Synthesis and antihypertensive effects of new methylthiomorpholinphenol derivatives

Article abstract of DOI:10.1016/j.ejmech.2007.04.003

We present in this work the synthesis and cardiovascular effects of new methylthiomorpholine compounds and they were compared with cardiovascular drugs such as captopril, losartan and omapatrilat.

Full text of DOI:10.1016/j.ejmech.2007.04.003

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 486e500
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antihypertensive effects of new
methylthiomorpholinphenol derivatives
a
a
a
b
a
A. Ma. Velazquez , L. Martınez , V. Abrego , M.A. Balboa , L.A. Torres ,
´
B. Camacho , S. Dıaz-Barriga , A. Romero , R. Lopez-Castanares , E. Angeles
´
a
a
a
c
a,
*
´
´
~
a Divisio´n de Ciencias Qu´ımico Biolo´gicas, Facultad de Estudios Superiores Cuautitla´n, Universidad Nacional Auto´noma de Me´xico,
54740 Cuautitla´n Izcalli, Estado de Me´xico, Mexico
b Facultad de C. Qu´ımicas, UNACH, Mexico
c Facultad de Qu´ımica, Universidad Auto´noma del Estado de Me´xico, Toluca, Estado de Me´xico, Mexico
Received 17 March 2006; received in revised form 25 March 2007; accepted 4 April 2007
Available online 25 April 2007
Abstract
We present in this work the synthesis and cardiovascular effects of new methylthiomorpholine compounds and they were compared with
cardiovascular drugs such as captopril, losartan and omapatrilat.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Cardiovascular effects; Thiomorpholin; Methylthiomorpholinphenols
1. Introduction
cardiovascular disease in both men and women, and in differ-
ent ethnic groups [7e9]. Risk factors for cardiovascular dis-
ease are prevalent in men and women [10]. In young adults,
education level is inversely associated with 5-year weight
gain [11] and 10-year incidence of high blood pressure [12],
while financial hardship is associated with 10-year incidence
of hypertension [13].
The dihydropyridine calcium channel blocker compounds
such as nifedipine and isradipine were originally developed
for the treatment of hypertension [14,15], and today there
are many compounds used as antihypertensives [16]. In
1979, a research group in the People’s Republic of China
noted, while examining the antimalarial properties of deriva-
tives of febrifugine, that one compound in clinical trials, chan-
grolin, Fig. 1, was effective as an arrhythmic agent. In 1983,
Stout and his research group of the American Hospital Supply
Corporation, McGaw Park, Illinois, studied the structure of
changrolin for its dissimilarity with currently marketed anti-
arrhythmics [17e20]; there are also other recent studies about
the biological structureeactivity relationships [21,22]. And so,
we take the phenol and methylpyrrolidine rings as a structural
In the last twenty years, cardiovascular diseases have be-
come the world’s leading cause of death [1]. In this setting,
well-formulated health promotion programs may play an im-
portant role, as they are thought to reduce chronic disease-re-
lated morbidity and mortality, as well as health care costs [2].
It is known that such health programs may be effectively de-
livered at the workplace, in addition to improve absenteeism
and work safety [3e6]. Under most real-world conditions, it
is difficult and costly for worksite health promotion programs
to follow strictly controlled research designs over an extended
period of time, impeding the evaluation and determination of
the most effective programmatic structure to achieve health
improvements. On the other hand, it is estimated that about
one million patients are hospitalized for acute coronary events
each year in the United States, and it is well known that low
socioeconomic status is associated with increased risk of
* Corresponding author. Tel./fax: þ52 55 56232066.
E-mail address: angeles@servidor.unam.mx (E. Angeles).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.04.003

