Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives

Article abstract of DOI:10.3109/14756366.2015.1108971

In the present paper, a novel series of dibenzofuran-piperazine derivatives were synthesized via the treatment of N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide with substituted piperazine derivatives. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR, mass spectral data; elemental analysis and HPLC analysis. Each derivative was evaluated for antiplatelet activity and anticholinesterase activity. Compound 2 m with 2-furoyl moiety exhibited high percentage inhibition as much as standard drug aspirin on arachidonic acid (AA)-induced platelet aggregation. None of the compounds presented significant inhibitor effect on collagen-induced platelet aggregation. Furthermore, the anticholinesterase activity of the compounds was determined and they did not show promising inhibitor activity compared with standard drug donepezil.

Full text of DOI:10.3109/14756366.2015.1108971

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Synthesis and biological evaluation of some
dibenzofuran-piperazine derivatives
Leyla Yurttaş, Usama Abu Mohsen, Yeşim Ozkan, Simla Cobanoglu, Serkan
Levent & Zafer Asım Kaplancikli
To cite this article: Leyla Yurttaş, Usama Abu Mohsen, Yeşim Ozkan, Simla Cobanoglu,
Serkan Levent & Zafer Asım Kaplancikli (2015): Synthesis and biological evaluation of some
dibenzofuran-piperazine derivatives, Journal of Enzyme Inhibition and Medicinal Chemistry,
DOI: 10.3109/14756366.2015.1108971
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ISSN: 1475-6366 (print), 1475-6374 (electronic)
Journal of Enzyme Inhibition and Medicinal Chemistry, Early Online: 1–7
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2015 Taylor & Francis. DOI: 10.3109/14756366.2015.1108971
RESEARCH ARTICLE
Synthesis and biological evaluation of some dibenzofuran-piperazine
derivatives
Leyla Yurttas¸1, Usama Abu Mohsen2, Yes¸im Ozkan3, Simla Cobanoglu3, Serkan Levent1, and Zafer Asım Kaplancikli1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey, 2Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Al-Azhar University, Gaza, Palestine, and 3Department of Biochemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Abstract
Keywords
In the present paper, a novel series of dibenzofuran-piperazine derivatives were synthesized via
the treatment of N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide with substituted pipera-
zine derivatives. The chemical structures of the compounds were elucidated by 1H NMR,
13C NMR, mass spectral data; elemental analysis and HPLC analysis. Each derivative was
evaluated for antiplatelet activity and anticholinesterase activity. Compound 2 m with 2-furoyl
moiety exhibited high percentage inhibition as much as standard drug aspirin on arachidonic
acid (AA)-induced platelet aggregation. None of the compounds presented significant inhibitor
effect on collagen-induced platelet aggregation. Furthermore, the anticholinesterase activity of
the compounds was determined and they did not show promising inhibitor activity compared
with standard drug donepezil.
Anticholinesterase activity, antiplatelet
activity, dibenzofuran, piperazine
History
Received 28 April 2015
Revised 28 September 2015
Accepted 7 October 2015
Published online 19 November 2015
Introduction
These limitations are among the reasons stimulating the search for
new antiplatelet drugs.
Platelets, also called trombocytes, play an essential role in
hemostasis and pathological thrombosis1–3. Platelet activation and
aggregation are important necessities in the pathogenesis of
athero thrombotic events characteristic of the acute coronary
syndromes (ACSs) or due to mechanical disruption of plaque by
percutaneous coronary interventions (PCIs). Hyperactivity of
platelets increase the risk of various vaso-occlusive diseases, such
as unstable angina, acute myocardial infarction and transient
ischemic attacks4,5. Antiplatelet therapy is a basic tool in the
prevention and treatment of thromboembolic diseases. In injured
vessels, blood aggregation is generated as a physiological defense
reaction by releasing biologically active compound, such as
adenosine 50-diphosphate (ADP), thrombin and prostaglandine
endoperoxide. Agonists such as thrombin, arachidonic acid (AA),
thromboxane A2 (TxA2), platelet-activating factor (PAF) and
collagen are able to induce platelet aggregation. Among these
agonists, AA is one of the most powerful agonists for platelet
activation6,7. Currently, essential antiplatelet drugs used for the
prophylaxis and treatment of thromboembolic diseases are
aspirin, ridogrel, ticlopidine, clopidogrel, dipyridamole, cilosta-
zol, tirofiban and sibrafiban8–12. Nevertheless, these orally
administered antiplatelet drugs have certain disadvantages, such
as gastric erosion, agranulocytosis, neutropenia, thrombocyto-
penia, aplastic anemia and thrombotic thrombocytopenic purpura
along with inefficient therapy13–16. Moreover, development of
Beraprost sodium (Figure 1) is a stable synthetic analaogue of
prostaglandin I2 (PGI2) which have both potent antiplatelet and
peripheral vasodilating actions. It possesses benzofurane ring in
its structure19,20. The drug which is in clinical trial in Europe and
USA presently, inhibits platelet aggregation induced by ADP,
collagen and arachidonic acid21. Aglafolin (Figure 1) is another
benzofuran including molecule, isolated from the stems of Aglaia
elliptifolia, was notified with effective inhibitor activity of platelet
aggregation induced by PAF both in vitro and in vivo22. Recently,
in a series of study Sidhu et al.23–27 and Thalji et al.28 have also
declared different benzofuran-bearing compounds with significant
antiplatelet activity. Moreover, benzofuran ring analog dibenzo-
furan-bearing compounds have been reported to exhibit a great
variety of biological some effects, including thrombosis29,30 and
anticholinesterase activity31–33 distinct from the mentioned above.
