Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases

Article abstract of DOI:10.2147/DDDT.S96315

This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice.

Full text of DOI:10.2147/DDDT.S96315

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O r i g i n a l r e s e a r c h
Design, synthesis, and antihypertensive activity of
curcumin-inspired compounds via ace inhibition
and vasodilation, along with a bioavailability study
for possible benefit in cardiovascular diseases
This article was published in the following Dove Press journal:
Drug Design, Development andTherapy
5 January 2016
Number of times this article has been viewed
Xiao-dong Zhuang1,*
li-zhen liao2,*
Xiao-bian Dong1
Xun hu1
Abstract: This study describes the synthesis of a novel series of curcumin-inspired compounds
via a facile synthetic route. The structures of these derivatives were ascertained using various
spectroscopic and analytic techniques. The pharmacological effects of the target analogs were
assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the syn-
thesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory con-
centrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE),
the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein
cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with
lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator
activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique.
The bioavailability of compound 4j was determined in experimental mice.
Yue guo1
Zhi-min Du1
Xin-xue liao1
li-chun Wang1
1Department of cardiology, First
affiliated hospital, sun Yat-sen
University, guangzhou, People’s
republic of china; 2Department of
health, guangdong Pharmaceutical
University, guangzhou higher
education Mega center, guangzhou,
People’s republic of china
Keywords: curcumin, synthesis, ACE inhibition, antihypertensive, vasodilation, bioavail-
ability
Introduction
*These authors contributed equally
to this work
Hypertension is deemed to be a major contributing factor to several cardiovascular
illnesses, including coronary heart disease, ischemia, and hemorrhagic stroke.1 Accord-
ing to recent estimates from the World Health Organization, hypertension is responsible
for the premature death of 7.5 million people each year, accounting for approximately
13% of total deaths.2 This disorder is not confined to poor countries, often affecting
also those in developed economies; for instance, approximately 77.9 million adults
in the US are affected by hypertension.3 Despite various therapeutic interventions to
control or treat hypertension, no individual clinical agent entirely serves the purpose.
Patients often have to take multiple drugs, each of which targets various mediators
responsible for high blood pressure. Such agents might include angiotensin-converting
enzyme (ACE) inhibitors/angiotensin-receptor blockers, β-blockers, and diuretics.
Drugs belonging to the ACE inhibitor family suppress the endogenous conversion of
angiotensin I to angiotensin II. Under the influence of angiotensin II, the blood vessels
are constricted, which results in elevated blood pressure.4 Consequently, the heart has to
use greater force to propel the blood into the arterioles, which exacerbates heart failure
together with weak cardiac muscles. It has been shown that levels of angiotensin II are
elevated in various cardiovascular illnesses. Thus, its inhibition lowers blood pressure
and the amount of energy required for the heart to maintain normal blood circulation.5
correspondence: li-chun Wang;
Xin-xue liao
Department of Cardiology, First Affiliated
hospital, sun Yat-sen University, no 58,
2nd Zhongshan road, guangzhou
510080, People’s republic of china
Tel +86 20 8733 2200
Fax +86 20 8733 2200
email wlc-lichun@hotmail.com;
liaoxinxue6371@126.com
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http://dx.doi.org/10.2147/DDDT.S96315

Zhuang et al
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Figure 1 Dual mode of action to treat hypertension.
Despite substantial progress toward an effective under- concluded that curcumin acts as a multifaceted agent, exhib-
standing of acute heart failure in recent decades, its manage- iting antioxidant, antibacterial, antifungal, antiviral, anti-
ment remains challenging. Major therapeutic interventions inflammatory, antiproliferative, and proapoptotic effects by
are based on diuretics supplemented by vasodilators. Vaso- targeting various key pathological functions.9
dilators have been found to significantly improve cardiac
However, because of poor bioavailability, the clinical
performance by decreasing arteriolar resistance. In particular, significance of curcumin is greatly compromised and various
these agents appreciably increase venous capacitance, which efforts have concentrated on improving its bioavailability.10
results in enlargement of the relative size of the venous blood The basic approach to this has adopted two strategies: the
pool along with decrease in preload and associated pressures.6 first strategy focuses on the development of delivery options
Thus, it can be suggested that vasodilators indirectly act on for curcumin (eg, nanoparticle, liposome, micelles, emulsion,
the heart, and reduce the cardiac burden of both acute and and microparticles), while the second strategy is concerned
chronic heart failure.
with the structural modification of curcumin. The latter
Together with antihypertensive drugs, vasodilators spe- approach has been widely accepted due to its versatility and
cifically correct major hemodynamic irregularities that arise the ease of introducing chemical diversity.11–15
as a result of primary hypertension and can act in an additive
This report describes the development of novel synthetic
manner to treat hypertension (Figure 1).7 This approach offers analogs inspired by curcumin and their subsequent pharma-
several advantages and exerts beneficial effects on associated cologic evaluation. In addition, metabolic and bioavailability
cardiac illnesses, and it improves the risk factors associated studies were conducted in mice.
with the disease.
