Synthesis of chlorinated tetracyclic compounds and testing for their potential antidepressant effect in mice

Article abstract of DOI:10.3390/molecules21010061

The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen- 11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)- N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively.

Full text of DOI:10.3390/molecules21010061

molecules
Communication
Synthesis of Chlorinated Tetracyclic Compounds
and Testing for Their Potential Antidepressant Effect
in Mice
Usama Karama *, Mujeeb A. Sultan , Abdulrahman I. Almansour and Kamal Eldin El-Taher 2
1
,
1
1
Received: 20 November 2015 ; Accepted: 31 December 2015 ; Published: 5 January 2016
Academic Editor: Maria Emília de Sousa
1
Chemistry Department, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451,
Saudi Arabia; Alhosami1983@yahoo.co.uk (M.A.S.); almansor@ksu.edu.sa (A.I.A.)
Department of Pharmacology, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451,
2
Saudi Arabia; eeltahir@ksu.edu.sa
*
Correspondence: Karama@ksu.edu.sa; Tel.: +966-114-675-894
Abstract: The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-
1-yl)-N-methylmethanamine ( ) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-
N-methylmethanamine ( ) as a homologue of the anxiolytic and antidepressant drugs benzoctamine
and maprotiline were described. The key intermediate aldehydes ( ) and ( ) were successfully
1
5
6
3
4
synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized
compounds were investigated for antidepressant activity using the forced swimming test.
Compounds (
antidepressant effects. These compounds significantly reduced the immobility times at a dose
0 mg/kg by 84.0%, 86.7% and 71.1% respectively.
5), (6) and (3) showed significant reduction in the mice immobility indicating significant
8
Keywords: chlorinated tetracyclic; antidepressants; synthesis; forced swimming test
1
. Introduction
Depression is the most common psychiatric disorder and is among the 10 leading causes of
morbidity and mortality worldwide [1,2]. Recent studies have indicated that depression occurs in
all ethnic, racial, and socioeconomic groups and can occur at any age, from childhood to old age.
These studies concluded that depression is a common psychiatric disorder in the general population.
On an international scale, prevalence estimates of depression are consistently high; varying with
population studied and study design. Depression affects more than 340 million people globally [3].
Many of the most common drugs and drug candidates contain halogens. Halogen atoms are
often introduced in order to increase lipophilicity, binding affinity and membrane permeability, to
fill hydrophobic cavities in the protein binding site, to facilitate the blood-brain barrier crossing and
to prolong the lifetime of the drug thereby improves bioavailability [4–7]. All the selective serotonin
reuptake inhibitor (SSRI) antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine, and the very effective top-selling antidepressant drug sertraline possess halogen atoms
at specific positions , which are key determinants for the drugs specifity for serotonin transporter
(
SERT) [7].
The tetracyclic drugs benzoctamine 1-(9,10-dihydro-9,10-ethanoanthracen-9-yl)-N-methylmethanamine
and maprotiline 3-(9,10-dihydro-9,10-ethanoanthracen-9-yl)-N-methylpropanamine are bridged
anthracene compounds that do not possess halogen atoms [ ]. Despite their structural similarity,
8
benzoctamine is primarily an anxiolytic drug that exhibits antagonistic effects on norepinephrine, while
maprotiline is an antidepressant and anxiolytic drug that is useful as a norepinephrine uptake inhibitor.
Molecules 2016, 21, 61; doi:10.3390/molecules21010061
www.mdpi.com/journal/molecules