However, piperazine ring plays an important role for antiplatelet
activity34. By the effect of the findings about antiplatelet and
anticholinesterase activities of dibenzofurans and piperazines, it
was thought that it would be worthwhile to synthesize on a
combination system that bears these vital moieties on the same
chemical skeleton. Thus our research group synthesize dibezo-
furan-piperazine compounds so as to investigate probable
antiplatelet and anticholinesterase activity.
resistance to these drugs is another handicap for therapy17,18
.
Experimental
Chemistry
Address for correspondence: Leyla Yurttas¸, Anadolu University Faculty
of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu
University, Faculty of Pharmacy, Tepebas¸ı, Eskis¸ehir, 26470, Turkey.
Tel: +90 222 3350580/3783. Fax: +90 222 3350750.
All chemicals were purchased from Sigma-Aldrich Chemical Co (St.
Louis, MO) and Merck Chemicals (Merck KGaA, Darmstadt,
Germany). All melting points (m.p.) were determined by
Electrothermal
9100
digital
melting
point
apparatus
E-mail: lyurttas@anadolu.edu.tr

2
L. Yurttas¸ et al.
Journal of Enzyme Inhibition and Medicinal Chemistry, Early Online: 1–7
Figure 1. The chemical structures of beraprost and aglafolin.
(Electrothermal, Essex, UK) and are uncorrected. All the reactions (C ¼ C), 1267–926 (C–O, C–N). 1H NMR (500 MHz,
were monitored by thin-layer chromatography (TLC) using Silica DMSO-d6, ppm): ꢁ 2.23 (s, 3H, N–CH3), 2.42 (brs, 4H,
Gel 60 F254 TLC plates (Merck KGaA, Darmstadt, Germany). piperazine–H), 2.64 (brs, 4H, piperazine–H), 3.19 (s, 2H, –CO–
Spectroscopic data were recorded with the following instruments: IR, CH2), 4.04 (s, 3H, O–CH3), 7.37 (t, 1H, J: 7.5 Hz, Ar–H), 7.45
Shimadzu 8400S spectrophotometer (Shimadzu, Tokyo, Japan); (t, 1H, J: 7.5 Hz, Ar–H), 7.65 (d, 1H, J: 8 Hz, Ar–H), 7.85 (s, 1H,
NMR, Bruker DPX 500 NMR spectrometer (Bruker Bioscience, Ar–H), 8.08 (d, 1H, J: 7.5 Hz, Ar–H), 8.58 (s, 1H, Ar–H), 10.09
Billerica, MA, USA), in DMSO-d6, using TMS as internal standard; (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ 26.27,
M + 1 peaks were determined by AB Sciex-3200 Q-TRAP LC/MS/ 53.16, 55.59, 57.23, 61.67, 101.93, 103.20, 111.96, 118.24,
MS system (AB Applied Biosystems Co., MA). Purity of 120.24, 123.33, 124.66, 126.93, 127.76, 145.54, 150.20,
synthesized compounds was checked by Shimadzu LC-20 A 156.32, 168.77. For C20H23N3O3, calculated: 67.97% C, 6.56%
Prominence HPLC system, equipped with a Shimadzu DGU-14 A H, 11.89% N; found: 67.84% C, 6.54% H, 11.81% N. MS
degasser, LC-20 A dual piston pump, CTO-10 ASVP column oven [M + 1]+: m/z 354.
and SPD-MI20A PDA detector. Reodyne 7725i injection valve and a
stainless steel GL Science Inertsil ODS-3 (4.6 ꢀ 250 mm) column. N-(2-Methoxy-3-dibenzofuranyl)-2-(4-fenilpiperazin-1-yl)
Solvents for the separation compounds 2a, 2i, 2 l and 2m were: acetamide (2b)
solvent A, acetonitrile (95%); solvent B, water (5%) at a flow rate of
Yield 74%, m.p. 200–203 ꢁC. HPLC: 499.9% purity. IR (KBr,
1.0 ml/min and a sample injection volume of 20 ml. Solvents for the
cmꢂ1): ꢀmax 3356 (amide N–H), 1674 (C ¼ O), 1534–1313
separation of all other compounds were: solvent A, acetonitrile
(C ¼ C), 1269–926 (C–O, C–N). 1H NMR (500 MHz, DMSO-
(70%); solvent B, water (30%) at a flow rate of 1.2 ml/min and a
d6, ppm): ꢁ 2.23 (s, 3H, N–CH3), 2.75 (brs, 4H, piperazine–H),
sample injection volume of 20 ml. Elemental analyses were also
3.25 (brs, 4H, piperazine–H), 3.28 (s, 2H, –CO–CH2), 3.99 (s, 3H,
performed on a Leco TruSpec Micro CHN/CHNS elemental
O–CH3), 6.82 (t, 1H, J: 7.0 Hz, Ar–H), 6.99 (d, 1H, J: 7.5 Hz, Ar–
analyzer (Leco, St. Joseph, MI).
H), 7.25 (t, 1H, J: 8.5 Hz, Ar–H), 7.37 (t, 1H, J: 7.5 Hz, Ar–H),
7.45 (t, 1H, J: 8.0 Hz, Ar–H), 7.65 (d, 1H, J: 8 Hz, Ar–H), 7.85 (s,
Synthesis of the compounds
1H, Ar–H), 8.08 (1H, d, J: 7 Hz, Ar–H), 10.08 (s, 1H, N–H). 13C
N-(2-Methoxy-3-dibenzofuranyl)-2-chloroacetamide (1)
NMR (125 MHz, DMSO-d6, ppm): ꢁ 49.17, 53.23, 57.26, 61.76,
102.07, 103.20, 111.97, 116.02, 118.31, 119.50, 120.97, 123.34,
124.65, 126.95, 127.71, 129.46, 145.58, 150.18, 151.37,
156.32, 168.65. For C25H25N3O3, calculated: 72.27% C, 6.06%
H, 10.11% N; found: 72.26% C, 6.09% H, 10.21% N. MS
[M + 1]+: m/z 416.