Curcumin (diferuloylmethane), an active principal constit- Experimental
uent of Curcuma longa (family: Zingiberaceae), is known for The chemicals were procured from Sigma-Aldrich (St Louis,
its diverse medicinal properties. It was first isolated in 1815, MO, USA) and used without further purification. Established
and its chemical structure was established by J Milobedzka spectroscopic and analytic methods were used to ascertain
and V Lampe (Germany) approximately 100 years later.8 the purity and integrity of the synthesized derivatives,
The importance of curcumin in drug discovery is easily including Fourier transform infrared (FTIR) spectroscopy,
seen by the fact that, within a span of approximately two 1H-nuclear magnetic resonance (NMR), 13C NMR, and mass
decades, more than 2,000 publications on the subject have spectroscopy. The completion of the reaction was monitored
been indexed in the PubMed database. These studies have by thin-layer chromatography using silica gel G-coated Al
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curcumin like derivatives as antihypertensive agents
(3e,5e)-3,5-dibenzylidene-1-ethylpiperidin-4-one (4a)
Yield: 83%; mp: 168°C–169°C; molecular weight (MW):
303.16; Rf: 0.59; FTIR (νmax; cm-1 KBr): 3,128 (C–Hstr aro-
matic), 2,982 (C–Hstr alkanes), 1,727 (C=Ostr), 1,523 (C=Cstr),
1,476 (C=Nstr), 985, 882; 1H NMR (400 MHz, DMSO, TMS)
δ ppm: 7.64 (s, 2H, CH), 7.48 (m, 4H, Ar–H), 7.41 (m, 4H,
Ar–H), 7.34 (s, 2H, Ar–H), 3.41 (m, 4H, methylene), 2.61
(s, 2H, methylene), 1.09 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO) δ ppm: 186.4, 145.8, 140.5, 135.3, 128.8, 128.2,
127.9, 53.5, 52.5, 13.5; Mass: 304.18 (M + H)+; elemental
analysis for C21H21NO: calculated: C, 82.13; H, 6.98; N, 4.62.
Found: C, 82.09; H, 6.99; N, 4.63.
plates (0.5 mm thickness; Merck, Darmstadt, Germany). After
spotting, the plates were evaluated in an iodine chamber. The
uncorrected melting points of products were determined using
a melting point apparatus (Electrothermic model, MP-1).
FTIR (in KBr) spectra were determined using a PerkinElmer
Spectrum RX-I spectroscope (Perkin Elmer Instruments,
Buckinghamshire, UK). Proton and carbon NMR spectra
(1H NMR and 13C NMR) were recorded using a Bruker
Avance II 400 Fourier-Transform-NMR spectrometer (Bruker
Corporation, Billerica, MA, USA) in Dimethyl sulfoxide-d6
(DMSO-d6), with tetramethylsilane (TMS) as the internal
standard. The chemical shifts are expressed as δ values
(ppm), downfield from TMS as the internal standard. Liquid
chromatography–mass spectroscopy on a Waters ZQ-4000
using the electrospray ionization technique was used to record
the mass spectra of the synthesized derivatives. The elemental
analysis was conducted using the Vario Elemental Analyzer
(Elementar, Hanau, Germany).
(3e,5e)-3,5-dibenzylidene-1-propylpiperidin-4-one (4b)
Yield: 75%; mp: 182°C–183°C; MW: 317.42; Rf: 0.52;
FTIR (νmax; cm-1 KBr): 3,136 (C–Hstr aromatic), 2,989
(C–Hstr alkanes), 1,721 (C=Ostr), 1,529 (C=Cstr), 1,471
(C=Nstr), 989, 886; 1H NMR (400 MHz, DMSO, TMS) δ ppm:
7.67 (s, 2H, CH), 7.58 (m, 4H, Ar–H), 7.45 (m, 4H, Ar–H),
7.31 (s, 2H, Ar–H), 3.45 (m, 4H, methylene), 2.46 (s, 2H,
methylene), 1.43 (s, 2H, methylene), 0.92 (s, 3H, CH3); 13C
NMR (100 MHz, DMSO) δ ppm: 186.3, 145.9, 140.7, 135.3,
128.7, 128.3, 127.2, 59.6, 53.8, 21.6, 11.8; Mass: 318.46 (M
+ H)+; elemental analysis for C22H23NO: calculated: C, 83.24;
H, 7.30; N, 4.41. Found: C, 83.27; H, 7.31; N, 4.40.
general procedure for synthesis of
substituted 3,5-bisarylidene-piperidin-
4-ones, 3 (a–p)
4-Piperidone hydrate hydrochloride (0.10 mol) was taken
along with desired aromatic aldehydes (0.20 mol) and acetic
acid (150 mL) in a 250 mL round bottom flask. Addition-
ally, through this reaction mixture, HCl (g) was flushed for
30 minutes with continuous stirring to afford solid pale-
orange-colored precipitate. After that, HCl was removed and
the mixture was stirred constantly overnight. The resultant
precipitate was then filtered to furnish the corresponding
analogs 3 (a–p).
(3e,5e)-3,5-dibenzylidene-1-butylpiperidin-4-one (4c)
Yield: 68%; mp: 187°C–188°C; MW: 331.45; Rf: 0.69; FTIR
(νmax; cm-1 KBr): 3,128 (C–Hstr aromatic), 2,991 (C–Hstr
Alkanes), 1,716 (C=Ostr), 1,522 (C=Cstr), 1,476 (C=Nstr),
982, 884; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 7.64
(s, 2H, CH), 7.57 (m, 4H, Ar–H), 7.43 (m, 4H, Ar–H), 7.32
(s, 2H, Ar–H), 3.41 (m, 4H, methylene), 2.45 (s, 2H, methyl-
ene), 1.36 (s, 2H, methylene), 1.31 (s, 2H, methylene), 0.98
(s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ ppm: 186.2,
145.8, 140.4, 135.3, 128.7, 128.2, 127.9, 57.1, 53.8, 30.2,
20.4, 13.7; Mass: 333.48 (M+H)+; elemental analysis for
C23H25NO: calculated: C, 83.34; H, 7.60; N, 4.23. Found:
C, 83.36; H, 7.58; N, 4.21.
synthesis of title analogs 4 (a–p)
To the above solution of respective compound 3, appropri-
ate acyl chloride (0.01 mol) was added in the presence of
dry pyridine at room temperature for 2 hours. The resultant
mixture was then diluted with ethyl acetate and extracted
with 3 N HCl, saturated solution of NaHCO3 (aq.), and
brine. After rigorous extraction, the pooled solution was
dried over magnesium sulfate and the solvent was removed.
