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. 2017 Jan 13;8(2):465–470. doi: 10.1039/c6md00647g

Synthesis and biological evaluation of 8-hydroxy-2,7-naphthyridin-2-ium salts as novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)† ‡

M Schiedel a, A Fallarero b, C Luise c, W Sippl c, P Vuorela b, M Jung a,✉
PMCID: PMC6072306  PMID: 30108764

graphic file with name c6md00647g-ga.jpgDiscovery of 8-hydroxy-2,7-naphthyridinium salts as a novel class of cholinesterase inhibitors inspired by the natural product chelerythrine.

Abstract

By analogy with the natural product chelerythrine, which has been identified as an inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), we prepared a small series of 8-hydroxy-2,7-naphthyridin-2-ium salts. Spectroscopic analyses allowed us to elucidate the zwitterionic nature of 2,7-naphthyridin-1(7H)-ones, the neutral state of 8-hydroxy-2,7-naphthyridin-2-ium salts. Among the tested compounds, we identified dual inhibitors of AChE and BChE as well as an inhibitor showing a preferential inhibition of AChE over BChE. By in vitro characterization in combination with docking studies, we were able to identify structural features that influence the biological activity of 8-hydroxy-2,7-naphthyridin-2-ium salts.

1. Introduction

The enzyme family of cholinesterases (ChEs) catalyses the hydrolysis of choline-based esters to terminate cholinergic signal transmission.1 There are two different types of cholinesterases, which were termed according to their substrate preferences: acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8). AChE is mainly found in chemical synapses of the central and peripheral nervous systems and in the membranes of erythrocytes, while BChE is primarily present in the blood. However, to some extent, BChE can be found in the CNS as well.2 In contrast to AChE and its well-known function as a pivotal regulator of cholinergic neurotransmission, BChE is widely viewed as a “backup enzyme” for AChE and a general-purpose metabolizer of bioactive esters in the diet. Yet, recent reports highlight the role of BChE as a co-regulator of acetylcholine levels in the human brain as well as its influence on the control of aggression and social stress by hydrolysing the peptide hormone ghrelin.3,4 A dysregulation of cholinergic signal transduction has been associated with several diseases like myasthenia gravis,5 postoperative ileus,6 bladder dysfunction,7 glaucoma,8 and Alzheimer's disease (AD).9 The hallmarks of AD are the formation of amyloid β (Aβ) plaques, neurofibrillary tangles, and a drastic decrease in hippocampal and cortical levels of acetylcholine.10 A multitude of evidence indicate that the pathological accumulation of Aβ in the CNS leads to various damaging events, which finally cause neuronal destruction, cholinergic deficit, and decreased cognitive function. To counteract the deprived cholinergic neurotransmission by blocking the inactivation of acetylcholine, the inhibition of AChE is a highly relevant therapeutic approach for the symptomatic treatment of AD. In the mid-1990s, the development of AChE inhibitors (AChEIs) resulted in the approval of three drugs (donepezil (1, Fig. 1), rivastigmine, and galantamine) for the treatment of mild-to-moderate AD. While the carbamate rivastigmine, classified as a “pseudo-irreversible AChEI”, forms a covalent adduct with the serine residue of the catalytic triad of AChE, donepezil and galantamine are reversible AChEIs that compete with acetylcholine for AChE binding.11 To date, these drugs represent the first line pharmacotherapy for the treatment of mild-to-moderate AD. In addition to the disease alleviating effects of AChEIs due to an amplification of the deprived cholinergic activity, various studies demonstrated that AChEIs are also able to prevent Aβ oligomerization, at least to some extent.12 AChE is considered as the main cholinesterase to target in the AD scenario, however, there are studies that highlight the role of BChE in the progression of AD.13–15 These studies indicate that in the course of disease progression, the AChE activity decreases while the activity of BChE remains unaffected or is even elevated.13,14 Since BChE is able to compensate for an inhibition of AChE, at least to a certain extent,16 the inhibition of BChE seems to be an attractive therapeutic concept in AD as well. Several potent and selective BChE inhibitors have been developed over the last decade.15,17–21 However, none of these BChEIs has received the approval for AD treatment yet. Notably, the approved AD drug rivastigmine is a dual inhibitor of AChE and BChE,22 while donepezil and galantamine show a high selectivity for AChE.23,24 However, efforts were made either to achieve BChE inhibition of galantamine and donepezil by a chemical modification of their structures or to discover novel chemotypes as dual ChEIs.25–30 We have identified natural products with an isoquinoline scaffold as ChEIs, among these is chelerythrine (2, Fig. 1), a dual inhibitor of AChE and BChE. Moreover, chelerythrine was shown to prevent Aβ aggregation and to disaggregate already formed Aβ aggregates.31