Chloroacetyl chloride (0.2 mol, 16 ml) was added drop wise over
15 min to a magnetically stirring solution of 2-methoxy-3-
aminodibenzofuran (0.2 mol) and triethylamine (0.2 mol, 28 ml)
in dry THF (200 ml) at 0–5 ꢁC and the reaction mixture was
stirred for one hour at room temperature. After controlled the
reaction ending by TLC, it completed and the solvent was
evaporated under reduced pressure and then water was added to
wash the resulting solid and the mixture was filtered, dried and
recrystallized from ethanol to give compound 1.
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(2-methylphenyl)piperazin-
1-yl]acetamide (2c)
Yield 70–73%, m.p. 168–170 ꢁC. HPLC:499.9% purity. IR (KBr,
General synthesis procedure for N-(2-methoxy-3-dibenzofuranyl)- cmꢂ1): ꢀmax 3329 (amide N–H), 1670 (C ¼ O), 1538–1325
1
2-(4-substituted piperazin-1-yl)acetamide derivatives (2a-m)
(C ¼ C), 1276–9265 (C–O, C–N). H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.25 (s, 3H, C–CH3), 2.77 (brs, 4H, piperazine–H),
2.96 (brs, 4H, piperazine–H), 3.29 (s, 2H, –CO–CH2), 4.05 (s, 3H,
O–CH3), 6.99 (t, 1H, J: 6.5 Hz, Ar–H), 7.08 (d, 1H, J: 9.0 Hz, Ar–
H), 7.17–7.21 (m, 3H, Ar–H), 7.37 (t, 1H, J: 7.5 Hz, Ar–H), 7.47
(t, 1H, J: 8.0 Hz, Ar–H), 7.67 (d, 1H, J: 8.5 Hz, Ar–H), 7.87 (s,
1H, Ar–H), 8.09 (1H, d, J: 7.5 Hz, Ar–H), 10.11 (s, 1H, N–H). 13C
NMR (125 MHz, DMSO-d6, ppm): ꢁ 18.04, 52.28, 53.75, 57.32,
61.76, 102.04, 103.23, 111.97, 118.30, 119.23, 120.97, 123.34,
123.47, 124.66, 126.95, 127.11, 127.75, 131.36, 132.33, 145.60,
150.20, 151.60, 156.32, 168.76. For C26H27N3O3, calculated:
Compound 1 (10 mmol) was refluxed with 1-substituted pipera-
zine derivatives (10 mmol) and potassium carbonate (10 mmol) in
acetone for 5 h (200 ꢁC). After TLC screening, the solvent was
evaporated and then water was added to wash the resulting solid
and the mixture was filtered and the obtained crude product was
dried and then crystallized from ethanol.
N-(2-Methoxy-3-dibenzofuranyl)-2-(4-methylpiperazin-1-yl)
acetamide (2a)
Yield 72–75%, m.p. 166–168 ꢁC. HPLC: 95.2% purity. IR (KBr, 72.71% C, 6.34% H, 9.78% N; found: 72.76% C, 6.36% H, 9.71%
cmꢂ1): ꢀmax 3346 (amide N–H), 1671 (C ¼ O), 1541–1316 N. MS [M + 1]+: m/z 430.

DOI: 10.3109/14756366.2015.1108971
Synthesis and biological evaluation
3
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(3-methylphenyl)piperazin- J: 8.0 Hz, Ar–H), 8.60 (s, 1H, Ar–H), 10.07 (s, 1H, N–H). 13C
1-yl]acetamide (2d)
NMR (125 MHz, DMSO-d6, ppm): ꢁ 49.12, 53.20, 55.37, 57.26,
61.75, 102.08, 102.15, 103.18, 104.82, 108.63, 111.96, 118.31,
120.96, 123.33, 124.66, 126.95, 127.71, 130.15, 145.59, 150.18,
152.72, 156.32, 160.73, 168.63. For C26H27N3O4, calculated:
70.09% C, 6.11% H, 9.43% N; found: 70.07% C, 6.18% H, 9.51%
N. MS [M + 1]+: m/z 446.
Yield 78–81%, m.p. 77–82 ꢁC. HPLC: 99.1% purity. IR (KBr,
cmꢂ1): ꢀmax 3338 (amide N–H), 1673 (C ¼ O), 1562–1311
(C ¼ C), 1249–926 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.25 (s, 3H, C–CH3), 2.73 (brs, 4H, piperazine–H),
3.23 (brs, 4H, piperazine–H), 3.28 (s, 2H, –CO–CH2), 4.05 (s, 3H,
O–CH3), 6.63 (d, 1H, J: 7.5 Hz, Ar–H), 6.77 (d, 1H, J: 8.0 Hz, Ar–
H), 6.81 (s, 1H, Ar–H), 7.12 (t, 1H, J: 8.0 Hz, Ar–H), 7.37 (t, 1H,
J: 7.5 Hz, Ar–H), 7.43 (t, 1H, J: 8.0 Hz, Ar–H), 7.87 (s, 1H, Ar–
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(4-methoxyphenyl)pipera-
zin-1-yl]acetamide (2 h)
H), 7.65 (2H, d, J: 8.0 Hz, Ar–H), 8.08 (1H, d, J: 7.5 Hz, Ar–H), Yield 69–73%, m.p. 181–184 ꢁC. HPLC: 99.1% purity. IR (KBr,
10.07 (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ cmꢂ1): ꢀmax 3349 (amide N–H), 1673 (C ¼ O), 1519–1298
21.89, 49.21, 53.26, 57.26, 61.78, 102.07, 103.18, 111.96, 113.17, (C ¼ C), 1275–927 (C–O, C–N). 1H NMR (500 MHz, DMSO-
116.70, 118.31, 120.33, 120.95, 123.32, 124.66, 126.94, 127.72, d6, ppm): ꢁ 2.74 (brs, 4H, piperazine–H), 3.13 (brs, 4H,
129.27, 138.51, 145.58, 150.19, 151.39, 156.33, 168.63. For piperazine–H), 3.27 (s, 2H, –CO–CH2), 3.70 (s, 3H, O–CH3),
C26H27N3O3, calculated: 72.71% C, 6.34% H, 9.78% N; found: 4.0 (s, 3H, O–CH3), 6.84 (d, 2H, J: 8.0 Hz, Ar–H), 7.38 (t, 1H, J:
72.82% C, 6.21% H, 9.73% N. MS [M + 1]+: m/z 430.