The resulting solid was dissolved in methanol and cooled
(3e,5e)-3,5-dibenzylidene-1-pentylpiperidin-4-one (4d)
saturated solution of ammonia was added to it. This mixture Yield: 62%; mp: 180°C–181°C; MW: 345.48; Rf: 0.79; FTIR
was kept in a sealed container overnight at room temperature (νmax; cm-1 KBr): 3,138 (C–Hstr aromatic), 2,978 (C–Hstr
with constant stirring. On the next day, before opening the alkanes), 1,719 (C=Ostr), 1,518 (C=Cstr), 1,468 (C=Nstr), 987,
vessel, it was cooled, and evaporated to dryness. The residue 881; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 7.62 (s, 2H,
was further purified with the help of column chromatography CH), 7.59 (m, 4H, Ar–H), 7.41 (m, 4H, Ar–H), 7.34 (s, 2H,
with the assumed polarity of the solvent to afford the pure Ar–H), 3.38 (m, 4H, methylene), 2.43 (s, 2H, methylene),
crystalline 4 (a–p).
1.35 (s, 2H, methylene), 1.32 (s, 2H, methylene), 1.28 (s, 2H,
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methylene), 1.02 (s, 3H, CH3); 13C NMR (100 MHz, DMSO)
δ ppm: 186.4, 145.9, 140.2, 135.3, 128.7, 128.2, 127.6, 57.3,
53.2, 29.5, 28.2, 22.4, 14.1; Mass: 346.46 (M + H)+; elemental
analysis for C24H27NO: calculated: C, 83.44; H, 7.88; N, 4.05.
Found: C, 83.42; H, 7.88; N, 4.04.
(3e,5e)-3,5-bis(3,4-dihydroxybenzylidene)-1-
pentylpiperidin-4-one (4h)
Yield: 77%; mp: 219°C–221°C; MW: 409.47; Rf: 0.56; FTIR
(νmax; cm-1 KBr): 3,462 (O–Hstr), 3,147 (C–Hstr aromatic),
2,993 (C–Hstr alkanes), 1,727 (C=Ostr), 1,534 (C=Cstr), 1,472
1
(C=Nstr), 989, 871; H NMR (400 MHz, DMSO, TMS)
δ ppm: 7.62 (s, 2H, CH), 7.21–6.93 (m, 6H, Ar–H), 5.37 (s,
4H, Ar–OH), 3.39 (m, 4H, methylene), 2.46 (s, 2H, methyl-
ene), 1.37 (s, 2H, methylene), 1.31 (s, 2H, methylene), 1.27
(s, 2H, methylene), 1.02 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO) δ ppm: 186.5, 146.7, 145.8, 140.4, 127.9, 126.4,
117.3, 115.2, 57.5, 53.9, 29.5, 28.2, 22.6, 14.2; Mass: 410.49
(M + H)+; elemental analysis for C24H27NO5: calculated: C,
70.40; H, 6.65; N, 3.42. Found: C, 70.42; H, 6.67; N, 3.43.
(3e,5e)-3,5-bis(3,4-dihydroxybenzylidene)-1-ethylpiperidin-
4-one (4e)
Yield: 59%; mp: 203°C–204°C; MW: 367.40; Rf: 0.71; FTIR
(νmax;cm-1 KBr):3,448(O–Hstr), 3,142(C–Hstraromatic),2,984
(C–Hstr alkanes), 1,714 (C=Ostr), 1,512 (C=Cstr), 1,458 (C=Nstr),
981, 879; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 7.65 (s,
2H, CH), 7.17–6.93 (m, 6H, Ar–H), 5.42 (s, 4H, Ar–OH),
3.39 (m, 4H, methylene), 2.68 (s, 2H, methylene), 1.04
(s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ ppm: 186.5,
146.7, 145.9, 145.2, 140.8, 127.9, 126.4, 117.3, 115.2, 53.5, (3e,5e)-1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)
52.4, 13.5; Mass: 368.42 (M + H)+; elemental analysis for piperidin-4-one (4i)
C21H21NO5: calculated: C, 68.65; H, 5.76; N, 3.81. Found: Yield: 65%; mp: 232°C–233°C; MW: 483.55; Rf: 0.67; FTIR
C, 68.67; H, 5.75; N, 3.81.
(νmax; cm-1 KBr): 3,156 (C–Hstr aromatic), 2,983 (C–Hstr
alkanes), 2,857 (O–CH3str), 1,721 (C=Ostr), 1,539 (C=Cstr),
1,475 (C=Nstr), 982, 876; 1H NMR (400 MHz, DMSO, TMS)
δ ppm: 7.58 (s, 2H, CH), 6.73– (m, 4H, Ar–H), 3.92 (s, 18H,
(3e,5e)-3,5-bis(3,4-dihydroxybenzylidene)-1-
propylpiperidin-4-one (4f)
Yield: 81%; mp: 208°C–209°C; MW: 381.42; Rf: 0.78; FTIR Ar–OCH3), 3.37 (m, 4H, methylene), 2.68 (s, 2H, methylene),
(νmax; cm-1 KBr): 3,452 (O–Hstr), 3,146 (C–Hstr aromatic),2,987 1.04 (s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ ppm:
(C–Hstr alkanes), 1,718 (C=Ostr), 1,513 (C=Cstr), 1,464 (C=Nstr), 186.3, 153.2, 145.4, 140.2, 138.6, 125.3, 107.2, 60.8, 56.3,
986, 872; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 7.61 (s, 53.8, 52.9, 13.6; Mass: 484.58 (M + H)+; elemental analysis
2H, CH), 7.19–6.93 (m, 6H, Ar–H), 5.41 (s, 4H, Ar–OH), for C27H33NO7: calculated: C, 67.06; H, 6.88; N, 2.90. Found:
3.41 (m, 4H, methylene), 2.48 (s, 2H, methylene), 1.42 C, 67.09; H, 6.89; N, 2.89.
