using the newly developed LC-MS/MS technique
  51. A green strategy for obtaining anthraquinones from Rheum tanguticum by subcritical water
  52. Cadmium (Cd) chloride affects the nutrient uptake and Cd-resistant bacterium reduces the adsorption of Cd in muskmelon plants
  53. Removal of H2S by vermicompost biofilter and analysis on bacterial community
  54. Structural cytotoxicity relationship of 2-phenoxy(thiomethyl)pyridotriazolopyrimidines: Quantum chemical calculations and statistical analysis
  55. A self-breaking supramolecular plugging system as lost circulation material in oilfield
  56. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives
  57. Application of drug–metal ion interaction principle in conductometric determination of imatinib, sorafenib, gefitinib and bosutinib
  58. Synthesis and characterization of a novel chitosan-grafted-polyorthoethylaniline biocomposite and utilization for dye removal from water
  59. Optimisation of urine sample preparation for shotgun proteomics
  60. DFT investigations on arylsulphonyl pyrazole derivatives as potential ligands of selected kinases
  61. Treatment of Parkinson’s disease using focused ultrasound with GDNF retrovirus-loaded microbubbles to open the blood–brain barrier
  62. New derivatives of a natural nordentatin
  63. Fluorescence biomarkers of malignant melanoma detectable in urine
  64. Study of the remediation effects of passivation materials on Pb-contaminated soil
  65. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
  66. Withania frutescens: Chemical characterization, analgesic, anti-inflammatory, and healing activities
  67. Design, synthesis and pharmacological profile of (−)-verbenone hydrazones
  68. Synthesis of magnesium carbonate hydrate from natural talc
  69. Stability-indicating HPLC-DAD assay for simultaneous quantification of hydrocortisone 21 acetate, dexamethasone, and fluocinolone acetonide in cosmetics
  70. A novel lactose biosensor based on electrochemically synthesized 3,4-ethylenedioxythiophene/thiophene (EDOT/Th) copolymer
  71. Citrullus colocynthis (L.) Schrad: Chemical characterization, scavenging and cytotoxic activities
  72. Development and validation of a high performance liquid chromatography/diode array detection method for estrogen determination: Application to residual analysis in meat products
  73. PCSK9 concentrations in different stages of subclinical atherosclerosis and their relationship with inflammation
  74. Development of trace analysis for alkyl methanesulfonates in the delgocitinib drug substance using GC-FID and liquid–liquid extraction with ionic liquid
  75. Electrochemical evaluation of the antioxidant capacity of natural compounds on glassy carbon electrode modified with guanine-, polythionine-, and nitrogen-doped graphene
  76. A Dy(iii)–organic framework as a fluorescent probe for highly selective detection of picric acid and treatment activity on human lung cancer cells
  77. A Zn(ii)–organic cage with semirigid ligand for solvent-free cyanosilylation and inhibitory effect on ovarian cancer cell migration and invasion ability via regulating mi-RNA16 expression
  78. Polyphenol content and antioxidant activities of Prunus padus L. and Prunus serotina L. leaves: Electrochemical and spectrophotometric approach and their antimicrobial properties
  79. The combined use of GC, PDSC and FT-IR techniques to characterize fat extracted from commercial complete dry pet food for adult cats
  80. MALDI-TOF MS profiling in the discovery and identification of salivary proteomic patterns of temporomandibular joint disorders
  81. Concentrations of dioxins, furans and dioxin-like PCBs in natural animal feed additives
  82. Structure and some physicochemical and functional properties of water treated under ammonia with low-temperature low-pressure glow plasma of low frequency
  83. Mesoscale nanoparticles encapsulated with emodin for targeting antifibrosis in animal models
  84. Amine-functionalized magnetic activated carbon as an adsorbent for preconcentration and determination of acidic drugs in environmental water samples using HPLC-DAD
  85. Antioxidant activity as a response to cadmium pollution in three durum wheat genotypes differing in salt-tolerance
  86. A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing
  87. Synthesis and efficacy of herbicidal ionic liquids with chlorsulfuron as the anion
  88. Effect of isovalent substitution on the crystal structure and properties of two-slab indates BaLa2−xSmxIn2O7
  89. Synthesis, spectral and thermo-kinetics explorations of Schiff-base derived metal complexes
  90. An improved reduction method for phase stability testing in the single-phase region
  91. Comparative analysis of chemical composition of some commercially important fishes with an emphasis on various Malaysian diets
  92. Development of a solventless stir bar sorptive extraction/thermal desorption large volume injection capillary gas chromatographic-mass spectrometric method for ultra-trace determination of pyrethroids pesticides in river and tap water samples
  93. A turbidity sensor development based on NL-PI observers: Experimental application to the control of a Sinaloa’s River Spirulina maxima cultivation
  94. Deep desulfurization of sintering flue gas in iron and steel works based on low-temperature oxidation
  95. Investigations of metallic elements and phenolics in Chinese medicinal plants
  96. Influence of site-classification approach on geochemical background values
  97. Effects of ageing on the surface characteristics and Cu(ii) adsorption behaviour of rice husk biochar in soil
  98. Adsorption and sugarcane-bagasse-derived activated carbon-based mitigation of 1-[2-(2-chloroethoxy)phenyl]sulfonyl-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) urea-contaminated soils
  99. Antimicrobial and antifungal activities of bifunctional cooper(ii) complexes with non-steroidal anti-inflammatory drugs, flufenamic, mefenamic and tolfenamic acids and 1,10-phenanthroline
  100. Application of selenium and silicon to alleviate short-term drought stress in French marigold (Tagetes patula L.) as a model plant species
  101. Screening and analysis of xanthine oxidase inhibitors in jute leaves and their protective effects against hydrogen peroxide-induced oxidative stress in cells