Fig. 1. Chemical structures of the approved AChEI donepezil hydrochloride (1) and the dual ChEI chelerythrine (2) in comparison with the generic structure of 8-hydroxy-2,7-naphthyridin-2-ium chloride (3).

Fig. 1

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Kinetic analyses revealed that chelerythrine binds to both the catalytic site and the peripheral anionic site (PAS) of AChE.31 By analogy with chelerythrine with its quaternary ammonium group that is linked by three carbons to an oxygen, we aimed to develop 8-hydroxy-2,7-naphthyridin-2-ium salts (3) as potential inhibitors of AChE and BChE. The synthesis of the highly fluorescent 8-hydroxy-2,7-naphthyridin-2-ium salts, as well as their conjugated bases, the 2,7-naphthyridin-1(7H)-ones, has already been published,32–35 however, no distinct biological activity has been attributed to this chemotype. Instead, the formation of 8-hydroxy-2,7-naphthyridin-2-ium salts was utilized as an operating principle of several fluorescence-based assay methods to detect nicotinamide and its analogues.34,36–38

2. Results and discussion

2.1. Design of the 8-hydroxy-2,7-naphthyridin-2-ium salts as ChEIs

Since natural products of the 8-methoxyisoquinoline group, e.g. chelerythrine (2), palmatine, and berberine, have been identified as ChEIs,31 we designed 8-hydroxy-2,7-naphthyridin-2-ium salts (3) as potential inhibitors of AChE and BChE, based on their similarity to the 8-methoxyisoquinoline scaffold. The binding mode of 8-methoxyisoquinolines is unknown, because these compounds have not been co-crystallized with ChEs yet. Therefore, we aimed to generate structurally different 8-hydroxy-2,7-naphthyridin-2-ium salts to gain first insights into structural motifs that influence the biological activity. According to the synthetic procedure (see below), the residues at positions 2 and 6 of the 2,7-naphthyridin-2-ium scaffold could be easily modified by using different N1-alkylated nicotinamide derivatives and enolizable ketones, respectively, as starting materials for the formation of the 8-hydroxy-2,7-naphthyridin-2-ium salts. By analogy with the N-benzylated AChEI donepezil (1), we synthesized a number of compounds that bear a benzyl moiety in position 2 of the 2,7-naphthyridin-2-ium scaffold. Docking of substituted 8-hydroxy-2,7-naphthyridin-2-ium salts and comparison with the binding mode of donepezil at AChE showed that bulky aromatic rings (e.g. naphthyl) at position 6 show favourable interaction with Trp279 that is a part of the peripheral anionic site (PAS).