7.5 Hz, Ar–H), 7.45 (t, 1H, J: 7.5 Hz, Ar–H), 7.65 (d, 2H, J:
8.5 Hz, Ar–H), 7.85 (s, 1H, Ar–H), 8.08 (2H, d, J: 7.5 Hz, Ar–H),
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(4-methylphenyl)piperazin- 8.60 (1H, s, Ar–H), 10.09 (s, 1H, N–H). 13C NMR (125 MHz,
1-yl]acetamide (2e)
DMSO-d6, ppm): ꢁ 50.57, 53.33, 55.68, 57.25, 61.74, 102.05,
103.19, 111.96, 114.80, 117.97, 118.30, 120.95, 123.33, 124.66,
126.95, 127.73, 145.58, 145.73, 150.19, 153.54, 156.32, 168.66.
For C26H27N3O4, calculated: 70.09% C, 6.11% H, 9.43% N;
found: 70.01% C, 6.15% H, 9.50% N. MS [M + 1]+: m/z 446.
Yield 74–78%, m.p. 192–195 ꢁC. HPLC:499.9% purity. IR (KBr,
cmꢂ1): ꢀmax 3258 (amide N–H), 1675 (C ¼ O), 1589–1302
(C ¼ C), 1242–925 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.20 (s, 3H, C–CH3), 2.74 (brs, 4H, piperazine–H),
3.19 (brs, 4H, piperazine–H), 3.27 (s, 2H, –CO–CH2), 4.05 (s, 3H,
O–CH3), 6.89 (d, 1H, J: 8.5 Hz, Ar–H), 7.05 (d, 1H, J: 8.5 Hz, Ar–
H), 7.38 (t, 1H, J: 7.5 Hz, Ar–H), 7.47 (t, 1H, J: 7.5 Hz, Ar–H),
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(4-nitrophenyl)piperazin-
1-yl]acetamide (2i)
7.65 (d, 2H, J: 8.0 Hz, Ar–H), 7.85 (s, 1H, Ar–H), 8.08 (2H, d, J: Yield 72–73%, m.p. 285–290 ꢁC. HPLC: 99.2% purity. IR (KBr,
8.0 Hz, Ar–H), 8.60 (1H, s, Ar–H), 10.08 (s, 1H, N–H). 13C NMR cmꢂ1): ꢀmax 3354 (amide N–H), 1676 (C ¼ O), 1512–1319
(125 MHz, DMSO-d6, ppm): ꢁ 20.51, 49.67, 53.25, 57.25, 61.75, (C ¼ C), 1213–927 (C–O, C–N). 1H NMR (500 MHz, DMSO-
102.06, 103.20, 111.97, 116.27, 118.30, 120.96, 123.33, 124.65, d6, ppm): ꢁ 2.74 (brs, 4H, piperazine–H), 3.59 (brs, 4H,
126.95, 127.72, 128.33, 129.89, 145.58, 149.31, 150.19, 156.32, piperazine–H), 3.30 (s, 2H, –CO–CH2), 4.39 (s, 3H, O–CH3),
168.66. For C26H27N3O3, calculated: 72.71% C, 6.34% H, 9.78% 7.12 (d, 2H, J: 8.0 Hz, Ar–H), 7.35 (t, 1H, J: 7.5 Hz, Ar–H), 7.45
N; found: 72.85% C, 6.36% H, 9.78% N. MS [M + 1]+: m/z 430. (t, 1H, J: 7.5 Hz, Ar–H), 7.65 (d, 2H, J: 8.0 Hz, Ar–H), 7.80 (s,
1H, Ar–H), 8.05 (2H, d, J: 8.5 Hz, Ar–H), 8.59 (1H, s, Ar–H),
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(2-methoxyphenyl)pipera-
zin-1-yl]acetamide (2f)
10.03 (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ
50.72, 54.33, 57.25, 62.67, 103.09, 104.43, 113.61, 118.21,
121.59, 123.33, 124.66, 125.20, 126.95, 127.31, 128.82, 138.54,
146.84, 150.08, 153.73, 156.32, 168.81. For C25H24N4O5,
calculated: 65.21% C, 5.25% H, 12.17% N; found: 65.25% C,
5.15% H, 12.20% N. MS [M + 1]+: m/z 461.