  102. Synthesis and physicochemical studies of a series of mixed-ligand transition metal complexes and their molecular docking investigations against Coronavirus main protease
  103. A study of in vitro metabolism and cytotoxicity of mephedrone and methoxetamine in human and pig liver models using GC/MS and LC/MS analyses
  104. A new phenyl alkyl ester and a new combretin triterpene derivative from Combretum fragrans F. Hoffm (Combretaceae) and antiproliferative activity
  105. Erratum
  106. Erratum to: A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  107. Review Articles
  108. Sinoporphyrin sodium, a novel sensitizer for photodynamic and sonodynamic therapy
  109. Natural products isolated from Casimiroa
  110. Plant description, phytochemical constituents and bioactivities of Syzygium genus: A review
  111. Evaluation of elastomeric heat shielding materials as insulators for solid propellant rocket motors: A short review
  112. Special Issue on Applied Biochemistry and Biotechnology 2019
  113. An overview of Monascus fermentation processes for monacolin K production
  114. Study on online soft sensor method of total sugar content in chlorotetracycline fermentation tank
  115. Studies on the Anti-Gouty Arthritis and Anti-hyperuricemia Properties of Astilbin in Animal Models
  116. Effects of organic fertilizer on water use, photosynthetic characteristics, and fruit quality of pear jujube in northern Shaanxi
  117. Characteristics of the root exudate release system of typical plants in plateau lakeside wetland under phosphorus stress conditions
  118. Characterization of soil water by the means of hydrogen and oxygen isotope ratio at dry-wet season under different soil layers in the dry-hot valley of Jinsha River
  119. Composition and diurnal variation of floral scent emission in Rosa rugosa Thunb. and Tulipa gesneriana L.
  120. Preparation of a novel ginkgolide B niosomal composite drug
  121. The degradation, biodegradability and toxicity evaluation of sulfamethazine antibiotics by gamma radiation
  122. Special issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  123. Insight into the cadmium and zinc binding potential of humic acids derived from composts by EEM spectra combined with PARAFAC analysis
  124. Source apportionment of soil contamination based on multivariate receptor and robust geostatistics in a typical rural–urban area, Wuhan city, middle China
  125. Special Issue on 13th JCC 2018
  126. The Role of H2C2O4 and Na2CO3 as Precipitating Agents on The Physichochemical Properties and Photocatalytic Activity of Bismuth Oxide
  127. Preparation of magnetite-silica–cetyltrimethylammonium for phenol removal based on adsolubilization
  128. Topical Issue on Agriculture
  129. Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions
  130. The effect of silica-calcite sedimentary rock contained in the chicken broiler diet on the overall quality of chicken muscles
  131. Physicochemical properties of selected herbicidal products containing nicosulfuron as an active ingredient
  132. Lycopene in tomatoes and tomato products
  133. Fluorescence in the assessment of the share of a key component in the mixing of feed
  134. Sulfur application alleviates chromium stress in maize and wheat
  135. Effectiveness of removal of sulphur compounds from the air after 3 years of biofiltration with a mixture of compost soil, peat, coconut fibre and oak bark
  136. Special Issue on the 4th Green Chemistry 2018
  137. Study and fire test of banana fibre reinforced composites with flame retardance properties
  138. Special Issue on the International conference CosCI 2018
  139. Disintegration, In vitro Dissolution, and Drug Release Kinetics Profiles of k-Carrageenan-based Nutraceutical Hard-shell Capsules Containing Salicylamide
  140. Synthesis of amorphous aluminosilicate from impure Indonesian kaolin
  141. Special Issue on the International Conf on Science, Applied Science, Teaching and Education 2019
  142. Functionalization of Congo red dye as a light harvester on solar cell
  143. The effect of nitrite food preservatives added to se’i meat on the expression of wild-type p53 protein
  144. Biocompatibility and osteoconductivity of scaffold porous composite collagen–hydroxyapatite based coral for bone regeneration
  145. Special Issue on the Joint Science Congress of Materials and Polymers (ISCMP 2019)
  146. Effect of natural boron mineral use on the essential oil ratio and components of Musk Sage (Salvia sclarea L.)
  147. A theoretical and experimental study of the adsorptive removal of hexavalent chromium ions using graphene oxide as an adsorbent
  148. A study on the bacterial adhesion of Streptococcus mutans in various dental ceramics: In vitro study
  149. Corrosion study of copper in aqueous sulfuric acid solution in the presence of (2E,5E)-2,5-dibenzylidenecyclopentanone and (2E,5E)-bis[(4-dimethylamino)benzylidene]cyclopentanone: Experimental and theoretical study
  150. Special Issue on Chemistry Today for Tomorrow 2019
  151. Diabetes mellitus type 2: Exploratory data analysis based on clinical reading
  152. Multivariate analysis for the classification of copper–lead and copper–zinc glasses
  153. Special Issue on Advances in Chemistry and Polymers
  154. The spatial and temporal distribution of cationic and anionic radicals in early embryo implantation
  155. Special Issue on 3rd IC3PE 2020
  156. Magnetic iron oxide/clay nanocomposites for adsorption and catalytic oxidation in water treatment applications
  157. Special Issue on IC3PE 2018/2019 Conference
  158. Exergy analysis of conventional and hydrothermal liquefaction–esterification processes of microalgae for biodiesel production
  159. Advancing biodiesel production from microalgae Spirulina sp. by a simultaneous extraction–transesterification process using palm oil as a co-solvent of methanol
  160. Topical Issue on Applications of Mathematics in Chemistry
  161. Omega and the related counting polynomials of some chemical structures
  162. M-polynomial and topological indices of zigzag edge coronoid fused by starphene
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