(s, 2H, methylene), 1.02 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO)δppm:186.4,146.5,145.8,140.8,127.8,126.4,117.2, (3e,5e)-1-propyl-3,5-bis(3,4,5-trimethoxybenzylidene)
115.4, 59.8, 53.9, 21.8, 11.8; Mass: 382.46 (M + H)+; elemen- piperidin-4-one (4j)
tal analysis for C22H23NO5: calculated: C, 69.28; H, 6.08; Yield: 69%; mp: 238°C–239°C; MW: 497.58; Rf: 0.72; FTIR
N, 3.67. Found: C, 69.30; H, 6.07; N, 3.67.
(νmax; cm-1 KBr): 3,159 (C–Hstr aromatic), 2,987 (C–Hstr
alkanes), 2,859 (O–CH3str), 1,723 (C=Ostr), 1,545 (C=Cstr), 1,478
(C=Nstr), 987, 872; 1H NMR (400 MHz, DMSO, TMS) δ ppm:
7.63 (s, 2H, CH), 6.79– (m, 4H, Ar–H), 3.91 (s, 18H, Ar-
(3e,5e)-1-butyl-3,5-bis(3,4-dihydroxybenzylidene)
piperidin-4-one (4g)
Yield: 73%; mp: 212°C–213°C; MW: 395.45; Rf: 0.67; FTIR OCH3), 3.39 (m, 4H, methylene), 2.47 (s, 2H, methylene), 1.43
(νmax; cm-1 KBr): 3,459 (O–Hstr), 3,142 (C–Hstr aromatic), (s, 2H, methylene), 0.92 (s, 3H, CH3); 13C NMR (100 MHz,
2,989 (C–Hstr alkanes), 1,724 (C=Ostr), 1,529 (C=Cstr), 1,478 DMSO) δppm:186.4, 153.2, 145.9, 140.7, 138.5, 125.2, 107.5,
1
(C=Nstr), 981, 879; H NMR (400 MHz, DMSO, TMS) 60.9, 59.7, 56.2, 53.9, 21.7, 11.8; Mass: 498.61 (M + H)+;
δ ppm: 7.59 (s, 2H, CH), 7.19–6.91 (m, 6H, Ar–H), 5.39 elemental analysis for C28H35NO7: calculated: C, 67.59;
(s, 4H, Ar–OH), 3.42 (m, 4H, methylene), 2.47 (s, 2H, meth- H, 7.09; N, 2.81. Found: C, 67.61; H, 7.08; N, 2.81.
ylene), 1.38 (s, 2H, methylene), 1.29 (s, 2H, methylene), 1.04
(s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ ppm: 186.5, (3e,5e)-1-butyl-3,5-bis(3,4,5-trimethoxybenzylidene)
146.8, 145.7, 140.6, 127.9, 126.3, 117.2, 115.4, 57.2, 53.9, piperidin-4-one (4k)
30.8, 20.5, 13.8; Mass: 396.48 (M + H)+; elemental analysis Yield: 74%; mp: 252°C–253°C; MW: 511.61; Rf: 0.57; FTIR
for C23H25NO5: calculated: C, 69.86; H, 6.37; N, 3.54. Found: (νmax; cm-1 KBr): 3,163 (C–Hstr aromatic), 2,992 (C–Hstr
C, 69.89; H, 6.39; N, 3.54.
alkanes), 2,861 (O–CH3str), 1,714 (C=Ostr), 1,548 (C=Cstr),
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curcumin like derivatives as antihypertensive agents
1,474 (C=Nstr), 989, 877; 1H NMR (400 MHz, DMSO, TMS) 21.7, 11.8; Mass: 408.43 (M + H)+; elemental analysis for
δ ppm: 7.65 (s, 2H, CH), 6.82– (m, 4H, Ar–H), 3.89 (s, 18H, C22H21N3O5: calculated: C, 64.86; H, 5.20; N, 10.31. Found:
Ar–OCH3), 3.37 (m, 4H, methylene), 2.48 (s, 2H, methylene), C, 64.88; H, 5.21; N, 10.32.
1.37 (s, 2H, methylene), 1.31 (s, 2H, methylene), 0.96 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO) δ ppm: 186.4, 153.2, (3e,5e)-1-butyl-3,5-bis(4-nitrobenzylidene)piperidin-
145.9, 140.8, 138.4, 125.4, 107.4, 60.9, 57.2, 56.6, 53.8, 30.8, 4-one (4o)
20.5, 13.9; Mass: 512.63 (M + H)+; elemental analysis for Yield: 79%; mp: 254°C–255°C; MW: 421.45; Rf: 0.70; FTIR
C29H37NO7: calculated: C, 68.08; H, 7.29; N, 2.74. Found: (νmax; cm-1 KBr): 3,177 (C–Hstr aromatic), 2,989 (C–Hstr
C, 68.09; H, 7.30; N, 2.74.
