4-tert-Pentylphenoxyalkyl derivatives – Histamine H3 receptor ligands and monoamine oxidase B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.10.048

The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H₃ receptor affinity with K_i values below 760 nM. The inhibitory acti

Full text of DOI:10.1016/j.bmcl.2018.10.048

Accepted Manuscript
4-Tert-pentylphenoxyalkyl derivatives – histamine H3 receptor ligands and
monoamine oxidase B inhibitors
Dorota Łażewska, Agnieszka Olejarz-Maciej, Maria Kaleta, Marek Bajda,
Agata Siwek, Tadeusz Karcz, Agata Doroz-Płonka, Urszula Cichoń, Kamil
Kuder, Katarzyna Kieć-Kononowicz
PII:
S0960-894X(18)30850-3
https://doi.org/10.1016/j.bmcl.2018.10.048
BMCL 26107
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 April 2018
27 September 2018
30 October 2018
Please cite this article as: Łażewska, D., Olejarz-Maciej, A., Kaleta, M., Bajda, M., Siwek, A., Karcz, T., Doroz-
Płonka, A., Cichoń, U., Kuder, K., Kieć-Kononowicz, K., 4-Tert-pentylphenoxyalkyl derivatives – histamine H3
receptor ligands and monoamine oxidase B inhibitors, Bioorganic & Medicinal Chemistry Letters (2018), doi:
https://doi.org/10.1016/j.bmcl.2018.10.048
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4-Tert-pentylphenoxyalkyl derivatives – histamine H3 receptor ligands and monoamine
oxidase B inhibitors
Dorota Łażewska a*, Agnieszka Olejarz-Macieja, Maria Kaletaa, Marek Bajdab, Agata Siwekc,
Tadeusz Karcza, Agata Doroz-Płonkaa, Urszula Cichońa, Kamil Kudera, Katarzyna Kieć-
Kononowicza
aDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical
College, Medyczna Str. 9, 30-688 Kraków, Poland; b Department of Physicochemical Drug Analysis, Faculty of
Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Kraków, Poland; cDepartment of
Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688
Kraków, Poland
*Corresponding author: D. Ł.
Abstract
The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described
in this manuscript. All compounds (except one) showed human histamine H3 receptor affinity
with Ki values below 760 nM. The inhibitory activity toward human monoamine oxidase B
(hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the
compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-
pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC50
value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and
reversible. Further, recently described potent histamine H3 receptor ligands – 4-tert-
pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) – were evaluated for hMAO B
inhibitory activity, and some of them displayed activity in the submicromolar range. Selected
compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited
no activity. Moreover, molecular modeling studies were carried out for tested compounds to
explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds
for hMAO B over hMAO A.
Monoamine oxidase B (MAO B), the predominant isoform in the human brain,
catalyzes the oxidative deamination of β-phenylethylamine – an amine which stimulates the
release of dopamine and inhibits its neuronal reuptake. Moreover, oxidative deamination
causes release of hydrogen peroxide (H2O2), which contributes to the production of reactive
oxygen species (ROS) and participates in oxidative stress in the brain. In the human brain,
MAO B activity increases with age and is elevated in some degenerative diseases such as
Parkinson’s (PD), Alzheimer’s (AD) and Huntington’s.1 MAO B inhibition enhances the
activity of endogenous and exogenous dopamine and could prevent neurodegeneration.