A.Ma. Vela´zquez et al. / European Journal of Medicinal Chemistry 43 (2008) 486e500
487
Ar-CH2), 2.81 (4H, m, eSeCH2e), 2.71 (4H, m, eNe
CH2e). 13C NMR (CDCl3) d: 156 (C), 128.56 (CH), 128.31
(CH), 123.61 (C), 122.11 (C), 117.37 (CH), 61.63 (Ar-CH2),
54.27 (eSeCH2e), 27.73 (eNeCH2e). FAB-MS m/z
(rel%) (M þ 1) 244 (100%), 215, 180, 154.
N
OH
H
N
2.1.2.2. 4-tert-Butyl-2-(thiomorpholin-4-ylmethyl)phenol e com-
pound 3 (LQM302). IR (CHCl3 film) cmꢁ1 3456 (OeH),
3197 (Csp2 eH Ar), 2886 (Csp3 eH). 1H NMR (CDCl3) d:
10.33 (1H, s, OH), 7.18 (1H, dd, J ¼ 8.4 Hz, 2.7 Hz), 6.94
(1H, d, J ¼ 2.7 Hz), 6.74 (1H, d, J ¼ 8.4 Hz), 3.70 (2H, s, Ar-
CH2), 2.82 (4H, m, eSeCH2e), 2.71 (4H, m, eNeCH2e),
1.27 (9H, CH3). 13C NMR (CDCl3) d: 155 (C), 141.8 (C),
125.60 (CH), 125.49 (CH), 119.77 (C), 115.47 (CH), 62.51
(Ar-CH2), 54.36 (eNeCH2e), 33.84 (C), 31.48 (CH3), 27.79
(eSeCH2e). FAB-MS m/z (M þ 1) 266 (80%), 265 (100%),
163 (45%).
N
N
N
Fig. 1. Changrolin.
requirement to show cardiovascular effects and we change the
pyrrolidine rings to methylthiomorpholin rings. In our experi-
ence, methylmorpholinphenol and methylpiperidinylphenol
derivatives show cardiovascular effects [23] and, in the litera-
ture, there is only one report about the cardiovascular effects
of methylmorpholinphenols [24], and only two reports about
the biological activity of thiomorpholinphenols, which have
been reported with antimycobacterial activity [25] and against
Candida [26]. We now report, as part of the Drug Design in
Medicinal Chemistry Program of the UNAM, new methylthio-
morpholinphenol compounds with cardiovascular effects, con-
sidering that the development of new antihypertensive drugs is
justified as there is a need to search for medicines that promote
a decrease in blood pressure, such as monotherapy, to achieve
a good protection for most hypertensive patients and a reduc-
tion in adverse reactions.
2.1.2.3. 4-tert-Butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol e
compound 4 (LQM303). IR (CHCl3 film) cmꢁ1 3403 (OeH),
3089 (Csp2 eH Ar), 2986 (Csp3 eH). 1H NMR (CDCl3) d:
10.69 (1H, s, OH), 7.09 (2H, s,), 3.71 (4H, s, Ar-CH2), 2.86
(8H, m, eSeCH2e), 2.76 (8H, m, eNeCH2e), 1.27 (9H,
CH3). 13C NMR (CDCl3) d: 153.6 (C), 141.14 (C), 125.79
(CH), 121.22 (C), 58.81 (Ar-CH2), 54.42 (eNeCH2e), 33.78
(C), 31.47 (CH3), 27.74 (eSeCH2e). FAB-MS m/z (M þ 1)
381 (35%), 278 (100%), 175 (50%).
2.1.2.4. 4,6-Bis(thiomorpholin-4-ylmethyl)1,2,3-benzenetriol e
compound 5 (LQM304). IR (CHCl3 film) cmꢁ1 3429 (OeH),
3065 (Csp2 eH Ar), 2872 (Csp3 eH). 1H NMR (CDCl3) d: 8.401
(3H, s, OH), 6.20 (1H, s), 3.61 (4H, s, Ar-CH2), 2.81 (8H, m,
eSeCH2e), 2.72 (8H, m, eNeCH2e). 13C NMR (CDCl3) d:
144.8 (C), 132.51 (C), 118.42 (CH), 111.74 (C), 61.63 (Ar-
CH2), 54.22 (eNeCH2e), 27.81 (eSeCH2e). FAB-MS m/z
(M þ 1) 357 (10%), 254 (100%), 102 (91%).
2. Experimental
2.1. Chemistry
2.1.1. General methodology of synthesis
Methylthiomorpholinphenol compounds were prepared
from phenol derivatives (1 eq.), thiomorpholine (2.1 eq.) and
formaldehyde (37%) (2 eq.). They were mixed in a round flask
fitted with a condenser. The mixture was irradiated with infra-
red light using a medicinal infrared lamp (250 W) under sol-
vent-free conditions [27]. The reaction was monitored with
TLC using a gradient solvent system (n-hexane/ethylacetate)
until the reaction was complete. The products were purified
by recrystallization and by using silica gel column chromatog-
raphy using gradient solvents (n-hexane/ethylacetate). The
temperature of the reaction mixture is in the range of
120 ꢀCe180 ꢀC. Summary of reaction is described in Table 1.
2.1.2.5. 4-[1-(4-Hydroxy-3-(thiomorpholin-4-ylmethyl)phenyl)-
1-methylethyl]-2-(thiomorpholin-4-ylmethyl)phenol e compound
6 (LQM305). IR (CHCl3 film) cmꢁ1 3473 (OeH), 3034
(Csp2 eH Ar), 2895 (Csp3 eH). 1H NMR (CDCl3) d:10.42
(2H, s, OH), 7.0 (1H, dd, J ¼ 2.4 Hz, 8.4 Hz), 6.79 (1H, d,
J ¼ 2.4 Hz), 6.70 (1H, d, J ¼ 8.4 Hz), 3.64 (4H, s, Ar-CH2),
2.80 (8H, m, eSeCH2e), 2.74 (8H, m, eNeCH2e), 1.57
(3H, s, CH3). 13C NMR (CDCl3) d: 155.09 (C), 141.70 (C),
127.06 (CH), 126.85 (CH), 119.78 (C), 115.30 (CH), 62.48
(Ar-CH2), 54.35 (eNeCH2e), 41.38 (C), 31.07 (CH3),
27.83 (eSeCH2e). FAB-MS m/z (M þ 1) 459 (40%), 238
(100%), 237 (32%).
2.1.2. Spectroscopy
3. Biological activity
2.1.2.1. 4-Chloro-2-(thiomorpholin-4-ylmethyl)phenol e com-
pound 2 (LQM301). IR (CHCl3 film) cmꢁ1 3502 (OeH),
3010 (Csp2 eH Ar), 2985 (Csp3 eH). 1H NMR (CDCl3) d:
10.56 (1H, s, OH), 7.11 (1H, dd, J ¼ 8.7 Hz, 2.7 Hz), 6.94
(1H, d, J ¼ 2.7 Hz), 6.74 (1H, d, J ¼ 8.7 Hz), 3.65 (2H, s,
3.1. Materials and methods
We compared methylthiomorpholinphenol derivatives
with captopril (angiotensin-converting enzyme, ACE), losar-
tan (AT1 receptor antagonist) and omapatrilat (neutral