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Seizures, leukopenia and skin reactions are common side effects of maprotiline. Thus, antidepressants
compounds solving the aforementioned problems are desired. Based on the the above evidence, it
was decided to synthesis the novel chlorinated maprotiline analogues (5) and (6), since the insertion of
a chlorine atoms in the maprotiline related compounds could be a small change for a big improvement
aiding in the development of more potent analogues.
2
. Results and Discussion
2
.1. Chemistry
We outline a simple, flexible and economical synthetic route (Scheme 1) to the
corresponding 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (
and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine ( ) (Figure 1) [
The key step was Diels-Alder [4 + 2] cycloaddition reaction at room temperature in the presence of
a catalytic amount of boron trifluoride etherate between acrolein and 1,8-dichloroanthracene ( ),
which was obtained according to the literature procedure by the reduction of the commercial
available 1,8-dichloroanthraquinone ( ) with zinc powder in aqueous ammonia followed by an acidic
treatment [10]. The two isomeric cycloadducts ( ) and ( ) were separated by column chromatography
) and ( ) by direct reductive amination of the
5)
6
9].
2
1
3
4
and were converted to the desired amines (
corresponding aldehyde.
5
6
˝
Scheme 1. Synthesis of compounds (
3
5
) and (
6
). Reagents and conditions. (a) Zn, NH /H O, 100 C,
3
2
˝
h; HCl, isopropanol, 100 C , 3 h, 62%; (b) acrolein, CH Cl , BF3¨OEt , r. t., 3 h, 76%; (c) H , Pd/C,
2
2
2
2
NH CH , CH OH, r. t., 4 h, 85%.
2
3
3

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Figure 1. Benzoctamine, maprotiline and targeted analogues.
2
.2. Assessment of Antidepressant Activity Using Forced Swimming Test
Table 1 shows the Effect of compounds ( ), ( ), ( ) and (
mice—a model for testing antidepressant activity. As shown in Table 1; compounds (
) all at doses of 80 mg/kg produced significant decrease in immobility time (p < 0.05, n = 4) compared
with control vehicle and maprotiline. Compound and at the same dose were significantly more
active than compound ( ) (p < 0.05, n = 4). Only compounds ( ), and ( ) were significantly active
in reducing immobility time at doses of 40 mg/kg compared with control vehicle (p < 0.05, n = 4).
Compound ( ) was completely inactive in this test at all doses tested. Table 2 shows the percentage
3
4
5
6
) on forced swimming test in
), ( ) and
3
5
(6
5
6
3
3
5
4
decrease in immobility times induced by each dose compared with control vehicle.
Table 1. Effects on Immobility Duration.
Duration of Immobility in Seconds during the Last
Animal Group
Four Minutes of the Six Minute Period
0
mg/kg
10 mg/kg
20 mg/kg
40 mg/kg
80 mg/kg
Control vehicle
Maprotiline
225 ˘ 7
157 ˘ 5
240
240
240
240
156 ˘ 4
240
240
144 ˘ 5
134 ˘ 5
b
a,b
Treated with (
Treated with (
Treated with (
Treated with (
3)
4)
5)
6)
160˘11
65 ˘ 4
240
240
36 ˘ 4.9
b
a,b
200
˘
12.3
240
140 ˘ 7.9
a,b
240
30 ˘ 5
All values represent mean
with control.
˘
SEM. a p < 0.05, n = 4 compared with maprotiline, b p < 0.05, n = 4 compared
Table 2. Percentage decrease in Immobility Times.
Percentage Decrease for
Dosage of 40 mg/kg
Percentage Decrease for
Dosage of 80 mg/kg
Compound
(3)
(5)
(6)
28.9
37.8
-
71.1
84.0
86.7