Currently, two MAO B inhibitors – selegiline (1; Figure 1) and rasagiline (2; Figure 1) – are
used for symptomatic treatment of PD. Both of them are irreversible MAO B inhibitors.
Recently, a reversible inhibitor – safinamide (3; Figure 1) –was approved by the EMA and
FDA as an anti-Parkinson drug.2
Histamine H3 receptors (H3Rs) are widely expressed in the brain, particularly in the
area involved in cognitive processes and arousal. Pharmacological studies have suggested the
utility of histamine H3R antagonists/inverse agonists in the treatment of various human
disorders, e.g. AD, ADHD, PD, schizophrenia, narcolepsy and allergy.3 Ten years ago, in
medicinal chemistry has appeared the idea of designing multitarget-directed ligands (MTDLs)
as a new way to treat multifactorial diseases such as neurodegenerative disorders: AD or PD.4
In 2017, the first potent H3R and MAO B ligand – contilisant (4; Figure 1) – was
described by Bautista-Aguilera et al.5 This compound showed not only high affinity for
human H3R (Ki = 11 nM) and human MAOs (hMAO A IC50 = 145 nM; hMAO B IC50 = 78
nM), but also showed inhibitory activity at human cholinesterases (hAChE IC50 = 530 nM;
hBuChE IC50 = 1690 nM). Simultaneously modulation of the targets which contribute in the
development of AD or PD could bring better therapeutic effect in the treatment of these
multifactorial disorders.6
Some time ago we described 1-(3-(4-tert-pentylphenoxy)propyl)piperidine, named
DL77 (Figure 1).7 This compound showed high affinity for human H3R (hH3R) in vitro (Ki =
8.4 nM) and in vivo (ED50 = 2.1 ± 0.2 mg/kg; p.o. mice). Moreover, further tested in vivo, it
showed procognitive effects in rats8,9, anticonvulsant activity in rats8, and reduced both
ethanol intake and preference in mice10. Recently, we have described the synthesis of DL77
analogues with a longer alkyl chain (from 4-8 carbons) that also proved to be potent histamine
H3R ligands (9 nM ≤ Ki < 330 nM).11 Preliminary screening of our database of H3R ligands
for inhibitory activity toward hMAO B showed high inhibition of this enzyme by DL 77 (IC50
= 19 nM). Encouraged by these results, we have designed new analogues of DL77 – 4-tert-
pentylphenoxypropyl derivatives (Scheme 1) with different amine moieties. Herein, we report
the synthesis of these compounds, their histamine H3R affinity and hMAO B inhibition.
Moreover, 4-tert-pentylphenoxyalkyl derivatives previously described by Kuder et al.11 were
also evaluated for hMAO B activity in the present study.

selegiline (1)
hMAO Bbr IC50 = 6.8 nM
(Irr)
rasagiline (2)
hMAO Bbr IC50 = 14 nM
(Irr)
safinamide (3)
hMAO Bbr IC50 = 9 nM
(Rev)
Contilisant (4)
DL77
hH3R Ki = 10.8 nM
hMAO B IC50 = 78 nM hMAO A IC50 = 145 nM
hAChE IC50 = 530 nM hBuChE IC50 = 1690 nM
hH3R Ki = 8.4 nM
hMAO B IC50 = 19 nM
hMAO A IC50 > 10,000 nM
Figure 1. Structures of known MAO B inhibitors, contilisant and DL77. Irr – irreversible; Rev - reversible
Compounds 5-12 were synthesized as shown in Scheme 1 with moderate yields (24-47%). 1-
(3-Bromopropoxy)-4-tert-pentylbenzene was prepared from 4-tert-pentylphenol and
dibromopropane in freshly prepared sodium propanolate (50 mL; 1.15 g, 0.05 mol Na). The
final compounds were obtained by N-alkylation in a mixture of ethanol and water (21:4) in the
presence of potassium carbonate and potassium iodide as described previously.12 Final oily
compounds were transformed into solid hydrogen oxalates (except 7). All compounds were
fully characterized by NMR spectroscopy (1H and 13C), mass spectroscopy (LC/EST-MS) and
elemental analysis. The purity of compounds (HPLC-UV) was 100% (except 7 – 98%).
Synthesis of compounds 13-32 was described previously.11
Scheme 1. Synthetic pathway of compounds 5-12.(a)

(a)Reagents and conditions (a) C3H7ONa, 600C -3h, reflux - 3h (b) amine, K2CO3, KI, C2H5OH:H2O (21:4),
reflux, 20-48 h.
The affinity of new compounds (5-12) for hH3R was evaluated in a radioligand
α
binding assay with N-methylhistamine as a radioligand in CHO K1 cells stably expressing
hH3R. Results are presented as Ki values in Table 1. Generally, all tested compounds (5-12)
except one (9) showed hH3R affinities in the nanomolar range (Ki < 800 nM), most of them
with moderate strength (100 nM < Ki< 300 nM). The exchange of the amine moiety
(piperidine in DL77) for other amines (pyrrolidine, substituted piperidines, azepane) not only
did not improve the affinity but even caused its decline (e.g. DL77 vs 9). The most potent
compound (5) showed a Ki value of 63 nM.
Table 1. Pharmacological activity of compounds 5-32 and DL77.
Cmpd
.
R
m
n
human histamine
H3 receptora
Ki [nM]
human MAO human MAO
Bb
Ab
IC50 [nM]
(inhibition%