alkanes), 1,723 (C=Ostr), 1,559 (C=Cstr), 1,537 (NO2str),
1,478 (C=Nstr), 983, 892; 1H NMR (400 MHz, DMSO, TMS)
δ ppm: 8.24–8.03 (m, 4H, Ar–H), 7.78– (s, 2H, C–H), 3.39
(m, 4H, methylene), 2.47 (s, 2H, methylene), 1.36 (s, 2H,
(3e,5e)-1-pentyl-3,5-bis(3,4,5-trimethoxybenzylidene)
piperidin-4-one (4l)
Yield: 63%; mp: 267°C–268°C; MW: 525.63; Rf: 0.65; FTIR methylene), 1.31 (s, 2H, methylene), 0.99 (s, 3H, CH3);
(νmax; cm-1 KBr): 3,167 (C–Hstr aromatic), 2,994 (C–Hstr 13C NMR (100 MHz, DMSO) δ ppm: 186.4, 147.2, 145.9,
alkanes), 2,865 (O–CH3str), 1,716 (C=Ostr), 1,543 (C=Cstr), 141.4, 140.8, 129.3, 123.9, 57.3, 53.6, 30.8, 20.6, 13.8;
1,476 (C=Nstr), 981, 879; 1H NMR (400 MHz, DMSO, TMS) Mass: 422.46 (M + H)+; elemental analysis for C23H23N3O5:
δ ppm: 7.63 (s, 2H, CH), 6.79– (m, 4H, Ar–H), 3.87 (s, 18H, calculated: C, 65.55; H, 5.50; N, 9.97. Found: C, 65.58;
Ar–OCH3), 3.39 (m, 4H, methylene), 2.49 (s, 2H, methylene), H, 5.51; N, 9.98.
1.36 (s, 2H, methylene), 1.32 (s, 2H, methylene), 1.28 (s, 2H,
methylene), 0.92 (s, 3H, CH3); 13C NMR (100 MHz, DMSO) (3e,5e)-3,5-bis(4-nitrobenzylidene)-1-pentylpiperidin-
δ ppm: 186.4, 153.9, 145.8, 140.6, 138.5, 125.6, 107.8, 4-one (4p)
60.9, 57.4, 56.2, 53.9, 29.4, 28.5, 22.1, 14.2; Mass: 526.67 Yield: 74%; mp: 263°C–264°C; MW: 435.47; Rf: 0.59; FTIR
(M + H)+; elemental analysis for C30H39NO7: calculated: C, (νmax; cm-1 KBr): 3,182 (C–Hstr aromatic), 2,985 (C–Hstr
68.55; H, 7.48; N, 2.66. Found: C, 68.57; H, 7.47; N, 2.66.
alkanes), 1,728 (C=Ostr), 1,551 (C=Cstr), 1,539 (NO2str), 1,474
(C=Nstr), 987, 896; 1H NMR (400 MHz, DMSO, TMS) δ ppm:
8.27–8.05 (m, 4H, Ar–H), 7.74– (s, 2H, C–H), 3.42 (m, 4H,
methylene), 2.48 (s, 2H, methylene), 1.38 (s, 2H, methylene),
(3e,5e)-1-ethyl-3,5-bis(4-nitrobenzylidene)piperidin-
4-one (4m)
Yield: 76%; mp: 236°C–237°C; MW: 393.39; Rf: 0.68; FTIR 1.32 (s, 2H, methylene), 1.27 (s, 2H, methylene), 0.94 (s, 3H,
(νmax; cm-1 KBr): 3,169 (C–Hstr aromatic), 2,997 (C–Hstr CH3); 13C NMR (100 MHz, DMSO) δ ppm: 186.3, 147.3,
alkanes), 1,726 (C=Ostr), 1,549 (C=Cstr), 1,537 (NO2str), 1,479 145.8, 141.4, 140.8, 129.3, 123.9, 57.6, 53.9, 29.6, 28.3,
(C=Nstr), 984, 892; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 22.6, 14.2; Mass: 436.49 (M + H)+; elemental analysis for
8.28–8.06 (m, 4H, Ar–H), 7.74– (s, 2H, C–H), 3.42 (m, 4H, C24H25N3O5: calculated: C, 66.19; H, 5.79; N, 9.65. Found:
methylene), 2.68 (s, 2H, methylene), 1.03 (s, 3H, CH3); C, 66.21; H, 5.80; N, 9.65.
13C NMR (100 MHz, DMSO) δ ppm: 186.4, 147.2, 145.9,
141.3, 140.8, 129.6, 123.9, 53.6, 52.4, 13.5; Mass: 394.41 Pharmacologic activity
(M + H)+; elemental analysis for C21H19N3O5: calculated: C, in vitro ace inhibition assay
64.12; H, 4.87; N, 10.68. Found: C, 64.14; H, 4.89; N, 10.69. As described earlier, a colorimetric method was used to deter-
mine the in vitro ACE inhibitory activity of the synthesized
(3e,5e)-3,5-bis(4-nitrobenzylidene)-1-propylpiperidin-
4-one (4n)
derivatives. The determination began with the preparation
of a suspension of 1 g rabbit lung acetone powder (Sigma-
Yield: 86%; mp: 242°C–243°C; MW: 407.42; Rf: 0.75; FTIR Aldrich) in 10 mL of 0.05 M sodium borate buffer (pH 8.2)
(νmax; cm-1 KBr): 3,172 (C–Hstr aromatic), 2,985 (C–Hstr containing 0.3 M NaCl and 0.5% Triton X-100. This suspen-
alkanes), 1,729 (C=Ostr), 1,552 (C=Cstr), 1,534 (NO2str), 1,473 sion was then centrifuged at 15,000 rpm for 60 minutes at
(C=Nstr), 987, 895; 1H NMR (400 MHz, DMSO, TMS) δ ppm: 4°C. The resulting supernatant served as the source of ACE.