Yield 75%, m.p. 133–136 ꢁC. HPLC: 499.9% purity. IR (KBr,
cmꢂ1): ꢀmax 3358 (amide N–H), 1671 (C ¼ O), 1510–1339
(C ¼ C), 1285–926 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.75 (brs, 4H, piperazine–H), 3.08 (brs, 4H,
piperazine–H), 3.26 (s, 2H, –CO–CH2), 3.80 (s, 3H, O–CH3),
4.0 (s, 3H, O–CH3), 6.91–7.0 (m, 4H, Ar–H), 7.37 (t, 1H, J:
7.5 Hz, Ar–H), 7.38 (t, 1H, J: 7.5 Hz, Ar–H), 7.45 (t, 1H, J:
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(2-pyridyl)piperazin-
1-yl]acetamide (2j)
7.5 Hz, Ar–H), 7.65 (d, 1H, J: 8.0 Hz, Ar–H), 7.86 (s, 1H, Ar–H), Yield 74%, m.p. 177–179 ꢁC. HPLC: 499.9% purity. IR (KBr,
8.09 (1H, d, J: 7.5 Hz, Ar–H), 8.60 (1H, s, Ar–H), 10.13 (s, 1H, cmꢂ1): ꢀmax 3334 (amide N–H), 1678 (C ¼ O), 1512–1303
N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ 50.99, 53.54, (C ¼ C), 1280–925 (C–O, C–N). 1H NMR (500 MHz, DMSO-
55.85, 57.28, 61.81, 102.04, 103.21, 111.96, 112.49, 118.29, d6, ppm): ꢁ 2.63 (brs, 4H, piperazine–H), 3.25 (s, 2H, –CO–CH2),
118.53, 120.95, 121.39, 123.08, 123.33, 124.66, 126.94, 127.75, 3.79 (brs, 4H, piperazine–H), 4.0 (s, 3H, O–CH3), 6.65–6.69 (2H,
141.53, 145.59, 150.20, 152.54, 156.32, 168.72. For C26H27N3O4, m, Ar–H), 7.38 (d, 1H, J: 8.0 Hz, Ar–H), 7.42–7.45 (m, 2H, Ar–
calculated: 70.09% C, 6.11% H, 9.43% N; found: 70.04% C, H), 7.54 (t, 1H, J: 7.5 Hz, Ar–H), 8.08 (1H, d, J: 8.5 Hz, Ar–H),
6.14% H, 9.48% N. MS [M + 1]+: m/z 446.
8.47 (2H, d, J: 7.5 Hz, Ar–H), 10.03 (s, 1H, N–H). 13C NMR
(125 MHz, DMSO-d6, ppm): ꢁ 45.53, 53.05, 57.27, 61.86, 102.11,
103.19, 107.68, 111.97, 113.65, 118.32, 120.96, 123.33, 124.66,
126.95, 127.72, 138.05, 145.62, 148.06, 150.18, 156.33, 159.40,
168.64. For C23H23N5O3, calculated: 66.17% C, 5.55% H, 16.78%
N; found: 66.24% C, 5.45% H, 16.80% N. MS [M + 1]+: m/z 417.
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(3-methoxyphenyl)pipera-
zin-1-yl]acetamide (2 g)
Yield 68–71%, m.p. 130–132 ꢁC. HPLC: 99.3% purity. IR (KBr,
cmꢂ1): ꢀmax 3352 (amide N–H), 1667 (C ¼ O), 1516–1315
(C ¼ C), 1276–926 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.73 (brs, 4H, piperazine–H), 3.25 (brs, 4H,
piperazine–H), 3.27 (s, 2H, –CO–CH2), 3.72 (s, 3H, O–CH3),
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(2-pyrimidinyl)piperazin-
1-yl]acetamide (2 k)
3.99 (s, 3H, O–CH3), 6.40 (d, 1H, J: 8.5 Hz, Ar–H), 6.51 (s, 1H, Yield 69–71%, m.p. 183–186 ꢁC. HPLC: 99.4% purity. IR (KBr,
Ar–H), 6.75 (d, 1H, J: 8.5 Hz, Ar–H), 7.14 (t, 1H, J: 8.0 Hz, Ar– cmꢂ1): 3358 (amide N–H), 1669 (C ¼ O), 1542–1316 (C ¼ C),
1
H), 7.37 (t, 1H, J: 7.5 Hz, Ar–H), 7.45 (t, 1H, J: 8 Hz, Ar–H), 7.65 1288–926 (C–O, C–N). H NMR (500 MHz, DMSO-d6, ppm): ꢁ
(d, 1H, J: 8.0 Hz, Ar–H), 7.85 (s, 1H, Ar–H), 8.08 (d, 1H, 2.65 (brs, 4H, piperazine–H), 3.27 (s, 2H, –CO–CH2), 3.86 (brs,

4
L. Yurttas¸ et al.
Journal of Enzyme Inhibition and Medicinal Chemistry, Early Online: 1–7
4H, piperazine–H), 4.04 (s, 3H, O–CH3), 6.67 (t, 1H, J: 4.5 Hz, was placed in the cuvette of aggregometer and incubated for 5 min
Ar–H), 7.38 (t, 1H, J: 7.5 Hz, Ar–H), 7.46 (t, 1H, J: 7.5 Hz, Ar– at 37 ꢁC with 0.5 ml of test compound (or reference inhibitor, or
H), 7.66 (d, 1H, J: 8.0 Hz, Ar–H), 7.86 (s, 1H, Ar–H), 8.08 (2H, d, DMSO) before addition of 10 ml inducer (arachidonic acid, AA,
J: 8.5 Hz, Ar–H), 8.39 (2H, d, J: 5 Hz, Ar–H), 8.60 (s, 1H, Ar–H), 350 mM collagen, 5 mg/ml final concentration). The percentage of
10.03 (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ aggregation is determined as the ratio of heights of the
44.16, 53.03, 57.27, 61.85, 102.12, 103.18, 110.79, 111.97, aggregation curves with and without the test compound. Each
118.33, 120.96, 123.33, 124.66, 126.95, 127.71, 145.65, 150.18, curve is corrected automatically for the light absorption of PPP of
156.33, 158.44, 161.66, 168.61. For C23H23N5O3, calculated: the same donor. All experiments were performed in triplicate.