(inhibition %
at 1 µM)
at 10 µM)
5
63 ± 6.2
8.4 ± 1.3c
37 ± 5
4.5 ± 0.4
(5%)
---
---
1
2
1
1
DL77
19 ± 7
(14%)
6
7
437 ± 27
20 ± 2
22 ± 2
(5%)
(5%)
2-CH3
2
2
1
1
140 ± 15
2,6-
diCH3
8
9
100 ± 11
>1000
428 ± 45
417 ± 43
(11%)
(7%)
3-CH3
2
2
1
1
3,3-
diCH3
10
753 ± 58
962 ± 89
(7%)
3,5-
2
1
diCH3
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
147 ± 4
298 ± 17
140 ± 47d
46 ± 22d
238 ± 95d
68 ± 20d
8.8e
2070 ± 360
65 ± 23
ntf
(12%)
(10%)
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
ntf
4-CH3
---
2
3
2
2
2
3
2
2
2
3
2
2
2
3
2
2
2
3
2
2
2
3
1
1
2
2
2
2
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
379 ± 84
---
1228 ± 191
3-CH3
4-CH3
---
> 1000 (47%)
609 ± 165
> 1000 (28%)
> 1000 (29%)
> 1000 (48%)
1128 ± 240
---
13.6e
23.4e
21.4e
46.5e
33.8e
60.5e
41.2e
55e
3-CH3
4-CH3
---
> 1000 (21%)
> 1000 (46%)
> 1000 (37%)
390 ± 55
---
3-CH3
4-CH3
---
> 1000 (18%)
> 1000 (35%)
> 1000 (35%)
1495 ± 420
---
36.6e
64.4e
3-CH3
4-CH3
---
128.3e
325.9e
120.7e
308.1e
182.5e
ntf
> 1000 (22%)
> 1000 (33%)
> 1000 (37%)
> 1000 (40%)
ntf
ntf
ntf
ntf
---
3-CH3
4-CH3
---
25.0 ± 6.5
14g
710g
rasagiline (2)
ntf
7.7 ± 1.2
ntf
safinamide (3)
7.7 ± 1.8h
[3H] Nα-Methylhistamine binding assay performed with cell membrane preparation of CHO-K1 cells stably
a
expressing the human H3 receptor; mean value of two independent experiments ± SEM
b fluorometric AmplexTM Red MAO assay.13
c
[
125I] Iodoproxyfan binding assay performed with cell membrane preparation of CHO-K1 cells stably
expressing the human H3 receptor; mean value of two independent experiments ± SEM7
d
Nα-Methylhistamine binding assay performed with cell membrane preparation of HEK293 cells stably
expressing the human H3 receptor; mean value of triplicate independent experiments; data from Kuder et al.11