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3
. Experimental
3
.1. General Protocol
IR spectra were recorded on a Perkin-Elmer 883 spectrophotometer and peaks are expressed
´
ν (cm ). NMR spectra were recorded on a JEOL ECP 400 (400 MHz) instrument in CDCl and
3
1
as
chemical shifts are expressed as
δ ppm, and coupling constants (J) are given in Hertz. MS spectra
and HRMS were performed at the Department of Organic Chemistry of the University of Hannover,
Germany using EI at 70 eV.
3
.2. Synthesis
,8-Dichloroanthracene (
zinc dust (50.0 g, 765 mmol) in (200 mL) of aqueous 28% NH was stirred for 3 h at 100 C. After cooling
1
2). A suspension of 1,8-dichloroanthraquinone (1) (10.0 g, 36.1 mmol) and
˝
3
to room temperature, the resulting solid was separated by suction filtration. A CH Cl solution of
2
2
the resulting crude solid was combined with the CH Cl extract of the supernatant liquid and the
2
2
mixture dried over MgSO and concentrated under vacuo. The residual crude solid was dissolved in
4
a mixture of (500) mL of isopropanol and (50) mL of aqueous 12 M HCl and the resulting solution had
been refluxed for 3 h, then concentrated and partitioned between CH Cl and aqueous 5% NaHCO .
2
2
3
The organic layer was collected, dried over MgSO . The solvent was evaporated and the crude solid
4
product was recrystallized from a CH Cl –hexane mixture. The collected product was allowed to dry
2
2
˝
in the air for 24 h to provide (5.5 g, 62%) of 1,8-dichloroanthracene (2) as yellow needles: mp 153 C;
´
ν = 1617, 1547, 1438, 1300, 1210, 953, 872, 775, 720, 678 cm ; H-NMR (CDCl , 400 MHz)
3
1 1
IR (KBr):
13
δ = 7.25–7.88 (m, 6 H, ArH), 8.36(s, 1 H, ArH-10), 9.16 (s, 1 H, ArH-9); C-NMR (CDCl , 100 MHz)
δ = 120.9, 125.6, 126.0, 127.3, 127.6, 129.2, 132.4, 132.6; MS (EI) m/z (%) = 246 (100) [M] , 248 (65); HRMS
EI) Calcd. For C H C [M] 246.0003, Found 246.0001.
3
+
+
(
14
8
l2
4
1
,5-Dichloro-9,10-dihydro-9,10-ethanoanthracene-11-carbaldehyde (3)
,8-Dichloro-9,10-dihydro-9,10-ethanoanthracene-11-carbaldehyde (4)
Acrolein (1.65 mL, 23.8 mmol) was added to a solution of 1,8-dichlorolanthracene (2) (1.23 g,
5
mmol) in (70 mL) CH Cl followed by dropwise addition of BF OEt (0.63 mL, 5 mmol). The mixture
¨
2
2
3 2
was stirred at room temperature for 3 h. During this time the solution gradually turned brown, then
the reaction was quenched with brine and extracted 3 times with CH Cl . The organic layer was
2
2
collected and dried over Na SO and the solvent was removed in vacuo. Column chromatography
2
4
of the residue on silica gel (ethyl acetate/petroleum ether, 1:10) yields the aldehyde (
colorless oil (0.15 g, 10%) and the aldehyde (4) (R = 0.30) as colorless oil (1.0 g, 66%).
3) (R = 0.41) as
f
f
(3) IR (KBr):
= 2924, 1725, 1576, 1435, 1260, 1167, 1046, 770, 704 cm 1; 1H-NMR (CDCl , 400 MHz):
´
ν
3
δ = 2.01–2.04 (m, 1H, H-12), 2.10–2.12 (m, 1H, H-12), 2.81 (m, 1-H, H-11), 4.42 (t, J = 2.6, 1H, H-9), 5.71
13
(
d, J = 2.5, 1H, H-10), 7.10–7.36 (m, 6 H, ArH), 9.43 (d, J = 1.7, 1 H, CHO); C-NMR (CDCl , 100 MHz):
3
δ
= 27.8, 37.8, 44.3, 50.6, 122.2, 126.7, 127.6, 127.9,129.7, 136.2, 138.4, 145.7, 146.1, 200.7; MS (EI) m/z (%)
302 (20) [M] , 248 (85), 246 (100), 211 (5), 178 (4); HRMS (EI) Calcd. For C H1 OCl [M] 302.0265,
17 2 2
+
+
=
Found 302.0266.
= 2944, 1727, 1577, 1455, 1210, 1167, 785, 770 cm 1; H-NMR (CDCl , 400 MHz):
´
ν
3
1
(4
) IR (KBr):
δ = 2.04–2.07 (m, 1H, H-12), 2.11–2.12 (m, 1-H, H-12), 2.79 (m, 1H, H-11), 4.75 (d, J = 2.5, 1H, H-10), 5.48
13
(
t, J = 2.7, 1H, H-9), 7.04–7.28 (m, 6 H, ArH), 9.46 (d, J = 1.4, 1 H, CHO); C-NMR (CDCl , 100 MHz):
3
δ = 26.9, 36.6, 36.7, 45.5, 50.5, 122.1, 123.2, 127.1, 127.3, 129.7, 130.0, 141.5, 144.1, 201.7; MS (EI) m/z (%)
+
+
=
302 (20) [M] , 248 (75), 246 (100), 212 (8), 178(78); HRMS (EI) Calcd. For C H OCl [M] 302.0265,
17 12 2
Found 302.0265.