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Table 1
Experimental data of compounds 2e6
Compound
Structure
MP (ꢀC)
Yield (%)
60
Reaction time (min)
7
OH
2 (LQM301)
127e129
N
N
S
S
Cl
OH
3 (LQM302)
85e87
70
15
OH
4 (LQM303)
95e97
80
20
N
N
S
S
S
HO
OH
5 (LQM304)
193e195
87
11
N
N
S
OH
6 (LQM305)
163e165
50
11
N
S
H3C
CH3
S
N
OH

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489
Fig. 2. Doseeeffect curve of compound LQM301 in anesthetized male Wistar rat. The hypotensive effect of compound LQM301 was significant at doses of 1.0, 3.1
and 10.0 mg/kg. This compound significantly decreased heart rate at doses of 0.0001, 0.001 and 0.01 mg/kg.
endopeptidase inhibitor and ACE). The results of this work are
shown with a doseeeffect curve for each compound. An inva-
sive arterial pressure model was used to determine the com-
pounds’ hypotensive effect.
rats, weighing between 280 and 320 g. The rats were main-
tained on a 12 h light/12 h dark cycle and had free access to
standard rat chow and drinking water. The experimental proce-
dures were approved by the Institutional Animal Care and Use
Committee of our institution.
3.1.1. Reagents
Captopril SIGMA, omapatrilat and losartan were provided
by Bristol-Meyers-Squibb, and Merck Sharp & Dome Labora-
tories, respectively. All the compounds were synthesized in
Laboratorio de Quimica Medicinal, FESC-UNAM. We used
12 weeks old male Wistar normotensive and hypertensive
3.2. Determination of hypotensive effect
In order to establish the biological effect of methylthiomor-
pholin derivatives, we chose five compounds that were labeled
LQM301eLQM305 and solubilized using a mixture of 0.1 mL
Fig. 3. Doseeeffect curve of compound LQM302 in anesthetized male Wistar rat. The hypotensive effect of compound LQM302 turned out to be significant at
doses of 0.001, 0.1, 1.0, 3.1 and 10.0 mg/kg. This compound significantly decreased heart rate at doses of 0.01, 0.1, 1.0, and 10.0 mg/kg.