8.27–8.04 (m, 4H, Ar–H), 7.68– (s, 2H, C–H), 3.41 (m, 4H, This assay was based on determination of the level of hippuric
methylene), 2.45 (s, 2H, methylene), 1.42 (s, 2H, methylene), acid generated after hydrolysis of the substrate, hippuryl his-
0.96 (s, 3H, CH3); 13C NMR (100 MHz, DMSO) δ ppm: tidyl leucine (HHL; Sigma-Aldrich); the level of hydrolysis
186.5, 147.3, 145.8, 141.4, 140.8, 129.3, 123.9, 59.6, 53.9, was directly related to the inhibitory ability of the compound.
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A 1 mM solution of both test and standard drug (lisinopril) 5 mM l-cysteine hydrochloride and made up to the final
was preincubated with 7 mL ACE for 10 minutes at 37°C. To volume with the required quantity of buffer. The reaction
obtain a similar concentration for avoiding the interference, mixture was kept for 3 hours at 37°C and 500 μL of Griess
the final volume was adjusted using 0.05 M sodium borate reagent was added. After 20 minutes, the absorbance of the
buffer (pH 8.2) containing 0.3 M NaCl. A total of 50 mL of solution was determined at 550 nm. Sodium nitrite solu-
5 mM substrate (HHL) was used to start the enzyme reaction, tion (5–50 μM) was used as the standard for the calibration
and the mixture was incubated at 37°C. After 30 minutes, curve.
the reaction was stopped by adding 0.1 mL of 1 M HCl. The
hippuric acid thus produced was then allowed to react with
0.2 mL of pyridine and 0.1 mL of benzene sulfonyl chloride
(Sigma-Aldrich), to form a yellow solution. ACE inhibition
was expressed as percentage inhibition and calculated using
the following equation:
Bioavailability study of compound 4j
The plasma concentration of the test compound was ana-
lyzed in 20- to 25-week-old Swiss Webster mice. The
experiment was duly approved by the Institutional Animal
Ethical Committee. Mice were divided into control and test
groups (n=5), with the test group receiving compound 4j
(3 mg per 30 g body weight) by oral administration using
a dosing needle. Whole blood was collected and 4j was
isolated from the plasma. For this, the samples were
first precipitated with methanol (40%) and centrifuged
(14,000 rpm) for 10 minutes. The resulting supernatant
was used for high performance liquid chromatography
analysis. Ascentis RP-Amide was used as the stationary
phase for determining 4j, using gradient elution (buffer A
[50 mmol/L NaH2PO4, pH 4.3] for 0–5 minutes, a linear
change from buffer A to buffer B [70% acetonitrile] for
5–20 minutes, and buffer B for 5 minutes) at a flow rate of
0.7 mL/min. The level of analyte was determined using an
electrochemical detector.
T


Percentage inhibition =100−
×100




C
where T is the absorbance of the test reaction and C the
absorbance of the control reaction.
The IC50 was calculated using nonlinear regression.
A dose–response curve was obtained by plotting the percent-
age inhibition versus the concentration.
Vasodilator activity
For determination of the vasodilatory effect, Wistar albino
rats of either sex, weighing 175–200 g, were acquired.
The experiment was approved by the Institutional Animal
Ethical Committee. The rats were fed a standard laboratory
diet and had ad libitum access to water. The hearts of the
Results and discussion
experimental rats were excised and rapidly transferred to chemistry
Krebs–Henseleit buffer solution at 37°C. The pericardial As depicted in Figure 2, the target compounds were devel-
and lung tissues were removed and the aorta was cut just oped using a short and cost-effective route. The synthesis
below the point of division. After insertion of a glass cannula, was started using commercially available diverse aldehydes
perfusion with oxygenated Krebs–Henseleit buffer solution (2 eq.), which were allowed to react with 4-piperidone
was started. Each heart was then transferred to a glass per- hydrate hydrochloride (1 eq.) in acetic acid. This reaction
fusion apparatus and the heart rate was measured through a was carried out in an atmosphere of dry HCl gas to afford
chronometer connected to a physiograph. The solution of test salts of 3,5-diaryl-methylene-piperidone acid (3). This salt
compounds (10 μg) along with a standard solution (10 μg served as a template for the next reaction, in which it was
sodium nitroprusside) was administered by injection into acylated with numerous acyl chlorides to produce the target
the perfusion medium just above the aortic cannula, and the derivatives, 4 (a–p).
cardiac output was measured using a drop counter. Before
Pharmacological activity
ace inhibition assay
recording the parameters induced by BaCl2, normal heart
activity was recorded.16
The inhibitory activity of target analogs against ACE was
nO donor activity
determined in an enzyme inhibition assay using a colorimetric
Solutions of test compounds were dissolved in DMSO, main- method (Table 1). The experiment was carried out at 1.0 μM
taining the concentration at 100 μmol. The resulting solution concentration of test compounds and using lisinopril as a
was added to phosphate buffer (pH 7.4, 50 mM) containing standard. The target compounds were designed in such a
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curcumin like derivatives as antihypertensive agents
O
O
HO
OH
a
H
R
R
R
N
H
N
H
HCl
HCl
1
2
3
b
O
R
R
N
1–4
H3C
4
Figure 2 synthesis of curcumin-inspired derivative.