66.17% C, 5.55% H, 16.78% N; found: 66.24% C, 5.45% H, Inhibition of platelet aggregation was expressed as percentage of
16.80% N. MS [M + 1]+: m/z 418.
inhibition using the following equation:
% Inhibition
ꢀ
N-(2-Methoxy-3-dibenzofuranyl)-2-(4-benzylpiperazin-1-yl)
acetamide (2l)
ꢁ
maximum aggregation of compound-treated PRP
maximum aggregation of DMSO-treated PRP
¼
1 ꢂ
Yield 70–73%, m.p. 102–105 ꢁC. HPLC: 98.8% purity. IR (KBr,
cmꢂ1): ꢀmax 3348 (amide N–H), 1673 (C ¼ O), 1536–1312
(C ¼ C), 1284–927 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.62 (brs, 4H, piperazine–H), 3.20 (s, 2H, –CO–CH2),
3.60 (brs, 2H, C–CH2), 3.86 (brs, 4H, piperazine–H), 3.99 (s, 3H,
O–CH3), 7.31–7.38 (m, 5H, Ar–H), 7.38 (t, 1H, J: 8.5 Hz, Ar–H),
7.64 (d, 1H, J: 8.0 Hz, Ar–H), 7.85 (s, 1H, Ar–H), 7.08 (d, 1H, J:
7.5 Hz, Ar–H), 8.08 (d, 1H, J: 8.5 Hz, Ar–H), 8.57 (s, 1H, Ar–H),
10.06 (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6, ppm): ꢁ
53.14, 57.20, 61.59, 102.00, 103.20, 111.96, 118.27, 120.94,
123.33, 124.65, 126.94, 127.51, 127.72, 128.70, 129.55, 145.57,
150.18, 156.31, 168.66. For C26H27N3O3, calculated: 72.71% C,
6.34% H, 9.78% N; found: 72.74% C, 6.45% H, 9.82% N. MS
[M + 1]+: m/z 430.
ꢀ 100
AChE inhibition
All compounds were subjected to a slightly modified method of
Ellman’s test36 in order to evaluate their potency to inhibit the
AChE. The spectrophotometric method is based on the reaction of
released thiocholine to give a colored product with a chromogenic
reagent 5,5-dithio-bis(2-nitrobenzoic)acid (DTNB). AChE
(E.C.3.1.1.7 from Electric Eel, 500 units) and donepezil hydro-
chloride were purchased from Sigma Aldrich (Steinheim,
Germany). Potassium dihydrogen phosphate, DTNB, potassium
hydroxide, sodium hydrogen carbonate, gelatine and acetylthio-
choline iodide (ATC) were obtained from Fluka (Buchs,
Switzerland). Spectrophotometric measurements were performed
on a 1700 Shimadzu UV-1700 UV–Vis spectrophotometer.
Cholinesterase activity of the compounds (1–30) was measured
in 100 mM phosphate buffer (pH 8.0) at 25 ꢁC, using ATC as
substrates, respectively. DTNB (10 mM) was used in order to
observe absorbance changes at 412 nm. Donepezil hydrochloride
was used as a positive control37. Enzyme solutions were prepared
in gelatin solution (1%), at a concentration of 2.5 units/ml. AChE
and compound solution (50 mL) which is prepared in 2% DMSO at
a concentration range of 0.001–100 mM were added to 3.0 ml
phosphate buffer (pH 8 0.1) and incubated at 25 ꢁC for 5 min.
The reaction was started by adding DTNB (50 mL) and ATC
(10 mL) to the enzyme–inhibitor mixture. The production of the
yellow anion was recorded for 10 min at 412 nm. As a control, an
identical solution of the enzyme without the inhibitor is processed
following the same protocol. The blank reading contained 3.0 ml
buffer, 50 mL 2% DMSO, 50 mL DTNB and 10 mL substrate. All
processes were assayed in triplicate. The inhibition rate (%) was
calculated by the following equation:
N-(2-Methoxy-3-dibenzofuranyl)-2-[4-(2-furoyl)piperazin-1-yl]a-
cetamide (2 m)
Yield 75%, m.p. 150–154 ꢁC. HPLC: 95.9% purity. IR (KBr,
cmꢂ1): ꢀmax 3334 (amide N–H), 1678 (C ¼ O), 1512–1303
(C ¼ C), 1280–925 (C–O, C–N). 1H NMR (500 MHz, DMSO-
d6, ppm): ꢁ 2.65 (brs, 4H, piperazine–H), 3.28 (s, 2H, –CO–CH2),
3.78 (brs, 4H, piperazine–H), 4.05 (s, 3H, O–CH3), 6.64–6.65 (m,
2H, Ar–H), 7.04 (d, 1H, J: 3.5 Hz, Ar–H), 7.36 (t, 1H, J: 8.0 Hz,
Ar–H), 7.42 (t, 1H, J: 7.5 Hz, Ar–H), 7.65 (d, 1H, J: 8.5 Hz, Ar–
H), 7.86 (s, 1H, Ar–H), 8.08 (d, 1H, J: 7.5 Hz, Ar–H), 8.58 (s, 1H,
Ar–H), 10.03 (s, 1H, N–H). 13C NMR (125 MHz, DMSO-d6,
ppm): ꢁ 43.97, 53.26, 57.28, 61.55, 102.24, 103.17, 111.79,
111.97, 116.17, 118.40, 120.97, 123.33, 124.64, 126.97, 127.65,
145.24, 145.71, 147.41, 150.15, 156.34, 158.56, 168.44. For
C24H23N3O5, calculated: 66.50% C, 5.35% H, 9.69% N; found:
66.54% C, 5.32% H, 9.72% N. MS [M + 1]+: m/z 434.