Molecules 2016, 21, 61
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1-(4,5-Dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (
5). In two-necked
round-bottomed flask (40 mg 10% Pd/C) was wetted with methanol and the flask was evacuated,
then flushed with hydrogen two times, then a solution of (100 mg, 0.33 mmol) aldehyde ( ) in (5 mL)
3
methanol was added to the reaction mixture followed by the addition of (0.5 mL, 2 M) solution
of methylamine in methanol. The mixture was stirred for 4 hours at room temperature under H2
atmosphere (balloon). The reaction mixture was filtered through a pad of celite and the solvent was
˝
5 as white powder. mp 290 C; IR
removed in vacuo to yield (90 mg, 85%) of the corresponding amine
KBr):
´
1 1
(
ν
= 3440, 2942,2864, 2775, 1592, 1457, 1410, 1026, 936, 755, 742, 555 cm ; H-NMR (CDCl ,
3
4
5
00 MHz)
δ
= 1.27–1.37( m, 1H, H-12 ), 2.13–2.19 (m, 1H, H-12), 2.47–2.50 (m, 1H, H-11), 2.55–2.66 (m,
H, CH -N-CH ), 4.31 (t, J = 2.5, 1H, H-9), 4.63 (d, J = 2.0, 1H, H-10), 6.98–7.05 (m, 3 H, ArH), 7.17–7.19
2
3
13
(m; 2 H, ArH), 7.45–7.48 (m; 1 H, ArH); C-NMR (CDCl , 125 MHz)
δ
= 33.2, 33.9, 35.9, 43.7, 46.0,
3
+
5
4.7, 123.3, 123.5, 123.8, 125.6, 125.9, 126.0, 126.4, 139.3, 142.7, 142.9, 143.5. MS (EI): m/z (%) = 317 [M]
(not recorded), 306 (7), 305 (22), 251 (75), 250 (100), 220 (7), 219 (22), 179 (5), 179 (4), 178 (13), 111 (8).
1
-(1,8-Dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine ( ). In two-necked
round-bottomed flask (40 mg 10% Pd/C) was wetted with methanol and the flask was evacuated,
then flushed with hydrogen two times, then a solution of (100 mg, 0.33 mmol) aldehyde ( ) in (5 mL)
methanol was added to the reaction mixture followed by the addition of (0.5 mL, 2 M) solution of
methylamine in methanol. The mixture was stirred for 4 h at room temperature under H atmosphere
6
4
2
(
balloon). The reaction mixture was filtered through a pad of celite and the solvent was removed
˝
in vacuo to yield (90 mg, 85%) of the corresponding amine (
6
) as white powder. mp 310 C; IR
´
1 1
(KBr):
ν
= 3435, 2943, 2774, 1626, 1593, 1457, 1411, 1027, 937, 758, 742, 555 cm ; H-NMR (CDCl ,
3
5
5
2
00 MHz)
δ
= 1.24–1.26 (m, 1H, H-12), 2.04–2.08 (m, 1H, H-12), 2.38–2.40 (m, 1H, H-11), 2.45–2.54 (m,
H-CH -N-CH ), 4.21 (broad s, 1H, H-10), 4.52 (broad s, 1H, H-9), 6.98–7.05 (m, 3H, ArH), 7.17–7.19 (m,
2
3
13
H, ArH), 7.42–7.43 (m, 1H, ArH); C-NMR (CDCl , 125 MHz) δ = 33.1, 33.6, 35.5, 43.5, 45.8, 54.3, 123.4,
23.5, 123.8, 125.6, 126.0, 126.1, 126.5, 139.1, 142.4, 142.8, 143.4; MS (EI) m/z (%) = 318 (100) [M + H]+
3
1
,
+
2
84 (22), 186(15), 117 (53); HRMS (EI) Calcd. for C H NCl [M] 318.0816, Found 318.0809.
18
18
2
3
.3. Assessment of Antidepressant Activity Using Forced Swimming Test
To test for the presence of anti-depressant activity of the test compounds (
3), (4), (5
) and (6).
The forced swimming test described previously by David et al. [11] was used with very slightly
modification regarding the dimension of the vessel used as a swimming pool. This vessel consisted
of a glass cylinder having an internal diameter of 25 cm and water depth of 15 cm and maintained
˝
at 22 ˘ 2 C. Swiss white mice weighing 25 g each were divided into 21 groups (n = 4). One group
served as control vehicle and the others divided for each test compound and maprotiline.
The test compounds and maprotiline were dissolved in DMSO and examined at 4 dose levels 10,
2
0, 40, 80 mg/kg (i.p.). The compounds and maprotiline were administered 20 min before starting the
swimming test. The control group was administered the vehicle only in the same volume. Each mouse
was allowed to stay in the swimming pool for 6 min. Mice normally swim for 1–2 min and then
turn helpless and become immobile. An immobile mouse is considered the one that does not show
any swimming attempt but shows only movements that allows it to keep its head above the surface
of the water. Counting of the time of immobility started at the beginning of the third minutes of
placing the mouse into the swimming pool and ended by the end of the sixth minute. In this test
antidepressant drugs decrease time of immobility. Thus, for each test compound dose, the time of
immobility was calculated. The means
˘
SEM values were calculated for each group. The data
were analyzed using one-way ANOVA followed by Dunnet’s multiple comparison test. p < 0.05 was
considered to be statistically significant.The percentage decreases in immobility times induced by each
doses were calculated.