Notes: reagents and condition: (a) hcl (g), ch3cOOh; (b) acyl chlorides.
way as to create diversity around the core skeleton using the as the most promising inhibitor; the lowest level of activity
easiest possible synthetic steps. Therefore, aldehydes were was exhibited by compound 4o. The results showed that
chosen based upon their chemical character (ie, electron- nonsubstituted derivatives (R=H) exhibited moderate activ-
withdrawing and -donating groups). Later, different chain ity against ACE. Similar inhibitory potency (≈50 μM) was
lengths of acyl chlorides were used to assess their effects on demonstrated for compounds 4a and 4b, while lengthening
the bioactivity of the compounds. A comparative inhibition the N-acyl chain (compounds 4c and 4d) led to loss of the
analysis found that all of the synthesized derivatives exhibited activity.
considerable inhibition of ACE, with half-maximal inhibi-
The introduction of substituents resulted in marked
tory concentrations (IC50) ranging from 1.23 to 120.32 μM. improvements in inhibitory potency. For example, compound
Among the tested derivatives, compound 4j was identified 4e showed an IC50 of 32.16 μM against ACE. Furthermore,
significant improvements in activity were observed for the
next compound (4f), which contained an ethyl group as a
linker. However, a more than twofold decline in activity was
observed upon increasing the N-acyl linker length (4g and 4h).
The most prominent activity was shown by compounds that
contained a trimethoxy substituent (4i–4l). Compound 4j
demonstrated prominent inhibition of ACE, with an IC50
of 1.23 μM. However, this activity was reduced on further
extension of the chain length, with minimal activity in the
case of compound 4l. The rest of the compounds (4m–4p)
showed less activity against ACE.
Table 1 ace inhibitor effect of the designed inhibitors 4 (a–p)
Compound
R
Chain length
IC50 (μM)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
h
h
h
h
ch2
ch2ch2
ch2ch2ch2
ch2ch2ch2ch2
ch2
50.86
51.14
64.42
78.45
32.16
20.15
41.27
48.61
3.21
1.23
4.45
6.65
95.11
90.23
131.14
120.32
0.094
3,4-Dihydroxy
3,4-Dihydroxy
3,4-Dihydroxy
3,4-Dihydroxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
3,4,5-Trimethoxy
4-nitro
4-nitro
4-nitro
4-nitro
captopril
ch2ch2
ch2ch2ch2
ch2ch2ch2ch2
ch2
ch2ch2
ch2ch2ch2
ch2ch2ch2ch2
ch2
ch2ch2
ch2ch2ch2
ch2ch2ch2ch2
Structure–activity relationship studies suggested that
structural variations in the compounds had a marked influence
on activity. It has previously been found that substituents play
a critical role in generating activity. Compounds contain-
ing an electron-donating group proved to be more efficient
inhibitors than their electron-withdrawing congeners, while
nonsubstituted analogs had a mild effect on activity. The
4l
4m
4n
4o
4p
standard
Abbreviations: ace, angiotensin-converting enzyme; ic50, half-maximal inhibitory
concentrations.
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Zhuang et al
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length of the acyl side chain has its own influence on the the ligand (ie, trimethoxy phenyl) was found to be oriented
activity. Particularly, compounds containing a 2-N-acyl toward the aromatic residues of the active site (Tyr523 and
chain were found to be more efficient inhibitors than those Tyr520), and was identified as the main determinant of its
with different chain lengths. A detailed structure–activity stabilization in the active site. Comparing the molecular inter-
relationship analysis is shown in Figure 3.
actions of 4j versus lisinopril against tACE revealed a high
degree of resemblance.18 Thus, it appeared that compound
4j might have a similar mechanism of action.
Docking study
Docking is considered to be a powerful simulation of the
molecular recognition process. It is used to illustrate the Vasodilator activity
probable molecular interaction of a designed ligand with Animals have long been used to understand human biology.
the protein of interest, predict the affinity and activity of the In particular, in cardiovascular research, animal models have
ligand, and identify the energy of the interaction between allowed the study of associated diseases in the early stages,
the ligand and protein.17 To provide efficient results, it uses as well as mechanisms of therapeutic interventions. In this
algorithms such as molecular dynamics, Monte Carlo stimu- study, we used the Langendorff technique to generate a
lation, and fragment-based search methods. Thus, on the hypoxic–ischemic injury in a rat model. This technique has
basis of the in vitro results, a docking study was performed increased the ease with which arterial and venous perfusion
of compound 4j with tACE.
samples can be obtained and allows direct or indirect moni-
The crystal structure of human ACE (Protein Data Bank toring of such parameters as arteriovenous differences in pH,
[PDB]: 1O86) was used for this study. The cocrystallized PO2, ion content, substrate uptake, metabolite clearance, and
ligand of the protein (ie, lisinopril) was extracted, and het- enzyme leakage. Moreover, biopsies can be retrieved for
eroatoms and water molecules were removed to “clean” the biochemical or morphologic studies, or the whole heart can
protein for further analysis. The analysis was carried out be used. The Langendorff preparation is stable and can be
using the CDOCKER program within Discovery Studio 2.5 maintained for many hours, with minimal cardiac output and
(Accelrys, San Diego, CA, USA). Compound 4j was found to oxygen requirements.19
be efficiently accommodated in the deep cleft of the protein
Among the designed analogs, those compounds showing
cavity (Figure 4), making close interatomic contacts through most promise with respect to ACE inhibition (ie, 4i, 4j, 4k,
the formation of H-bonds with Glu162, His353, and Ala356. and 4l) were further selected for determination of their vaso-
The trimethoxy fragment of the compound was found to be dilator activity. For this, an in vitro experiment was conducted
buried inside the major cleft of the active site, surrounded using 10 μg of the test compounds on isolated rat hearts using
by the key catalytic residues (ie, Tyr523, Tyr520, Glu152, the Langendorff technique. The ability of the compound to
Asp453, Val380, Ala354, His353, Ser355, Lys454, Ala356, influence vasodilatation was determined by quantifying car-
His387, and Glu384). Moreover, the aromatic fragment of diac output and stroke volume in the experimental subjects.