2.2. Synthetic procedures and physicochemical characterization

The synthesis of the 8-hydroxy-2,7-naphthyridin-2-ium salts started with the N-alkylation of nicotinamide (4) with ethyl iodide or benzyl chloride to give the pyridinium salts (5a–b) in 29% and 71% yield, respectively.39,40 N1-Methyl nicotinamide was purchased from a commercial vendor. The 8-hydroxy-2,7-naphthyridin-2-ium salts were formed by the reaction of N1-alkylated nicotinamide derivatives with enolizable ketones, according to the general procedure published by Ukawa-Ishikawa et al.34 In an alkaline milieu at 0 °C, this one-pot synthesis was initiated by the nucleophilic attack of a deprotonated ketone to position 4 of the pyridinium salt to form 1,4-dihydropyridines with the general structure of 6. Notably, 1,4-dihydropyridines were not isolated. Upon the addition of formic acid and refluxing, the 8-hydroxy-2,7-naphthyridin-2-ium salts were formed by intramolecular condensation and oxidation in yields ranging from 2–33% (Scheme 1). All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectrometry (for detailed information see the ESI‡). UV-vis and fluorescence properties, including excitation and emission maxima (λmaxabs and λmaxem), absorption coefficient (ε), relative fluorescence intensity (FI) and fluorescence quantum yield (ΦF) are summarized in Table S1.‡ Since there is contrasting information on the chemical structure of the main product of the reaction between N1-alkylated nicotinamide derivatives with enolizable ketones, we put efforts into the structural elucidation of this chemotype. In 1947, Huff et al. postulated the nucleophilic attack of deprotonated methylketones in position 2 of the pyridinium salts resulting in 1,6-naphthyridin-5(1H)-ones (7, see Fig. 2).41 However, Kröhnke falsified this finding by melting point analyses, which clearly indicated that deprotonated methylketones attack N1-alkylated nicotinamide derivatives in position 4, finally leading to 2,7-naphthyridin-1(7H)-ones (8a).32 Even though Kröhnke's findings have already been verified by Birkofer et al. in the mid-1950s,42 it is surprising that up to the year 2009 several publications36,38 adopted the disproven structure of Huff et al. Our spectroscopic data (see the ESI‡) strongly supports the formation of 2,7-naphthyridines.

Scheme 1. Synthesis of 8-hydroxy-2,7-naphthyridin-2-ium salts 3a–h.

Scheme 1

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Fig. 2. Presentation of some chemotypes that have been proposed as the main products of the reaction of N1-alkylated nicotinamide derivatives with enolizable ketones in comparison with our suggestion (8b) for the uncharged state. 7 was taken from ref. 36, 38 and 41, 8a from ref. 32, 33 and 37, 3 from ref. 34 and 42, and 9 from ref. 42.

Fig. 2

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However, we think that the basicity as well as the spectroscopic properties of the uncharged 2,7-naphthyridin-1(7H)-ones (8a) can be much better explained by the zwitterionic resonance structure (8b), 2,7-naphthyridin-2-ium-8-olate. During the purification process, we observed distinct acid–base properties of the final products, which were either precipitated from an acidified aqueous layer by the addition of KOH to pH = 11 or from ethanol by adjusting to a pH value of 2. Thus, we aimed to characterize these acid–base properties in more detail. By recording the UV-vis spectra at different pH values (Fig. S1‡), we were able to determine a pKa value of 8.7 for compound 3a (see the ESI‡), which is consistent with an acid–base equilibrium between imidic acid 3 and its conjugate base 8b. This assumption could be further supported by NMR spectroscopy. In the 1H NMR spectra of the uncharged as well as the positively charged forms, dissolved in DMSO, the signals for the protons in positions 1 and 3 of the 2,7-naphthyridine scaffold are highly downfield shifted (>8.80 ppm) and nearly identical (see Table 1 and Fig. S2‡). This can be explained best by the existence of a positively charged nitrogen atom in position 2 of the zwitterionic and the positively charged state. For either aqueous or DMSO solution, we therefore suggest the existence of a pH-dependent equilibrium, which is dominated by the uncharged 2,7-naphthyridin-2-ium-8-olate (8b) and the positively charged 8-hydroxy-2,7-naphthyridin-2-ium ions (3).

Table 1. Chemical shifts in the 1H NMR spectra of compound 3b.