e
[
125I] Iodoproxyfan binding assay performed with cell membrane preparation of CHO-K1 cells stably
expressing the human H3 receptor; data from a single experiment with each concentration tested at least in
triplicate; data from Kuder et al.11
f not tested
g human brain MAO B or MAO A; data from Ref.14
h data from Ref.15
Inhibition of MAO B was evaluated using Amplex Red® Monoamine Oxidase kits.13
Rasagiline, pargyline and safinamide were used as reference inhibitors. The inhibitory activity
of compounds was evaluated by measuring their effects on the production of H2O2 by MAO-
B during the oxidative deamination of para-tyramine. First, compounds were tested at one
concentration (1 μM), then those with at least 50% inhibitory activity against a fully inhibited
enzyme were selected for further testing (IC50 evaluation). Data are collected in Table 1. The
exchange of amine moiety (piperidine in DL77) for others (see Table 1) strongly influenced
hMAO B activity: increased it (e.g. 5; IC50 = 4.5 nM), kept it on the same level (e.g. 6,7; IC50:
20-22 nM respectively) or decreased it (e.g. 8-12; IC50 ≥ 65 nM). Enlargement of the amine
ring caused a decrease in activity in the order: pyrrolidine (5) > piperidine (DL77) > azepane
(12). It appears that the introduction of a methyl substituent into the ortho position of
piperidine (e.g. 6 and 7) did not influence hMAO B inhibition. However, the least effective
was the 4-methylpiperidine moiety (11). This compound was preliminarily screened twice and
despite inhibition ≤ 50%, was fully evaluated for IC50. The obtained data (IC50 = 2070 nM)
confirmed its low inhibitory activity. In order to check the influence of alkyl chain length on
hMAO B inhibition, we tested 4-tert-pentylphenoxyalkyl derivatives (13-32) with different
amine moieties (piperidine, 3-methylpiperidine, 4-methylpiperidine and azepane) that have
recently been described by Kuder et al.11 Generally, elongation of a carbon chain resulted in
activity decrease (e.g. DL77 vs 13 vs 17 vs 21 vs 25 vs 29) with one exception – 24. This
hexyl azepane derivative (IC50 = 390 nM) showed higher activity than pentyl (20; IC50 = 1128
nM) and butyl (16; IC50 = 609 nM) derivatives. To sum up, not only the kind of amine moiety
but also the length of the carbon chain has an influence on hMAO B activity. There was no
correlation observed between the kind of amine moiety and the influence on hH3R affinity
and hMAO B inhibition. However, two of the most potent hH3R compounds (5, DL77) are
also among the strongest hMAO B inhibitors (pyrrolidine and piperidine derivatives,
respectively).
Then, selected compounds (DL77, 5-10, 12, 13) were screened (at concentration of 10 µM)
for monoamine oxidase A inhibition using Amplex Red® Monoamine Oxidase kits13 and
showed the percentage of inhibition < 15%.

Experiments of the reversibility of hMAO B inhibition by 4-tert-pentylphenoxy
derivatives were performed with compounds: DL77, 5, 6 and 7. hMAO B was first incubated
with inhibitors (at concentrations representing the IC80 value) in the presence of 10 μM para-
tyramine. After 22 minutes of incubation, the concentration of para-tyramine was increased to
1 mM. Fluorescence was measured every minute for 5 hours.14 Results are collected in Table
2 and shown in Figure 2.
Table 2. Investigation of the reversibility of reference hMAO B inhibitors and DL77, 5, 6, 7.
compound
rasagiline
safinamide
DL77
reversibility
irreversible
reversible
reversible
reversible
reversible
reversible
5
6
7
110
100
90
80
70
60
50
40
30
20
10
0
110
100
90
80
70
60
50
40
30
20
10
0
A
B
without inhibitor
Safinamide 30 nM
Rasagiline 100 nM
5 20 nM
without inhibitor
Safinamide 30 nM
DL77 70 nM
Rasagiline 100 nM
-10
100
200
[min]
300
0
100
200
[min]
300
110
100
90
80
70
60
50
40
30
20
10
0
110
C
D
without inhibitor
Safinamide 30 nM
6 80nM
without inhibitor
Safinamide 30 nM
7 90 nM
100
90
80
70
60
50
40
30
20
10
0
Rasagiline 100 nM
Rasagiline 100 nM
-10
-10
0
100
200
[min]
300
0
100
200
[min]
300
Figure 2. Investigation of reversibility of tested compounds DL77 (A), 5 (B), 6 (C) and 7 (D).
To investigate the modality of reversible inhibition of 4-tert-pentylphenoxy
derivatives on hMAO B, compound 5 was chosen for kinetic studies. For this purpose, the
hMAO-B activity was measured for various concentrations of 5 (0 nM, 0.2 nM, 0.5 nM and
20 nM) in the presence of six concentrations of para-tyramine (0.05, 0.1, 0.5, 1.0, 1.5 and 2.0
mM). Saturation curves and Lineweaver-Burk plots were prepared. As illustrated in Figure 3,
compound 5 displayed non-competitive inhibition (i.e. a decrease in Vmax values; all lines of
the plot intersect at the same point on the x-axis).
Figure 3. Lineweaver-Burk plot of 5.