Effect of substituent
3,4,5-trimethoxy >3,4-dihydroxy > H >4-NO2
O
O
O
O
O
O
H3C
H3C
CH3
CH3
N
N
CH2
CH3
O
O
H3C
CH3
H2C
n
H3C
Effect of chain length
2>1>3>4
4j
Figure 3 sar of target compound against ace inhibition along with most promising inhibitor, 4j.
Abbreviations: ace, angiotensin-converting enzyme; sar, structure–activity relationship.
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curcumin like derivatives as antihypertensive agents
ꢄ
ꢃ
ꢂ
ꢁ
ꢀ
Figure 4 Docking study of compound 4j in the active site of human ace.
Abbreviation: ace, angiotensin-converting enzyme.
Figure 6 effect of compounds on cardiac output in experimental rat.
Abbreviation: snP, sodium nitroprusside.
The effect of the compounds was also determined in the
presence of barium chloride (BaCl2)-induced vasoconstric-
tion (via inhibition of the K+ ion channels), which leads to
reductions in cardiac output and stroke volume.
nitric oxide (NO) by the Griess reaction. NO is a radical gas
that is also known as endothelium-derived relaxing factor.
It is used by the endothelium of blood vessels to signal to
the surrounding smooth muscle, via a cascade of biological
events, resulting in the relaxation of arteries and veins. This
relaxation leads to vasodilatation and increased blood flow.
Therefore, the ability to release NO˙ was calculated as the
percentage of NO2˙ (ie, as the ratio between the number of
NO2˙ mol detected and the number of mol of test derivatives,
multiplied by 100). At the tested dose, the entire set of com-
pounds showed considerable NO donor activity (Figure 8).
Moreover, it was surprising to find that an increasing number
of N-acyl side chains was associated with improvements in
donor capability, with the highest donor activity being seen
for compound 4l. Thus, chain length might have a prominent
influence on activity.
As shown in Figure 5, none of the tested derivatives was
associated with improvements in the heart rate. However,
the reduced cardiac output and stroke volume under the
influence of BaCl2 were significantly elevated on treatment
with the test compounds (Figures 6 and 7). Therefore, in
experimental rats, the tested analogs were associated with
improvements in cardiac blood flow without influencing the
contraction rate. This suggests that the target site of these
compounds might be the coronary blood vessels, rather than
the cardiac muscles.
To explore the probable mechanism of action of these
derivatives, they were further tested for their ability to donate
ꢃꢀ
ꢂꢀ
ꢁꢀ
ꢀ
ꢀꢁꢆꢀ
ꢀꢁꢀꢅ
ꢀꢁꢀꢄ
ꢀꢁꢀꢃ
ꢀꢁꢀꢂ
ꢀꢁꢀꢀ
Figure 5 effect of compounds on heart rate of experimental rat.
Abbreviation: snP, sodium nitroprusside.
Figure 7 effect of tested compound on stroke volume in experimental rat.
Abbreviation: snP, sodium nitroprusside.
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ꢅꢀꢀ
ꢆꢀ
ꢅꢀ
ꢃꢀ
ꢀ
&RPSRXQGꢈꢅM
&XUFXPLQ
ꢄꢀ
ꢃꢀ
ꢁꢀ
ꢂꢀ
ꢀ
ꢁL
ꢁM
ꢁN
ꢁ,
613 &XUFXPLQ
ꢀ
ꢁ
ꢂꢀ ꢂꢁ ꢃꢀ ꢃꢁ ꢄꢀ ꢄꢁ ꢅꢀ ꢆꢀ ꢇꢀ ꢂꢃꢀ ꢂꢅꢀ
7LPHꢀꢁPLQꢂ
Figure 8 effect of tested compounds on nO donor activity.
Abbreviations: nO, nitric oxide; snP, sodium nitroprusside.
Figure 9 Bioavailability of compound 4j and curcumin in experimental rats.
Because these compounds are derived from curcumin, it degradation and was able to persist for a long period of time
is important to compare the effects of the most promising of in the subject.
these compounds with those of curcumin. As can be seen in
Figures 5–8, the administration of curcumin did not result in Conclusion
any significant changes in the parameters discussed above, In this study, we created a series of antihypertensive com-
when compared with the normal control group.
pounds based upon curcumin in excellent yields via short
synthetic steps. These derivatives were able to reduce hyper-
tension in vitro and in experimental animal models via ACE
inhibition and vasodilation of the arterioles. The potentiation
Bioavailability of compound 4j after oral
administration in mice
The poor bioavailability of curcumin seriously hampers its of NO donor activity was identified as a probable mechanism
clinical efficacy and utility. A study have indicated that the for the vasodilatory activity. Moreover, the most promising
oral bioavailability of curcumin is very poor in experimental inhibitor, 4j, was found to resist metabolic deactivation in
rats because of its erratic absorption and ease of metabolism mice, resulting in better in vivo bioavailability compared
via glucuronidation.15 Because we developed the compounds with curcumin. With its excellent pharmacological activity
in this study with the aim of improving the bioavailability of and bioavailability, compound 4j might serve as a template
curcumin, it was important to gain insight regarding their bio- for the future discovery of novel agents and hence it warrants
availability. Therefore, the plasma concentrations of the most further research. Further studies are underway and will be
promising inhibitor, 4j, were determined using high-perfor- communicated in due course.
mance liquid chromatography after oral administration of 3
mg per 30 g body weight to experimental mice, along with Disclosure
parallel administration of curcumin in other group 2 g/kg.
In this bioavailability determination experiment, com-
The authors report no conflicts of interest in this work.
pound 4j was not detected until 10 minutes. As time went References
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