Protons Chemical shifts of the protonated state [ppm] Chemical shifts of the deprotonated state [ppm]
–OH 12.67 No signal
H-1 9.66 9.65
H-3 8.96–8.91 8.87–8.82
H-4 8.21 8.13
H-5 7.24 7.22
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2.3. Biological characterization of 8-hydroxy-2,7-naphthyridin-2-ium salts as ChEIs

To assess the inhibitory effects of the synthesized 8-hydroxy-2,7-naphthyridin-2-ium chlorides on AChE and BChE, the compounds were tested in an absorption-based hydrolase activity assay published by Karlsson et al.43 All compounds were initially tested at a concentration of 10 μM in parallel against horse serum BChE and electric eel AChE using the conditions described in our earlier contributions.43,44 The control inhibitor in all the trials is physostigmine (typically tested at 10 μM). Results are presented in Table 2. For further characterization, we selected the compounds that displayed more than 75% inhibition against any of the target enzymes at 10 μM to continue with dose–response experiments. The individual IC50 curves and the corresponding IC50 values are shown in Fig. 3. The in vitro inhibition data reveals that the benzylated compounds 3c and 3e act as dual inhibitors of both cholinesterases. As can be seen in Table 2, a benzyl moiety in position 2 of the 2,7-naphthyridine scaffold is of utmost importance for ChE inhibition. Furthermore, a naphthyl moiety in position 6 of the 2,7-naphthyridine scaffold seems to gain both BChE and AChE inhibition. These findings are consistent with the predicted binding modes of 3e for AChE and BChE (see chapter 2.4 and Fig. 4). Moreover, our inhibition data indicates that BChE inhibition seems to be more sensitive to modifications at the 2,7-naphthyridine scaffold, compared to AChE inhibition. Tetracyclic 3f inhibits AChE more potently than BChE.

Table 2. In vitro inhibition of BChE and AChE by 8-hydroxy-2,7-naphthyridin-2-ium salts 3a–h at a concentration of 10 μM.

Cpd Chemical structure BChE (inh% ± SD) AChE (inh% ± SD)
3a graphic file with name c6md00647g-u1.jpg 4.1 ± 2.9 51.6 ± 3.6
3b graphic file with name c6md00647g-u2.jpg 3.9 ± 2.7 45.9 ± 5.9
3c graphic file with name c6md00647g-u3.jpg 83.8 ± 1.5 76.4 ± 2.3
3d graphic file with name c6md00647g-u4.jpg 34.5 ± 4.7 59.5 ± 2.0
3e graphic file with name c6md00647g-u5.jpg 98.6 ± 0.3 97.1 ± 1.8
3f graphic file with name c6md00647g-u6.jpg 8.5 ± 4.3 77.3 ± 2.1
3g graphic file with name c6md00647g-u7.jpg n.d. a n.d. a
3h graphic file with name c6md00647g-u8.jpg 1.7 ± 3.2 48.5 ± 2.5
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an.d.: not detected.

Fig. 3. IC50 curves and IC50 values for the inhibition of BChE and AChE, respectively.

Fig. 3

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Fig. 4. Predicted binding modes of 3e for AChE and BChE. A) Predicted binding mode of 3e (colored cyan) for TcAChE. Water molecules are shown as red balls. Hydrogen bond interactions are represented as dashed lines. B) Comparison between the 3e docking pose for TcAChE and the co-crystallized inhibitor donepezil (colored orange). The surface of the binding pocket is shown and colored according to the hydrophobicity (hydrophilic = magenta, hydrophobic = green). C) Predicted binding mode of 3e (colored cyan) for BChE. D) Comparison between the 3e docking pose and the co-crystallized inhibitor benzyl pyridinium-4-methyltrichloroacetimidate (colored orange). The same color scheme as in Fig. 4B.