Antiplatelet activity
Platelet aggregation was measured with the APACT aggregometer
with software APACT professional version 1.1. (Automated
Platelet Aggregation and Coagulation Tracer, Biochemica
GmbH, Flacht, Germany) according to the turbidimetric method
described by Born et al.35. Platelet-rich plasma (PRP) and
platelet-poor plasma (PPP) were obtained at the Blood Center of
the Gazi University Hospital, Ankara. For collagen-induced
aggregation studies, PRP and PPP were prepared from the
venous blood from healthy volunteers who had not taken any
AC ꢂ AI
Inhibition % ¼
ꢀ 100
AC
where AI is the absorbance in the presence of the inhibitor, AC is
the absorbance of the control and AB is the absorbance of blank
reading. Both of the values are corrected with blank-reading
value. SPSS for Windows 15.0 was used for statistical analysis.
Data were expressed as mean SD.
drugs with antiplatelet activity for 15 d. In brief, freshly drawn Results and discussion
venous human citrated blood (3.2% sodium citrate, 9:1) was
Chemistry
centrifuged at 800 rpm and then at 3500 rpm for 10 min to obtain
PRP and PPP, respectively. Platelet numbers were determined The synthesis of the N-(2-methoxy-3-dibenzofuranyl)-2-(4-sub-
stituted piperazin-1-yl)acetamide derivatives (2a-m) were carried
with
a
cell counter (Swelab Alfa, ꢀ Boule Medical AB,
Stockholm, Sweden) and adjusted to 3.6 ꢀ 108 platelets/ml with
out as shown in Scheme 1. The starting material 2-methoxy-3-
PPP. The test compound (or the reference inhibitor) is dissolved in aminodibenzofuran was first acetylated with chloroacetyl chloride
dimethylsulfoxide (DMSO). To eliminate solvent effects, the final in tetrahidrofuran and trietilamin. The obtained intermediate
product N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide (1)
concentration of DMSO was fixed at51%. 199 ml sample of PRP

DOI: 10.3109/14756366.2015.1108971
Synthesis and biological evaluation
5
Scheme 1. Synthesis of the compounds (2a-m).
was then refluxed with piperazine derivatives in acetone with the
presence of potassium carbonate to give final compounds (2a-m).
The structures of the obtained compounds were elucidated using
spectral data. In the IR spectra, the characteristic N–H bands and
amide carbonyl functions were observed at 3329–3358 cmꢂ1. In
the NMR spectra, protons of piperazine ring were seen as broad
singlets at about 2.42–3.86 ppm range, changing different sub-
stituents bonded to the ring. For all compounds, peaks at about
3.19–3.30 ppm, 3.99–4.39 ppm and 10.03–10.13 ppm were seen
belonging to CH2CO, OCH3 and NH protons, respectively. M + 1
peaks in MS spectra were in agreement with the calculated
molecular weight of the title compounds (2a-m) and elemental
analysis results for C, H and N elements were satisfactory with
calculated values of the compounds. According to HPLC analysis,
purity ratio was found greater than 95% for all compounds. Peak
purity index of all compounds were also checked and no impurity
was determined. Some of the results were given as supplementary
material.
Table 1. Inhibitory data (100 mM) for compounds 2a-m against
arachidonic acid (AA, 350 mM) and collogen (5 mg/ml) induced platelet
aggregation.
% Inhibition
Compounds
AA (350 mM)
Collagen (5 mg/ml)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
Aspirin
4.7 6.7
10.2 7.1
5.8 8.2
1.1 1.6
2.8 3.9
1.6 1.2
11.0 3.4
7.38 8.9
7.6 10.8
3.6 3.6
9.5 3.6
0.3 0.3
100
3.08 4.34
7.93 0.96
4.41 4.63
NI
8.59 5.40
3.60 3.20
4.49 4.27
1.79 1.71
1.19 2.06
1.66 1.50
3.56 3.22
2.20 3.25
1.87 2.70
–
100
Biology
NI: no inhibition.
The antiplatelet activity of the N-(2-methoxy-3-dibenzofuranyl)-
2-(4-substituted piperazin-1-yl)acetamide derivatives (2a-m) was
studied according to Born test. The arachidonic acid or collagen compounds 2j with 2-pyridyl, 2k with 2-pyrimidyl and 2 l with
were used as inducer of platelet aggregation on citrated platelet benzyl substitutions. At this point, it can be claimed that distance
rich human plasma and aspirin was used as standard drug. The with a carboyl function or any other groups between piperazine
synthesized 13 compounds were studied at 100 mM concentration and heterocyclic or any aromatic ring is important for the
as initial dose and the inhibition percentages were shown in antiplatelet activity of the studied compounds. This is an
Table 1. Compound 2m bearing 2-furoyl moiety exhibited the interesting finding for further studies.
highest inhibition percentage of 100% which is nearly about
The anticholinesterase activities were also determined by
standard drug’s inhibition value (100%). The other compounds slightly modified Ellman’s assay. All final compounds (2a-m)
(2a-l) displayed inhibition values below 10%. IC50 was calculated were tested for their inhibition potency against AChE (Table 3).