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4
. Conclusions
In conclusion, novel chlorinated tetracyclic compounds were successfully synthesized as
analogues of benzoctamine and maprotiline by a simple, economical and flexible three-step formal
synthesis from simple and cheap starting materials. The key cyclisation step was accomplished through
the Diels-Alder reaction at room temperature. The two target compounds proved to possess potential
antidepressant activity as tested by the forced swimming test in mice.
Acknowledgments: The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University, for funding the work through the research group project No. RGP-VPP-128.
Author Contributions: U.K., M.A.S. and A.I.A. contributed the design, synthesis and characterization of the
products. K.E.E. performed the antidepressant activity test. U.K., M.A.S. and K.E.E. wrote the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
González, H.M.; Tarraf, W.; Whitfield, K.E.; Vega, W.A. The epidemiology of major depression and ethnicity
in the united states. J. Psychiatr. Res. 2010, 44, 1043–1051. [CrossRef] [PubMed]
2
.
McKenna, M.T.; Michaud, C.M.; Murray, C.J.; Marks, J.S. Assessing the burden of disease in the united states
using disability-adjusted life years. Am. J. Prev. Med. 2005, 28, 415–423. [CrossRef] [PubMed]
Collins, K.A.; Fitterling, H.L. Physical exercise and depression. Mt. Sinai J. Med. 2009, 76, 204–214.
Parisini, E.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G. Halogen bonding in halocarbon–protein
complexes: A structural survey. Chem. Soc. Rev. 2011, 40, 2267–2278. [CrossRef] [PubMed]
Erdelyi, M. Halogen bonding in solution. Chem. Soc. Rev. 2012, 41, 3547–3557. [CrossRef] [PubMed]
3
4
.
.
5
6
.
.
Kolá rˇ , M.; Hobza, P.; Bronowska, A.K. Plugging the explicit
013, 49, 981–983. [CrossRef] [PubMed]
σ-holes in molecular docking. Chem. Commun.
2
7
8
9
1
1
.
.
.
Liu, Y.; Xu, Z.; Yang, Z.; Chen, K.; Zhu, W. A knowledge-based halogen bonding scoring function for
predicting protein-ligand interactions. J. Mol. Model. 2013, 19, 5015–5030. [CrossRef] [PubMed]
Wilhelm, M.; Schmidt, P. Synthese und eigenschaften von 1-aminoalkyl-dibenzo[b,e]bicyclo[2.2.2]octadienen.
Helv. Chim. Acta 1969, 52, 1385–1395. [CrossRef] [PubMed]
Karama, U.S.; Sultan, M.A.S.; EL-Tahir, K.E.H.; Almansour, A.I. Antidepressant Compounds. U.S. Patent
9
125866 B1, 8 September 2015.
0. House, H.O.; Ghali, N.I.; Haack, J.L.; van Derveer, D. Reactions of the 1,8-diphenylanthracene system.
J. Org. Chem. 1980, 45, 1807–1817. [CrossRef]
1. David, D.J.P.; Renard, C.E.; Jolliet, P.; Hascoët, M.; Bourin, M. Antidepressant-like effects in various mice
strains in the forced swimming test. Psychopharmacology 2003, 166, 373–382. [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
(