To investigate the binding mode of the obtained compounds and to explain the reasons
of diverse activity as well as selectivity molecular modeling studies were performed. All
derivatives were docked into the active site of hMAO A and hMAO B as described in
Supplementary data. With respect to MAO-B all derivatives revealed similar general
orientation within the active site of enzyme. The differences in details were responsible for
varied activities (see Figure A in Supplementary data). The heterocyclic moieties of ligands
were located near cofactor (FAD) and interacted with Tyr398, Tyr435, Phe343 and Tyr60.
The protonated amine group of pyrrolidine, piperidine and azepane created hydrogen bond
with Gln206. Introduction of methyl groups into the position 3 or 4 of piperidine ring (e.g.
compounds 8-11) led to the occurrence of steric hindrance and usually decreased the activity.
The linker always occurred in extended conformation. However, the shorter chains (e.g.
compounds 5-7, DL77) provided the better fit of aromatic part of ligands to the active site.
Moreover, in case of 3-carbon linker hydrogen bond between oxygen atom of compounds and
hydroxyl group of Tyr326 might be observed. The 4-tert-pentylphenyl moiety of compounds
with three methylene groups in the chain was located in the lipophilic pocket, created by
Trp119, Leu167, Phe168, Leu171, Cys172, Ile198, Ile199, Ile316 and Tyr326. In case of
compounds with longer linkers the previously mentioned hydrogen bond with Tyr326 was not
observed. Moreover, the 4-tert-pentylphenyl group was moved toward the edge of lipophilic
pocket. Such changes in the binding mode led to significant decrease in the activity. The
binding mode of the most potent compound 5 is presented in Figure 4. Comparing the results
of docking to MAO-B with docking to MAO-A, the selectivity of ligands toward MAO B
could be easily judged. Replacement of Tyr326 and Ile199 from MAO-B by Ile335 and
Phe208, respectively in MAO-A led to significant change of shape and size of the active site
of enzyme. This was responsible for essential steric clashes when the tested compounds were
docked into MAO A and resulted in the lack of the activity (Figure 5).

Figure 4. The binding mode of the most active compound 5 within the active site of monoamine oxidase B. The
most important amino acid residues are shown as navy blue sticks while cofactor (FAD) as green ones.
Figure 5. The top-ranked pose of compound 5 (yellow) was located outside of the active site when docked into
monoamine oxidase A. The replacement of Tyr326 and Ile199 from MAO-B by Ile335 and Phe208 in MAO-A
changed the size and shape of the pocket, leading to the steric clashes and disabling the entry of compound to the

active site. The most important amino acid residues are shown as navy blue sticks while cofactor (FAD) as green
ones.
To sum up, the designed compounds, based on the H3R ligand - DL77, were
synthesized and evaluated in vitro for hH3R affinity and hMAO B inhibition. The performed
experiments confirmed the good affinity for hH3R (Ki < 1000 nM) and high hMAO B
inhibitory properties of a number of compounds. Among this series (5-12), three compounds
exhibited excellent hMAO B inhibition in the lower micro-molar range (IC50 ≤ 20 nM). These
potencies are comparable to the reference inhibitor rasagiline, which, under identical
conditions, inhibited hMAO B with an IC50 of 25 nM. The most potent compound in this
series - 5 (IC50 = 4.5 nM) showed non-competitive and reversible mode of the enzyme
inhibition. None of tested compounds showed any inhibitory activity for hMAO A. Molecular
modeling studies helped to identify interactions between compounds and enzymes as well as
understand the biological activity.
In conclusion, the presented 4-tert-pentylphenoxy scaffold is a new structural feature
in hMAO B inhibitors as contilisant, like many compounds, contains in its structure a
propargylamine moiety, which is considered to be responsible for MAO B inhibitory activity.
Moreover, these results encourage us for further exploration of this class of compounds as
potential active CNS agents as so far, not many nonimidazole hH3R ligands have been
described as hMAO B inhibitors.
Acknowledgment. This work was supported by Polish National Science Center on the basis
of decision DEC-2016/23/B/NZ7/02327 and by the EU COST Action CA15135 (DŁ and
KKK).
Supplementary data
Figure A, synthetic procedures and analytical data of compounds, assays of biological
evaluations, and molecular modeling studies.
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A series of 4-tertpentylphenoxy alkyl derivatives was synthesized and biologically
evaluated
Compounds tested in vitro showed human histamine H3 receptor affinity and human
monoamine oxidase B inhibitory activity
Compound 5 displayed affinity for hH3R with a Ki of 63 nM and inhibited hMAO B
activity with an IC50 value of 4.5 nM
Non-competitive inhibition of hMAO B for compound 5 in the enzyme kinetic study
was determined
For the most potent compounds investigation of the reversibility of hMAO B
inhibition was performed