only for compound 2 m as 26.1 mM, whereas the IC50 was Among these compounds, compound 2a with 4-methyl substitu-
calculated as 3.9 mM for standard drug aspirin (Table 2). The tion at the fourth position of piperazine ring and compound 2i
inhibitor effect of the compounds on the collagen-induced with 4-nitro phenyl substitution were found as the most active
aggregation was observed insuffiecient which was found less compounds. The inhibition percentages were calculated 42.0 and
than 8.9%. The final compounds possess an acetamide bearing 41.12% at 1 and 0.1 mM concentrations for compound 2a and the
4-substituted piperazine skeleton which is also present in drug inhibition percentages were calculated 41.35 and 30.22% at 1 and
named ranolazine that is used to treat a cardiovascular disease, 0.1 mM concentrations for compound 2i. The IC50 values could
chronic angina. In a recent study, to develop the activity potential, not be defined none of all compounds. The inhibition percentages
diazabicyclic ranolazine analogs were also investigated and they were not determined for compounds 2 h and 2m and these
have been determined with higher activity38. Besides the final compounds were evaluated as inactive at two tested concentra-
compounds differ from each other with the aromatic structure tions. Compounds 2e bearing 4-methyl phenyl moiety and
bonded to the fourth position piperazine ring. The high activity of compound 2k bearing 2-pyrimidyl moiety exhibited anticholines-
compound 2 m shows that heterocyclic aromatic structure terase activity with nearly 40% inhibition value at 1 mM
connected to piperazine is important for activity of the N-(2- concentration, but both of them did not exhibited similar
methoxy-3-dibenzofuranyl)-2-(4-substituted piperazin-1-yl)aceta- inhibition value at 0.1 mM which were found below 4%. The
mide derivatives. But same high activity was not seen for the other compounds showed relatively weak activity and the

6
L. Yurttas¸ et al.
Journal of Enzyme Inhibition and Medicinal Chemistry, Early Online: 1–7
Table 2. IC50 (mM) of the compound 2m on 350 mM AA-induced platelet
aggregation.
7. Mills DC. ADP receptors on platelets. Thromb Haemost 1996;76:
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Compound
IC50 (mM)
2m
Aspirin
26.1
3.9
9. Gachet C. ADP receptors of platelets and their inhibition. Thromb
Haemost 2001;8:222–32.
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Table 3. % AChE inhibition of the compounds and IC50 values.
AChE inhibition (%)
Compounds
1 mM
0.1 mM
IC50 (mM)*
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2 m
42.0 3.44
27.37 2.11
20.23 4.24
31.27 2.45
46.64 3.46
15.89 2.35
12.89 2.54
ND
41.35 1.75
5.79 2.54
41.24 3.41
12.80 2.21
ND
41.12 1.34
19.17 4.45
10.81 2.49
11.26 3.14
3.63 1.17
4.39 2.40
1.92 3.48
ND
30.22 2.19
1.78 3.45
3.92 4.12
0.23 2.43
ND
41
41
41
41
41
41
41
ND
41
41
41
41
ND
16. McKee SA, Sane DC, Deliargyris EN. Aspirin resistance in
cardiovascular disease: a review of prevalence, mechanisms, and
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18. Schros K. Antiplatelet drugs: a comparative review. Drugs 1995;50:
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Donepezil
99.01 4.89
95.52 5.01
0.054 0.002 (mM)
19. Hirano T, Yamori Y, Kanai N, et al. The effects of beraprost Na, a
stable prostacyclin analog, on animal models of stroke. Mol Chem
Neuropathol 1992;17:91–102.
20. Murai T, Muraoka K, Saga K, et al. Effect of beraprost sodium on
peripheral circulation insufficiency in rats and rabbits.
Arzneimittelforschung 1989;39:856–9.
21. Nishio S, Nagase H, Kanou K, et al. Research and development of
beraprost sodium, a new stable PGI2 analogue. Zasshi Yakugaku
1997;117:509–21.
22. Wu TS, Liou MJ, Kuoh CS, et al. Cytotoxic and antiplatelet
aggregation principles from Aglaia elliptifolia. J Nat Prod 1997;60:
606–8.
ND: not determined.
*IC50: 50% inhibitory concentration (means SD of three independent
experiments) of AChE.
inhibition values were found less than 27.37%. Standard drug
Donepezil was studied at lower concentrations for the purpose of
finding IC50 value and it was determined as 0.054 mM. None of
the compounds showed comparable activity with Donepezil and
significant anticholinesterase activity contrary to expectations.
23. Verghese J, Liang A, Sidhu PS, et al. First steps in the direction of
synthetic, allosteric, direct inhibitors of thrombin and factor Xa.
Bioorg Med Chem Lett 2009;19:4126–9.
24. Sidhu PS, Liang A, Mehta AY, et al. Rational design of potent,
small, synthetic allosteric inhibitors of thrombin. J Med Chem 2011;
54:5522–31.
25. Abdel Aziz MH, Sidhu PS, Liang A, et al. Designing allosteric
regulators of thrombin. Monosulfated benzofuran dimers selectively
interact with arg173 of exosite II to induce inhibition. J Med Chem
2011;55:6888–97.
Conclusion
Thirteen new N-(2-methoxy-3-dibenzofuranyl)-2-(4-substituted
piperazin-1-yl)acetamide derivatives were synthesized and eval-
uated for their antiplatelet and anticholinesterase activity.
Compound 2m bearing furoyl moiety was determined as a
strong antiplatelet active molecule as inhibitors of AA-induced
platelet aggregation. Inversely, none of the compounds showed
sufficient acetylcholinesterase inhibitory activity.
26. Sidhu PS, Mosier PS, Desai UR. On scaffold hopping: challenges in
the discovery of sulfated small molecules as mimetics of
glycosaminoglycans. Bioorg Med Chem Lett 2013;23:355–9.
27. Sidhu PS, Hamdy MH, Sarkar A, et al. Designing allosteric
regulators of thrombin. Exosite 2 features multiple sub-sites that can
be targeted by sulfated small molecules for inducing inhibition.
J Med Chem 2013;56:5059–70.
28. Thalji RK, Aiyar N, Davenport EA, et al. Benzofuran-substituted
urea derivatives as novel P2Y(1) receptor antagonists. Bioorg Med
Chem Lett 2010;20:4104–7.
Declaration of interest
The authors report no conflicts of interest.
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Supplementary material available online