Fig. 4

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2.4. Docking results

In order to rationalize the determined biological activities, docking of the inhibitors was carried out using the program Glide SP. The crystal structures of Electrophorus electricus AChE (EeAChE) in the apo form and Torpedo californica AChE (TcAChE) in complex with donepezil (PDB ID ; 1EEA, ; 1EVE) were selected for docking and rescoring studies.45 Both enzymes share an identical binding pocket with 100% sequence identity. Since the TcAChE structure shows a better resolution and was solved in complex with donepezil (PDB ID ; 1EVE) this protein structure was used for docking and rescoring. As an example, the predicted binding mode of the most potent inhibitor 3e is shown in Fig. 4A. For the docking experiments we used the protonated state of our ligand, since the pKa determination for the model compound 3a (pKa = 8.7) has clearly shown that this is the predominant state under physiological conditions (pH = 7.4) as well as under assay conditions (pH = 8.0). The quaternary nitrogen of 3e adopts the same position as the protonated amino group of donepezil inside the binding pocket allowing cation–π interactions with the surrounding aromatic residues (Trp84 and Phe330). The terminal phenyl ring of 3e occupies the same region as the phenyl ring of donepezil and interacts with Trp84 and Phe330 of the catalytically active site (CAS, Fig. 4B). The naphthyl moiety of 3e interacts with Trp279 through π–π interactions and with Ileu287 through van der Waals interaction in the peripheral pocket. A hydrogen bond between the phenol OH of 3e and a conserved water molecule (bound to Tyr121) further stabilizes the inhibitor position (Fig. 4A). All compounds under study show a similar binding mode to that described for 3e. The docking of the more rigid compound 3f shows that it interacts in a similar way to AChE making the relevant interactions with Tyr121 and Trp279 (Fig. S3‡). Also the quaternary nitrogen adopts the same position as that observed for 3e. Substitution with smaller moieties on positions 2 and 6 resulted in less favourable interaction energies compared to 3e. For the docking to BChE, the crystal structure of the human enzyme in complex with benzyl pyridinium-4-methyltrichloroacetimidate was chosen due to the structural similarity of the co-crystallized inhibitor to the 8-hydroxy-2,7-naphthyridin-2-ium salts and due to the absence of a crystal structure of horse serum BChE (Fig. 4C).46

The interaction of the benzyl pyridinium part of 3e with the lower part of the BChE binding pocket is similar to that observed for the co-crystallized inhibitor (Fig. 4D). A salt bridge between Asp70 and the quaternary nitrogen as well as a hydrogen bond between the phenol of 3e and one of the water molecules located in the BChE crystal structure is observed. The terminal naphthyl group is located at the entrance of the pocket nearby the residues Pro285 and Ser287 (Fig. 4C). In the case of 3f, which inhibits BChE less potently than AChE, the docking model for BChE shows that the rigid molecule is not able to adopt the favourable orientation (Fig. S4‡). Due to the missing benzyl group, the compound cannot be “anchored” in the correct position in the large BChE binding pocket. The salt bridge between the quaternary nitrogen of 3f and Asp70, cation–π interaction with Tyr332, as well as π–π interaction with Trp82 are not present due to the absence of the benzyl group. For experimental details see the ESI.‡

3. Conclusions

In this study, we designed and prepared a small series of 8-hydroxy-2,7-naphthyridin-2-ium salts as potential ChEIs by analogy with the natural product chelerythrine, known as a dual inhibitor of AChE and BChE. By spectroscopic analyses we were able to elucidate the zwitterionic nature of 2,7-naphthyridin-1(7H)-ones, the neutral form of 8-hydroxy-2,7-naphthyridin-2-ium salts. Among the synthesized compounds, we identified 3c and 3e as dual inhibitors of AChE and BChE as well as tetracyclic 3f inhibiting AChE more potently than BChE, which is a promising starting point for subsequent selectivity studies. These are the first biological activities that are attributed to 8-hydroxy-2,7-naphthyridin-2-ium salts. By in vitro characterization rationalized by docking studies, we gained first insights into ChE inhibition by using 8-hydroxy-2,7-naphthyridin-2-ium salts, which allowed us to identify structural features that influence inhibitor potency. Furthermore, the intrinsic fluorescence of the 8-hydroxy-2,7-naphthyridum salts may allow their use as molecular tools for esterase biochemistry and biology.

Supplementary Material

Click here for additional data file. (2.3MB, pdf)

Acknowledgments

We thank Volker Brecht and Sascha Ferlaino for performing the NMR measurements and Christoph Warth for the ESI-MS analyses.

Footnotes

†The authors declare no competing interests.

‡Electronic supplementary information (ESI) available: All the experimental details, NMR spectra, MS and HPLC analysis results. See DOI: 10.1039/c6md00647g

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