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Fig. 4. Doseeeffect curve of compound LQM303 in anesthetized male Wistar rat. The hypotensive effect of compound LQM303 was significant at all doses. This
compound significantly decreased heart rate at doses of 1.0, 3.1 and 10.0 mg/kg.
of chlorhydric acid solution (0.000592 M) and 0.9 mL physio-
logical saline solution, obtaining a final volume of 1.0 mL.
Subsequently, the rats were anesthetized with sodium pen-
tobarbital (45 mg/kg, ip), a tracheotomy was performed, the
right carotid artery was dissected and cannulated with a cathe-
ter (PE50) connected to a pressure transducer which was con-
nected to a Digi-Med Blood Pressure Analyzer to monitor
systolic (SAP), diastolic (DAP) and mean arterial pressure
Fig. 5. Doseeeffect curve of compound LQM304 in anesthetized male Wistar rat. The hypotensive effect of compound LQM304 decreased significantly at doses of
1.0, 3.1 and 10.0 mg/kg. This compound significantly decreased heart rate at doses of 0.01, 0.1, 1.0, 3.1 and 10.0 mg/kg.

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491
Fig. 6. Doseeeffect curve of compound LQM305 in anesthetized male Wistar rat. The hypotensive effect of compound LQM305 was significant at doses of 0.0001,
1.0, 3.1 and 10.0 mg/kg. This compound significantly decreased heart rate at doses of 0.01, 0.1, 1.0, 3.1 and 10.0 mg/kg.
(MAP), and heart rate. Registers were obtained using the pro-
gram DMSI-2000_1.
In the first stage, the biological activity of the compounds
was established using anesthetized normotensive rats with
the objective of establishing in a quick and practical manner
the biological effect of captopril, losartan, omapatrilat and the
LQM series compounds; in the second experimental stage, the
conscious spontaneous hypertensive rat model was applied to
Fig. 7. Doseeeffect curve of captopril (angiotensin-converting enzyme inhibitor) in anesthetized male Wistar rat. The hypotensive effect of the captopril was sig-
nificant at all doses. Its effect on heart rate was not significant.

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Fig. 8. Doseeeffect curve of losartan (AT1 receptor antagonist) in anesthetized male Wistar rat. The hypotensive effect of the Losartan was significant at all doses.
Its effect on heart rate was not significant.
Fig. 9. Doseeeffect curve of the reference drug omapatrilat (neutral endopeptidase inhibitor) in anesthetized male Wistar rat. The hypotensive effect of omapatrilat
was significant at all doses. The effect on heart rate was not significant.

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493
Fig. 10. Doseeeffect curves (AeD) of compounds LQM301, LQM302, LQM303 and LQM304 in normotensive anesthetized rat. Each graph shows the mathe-
matical model with its ED50 calculated.
Fig. 11. Doseeeffect curves (AeD) of compounds LQM305, captopril, losartan and omapatrilat in normotensive anesthetized rat. Each graph shows the mathe-
matical model with its ED50 calculated.

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Table 2
Mean effective dose of synthesized compounds and positive controls
Compound
LQM301
2.2122
LQM302
1.0410
LQM303
0.4111
LQM304
0.3631
LQM305
1.4091
Captopril
0.00062
Losartan
0.02815
Omapatrilat
0.0058
ED50 (mg/kg)
better evaluate hypotension effect, recording systolic and dia-
stolic arterial pressure and heart rate.
LQM301, LQM302, LQM304 and LQM305 compounds
showed a gradual effect on systolic, diastolic and mean arterial
pressure, starting at 0.1 mg/kg (Figs. 2e6), whereas captopril,
losartan and omapatrilat, showed the same effect at 0.001 mg/kg.
Regarding heart rate, LQM302eLQM305, reduced it gradu-
ally and significantly, whereas captopril, losartan and omapa-
trilat did not show a significant effect on this variable.
Table 2 shows ED50 in mg/kg of LQM301eLQM305, and
the three reference drugs. Captopril showed the lowest ED50
among all the compounds. On the other hand, it was deter-
mined that captopril’s ED50 is three times lower than
LQM303, LQM304 and four times lower than LQM301,
LQM302 and LQM305.
The biological activity of each compound (LQM301e
LQM305) was determined by means of a doseeeffect curve
(0.0001, 0.001, 0.01, 0.1, 1.0, 3.1 and 10 mg/kg IV, n ¼ 5).
Each compound was administered through the femoral vein.
The captopril, omapatrilat and losartan doseeeffect curves
were determined (0.0001, 0.001, 0.01, 0.1 and 1.0 mg/kg IV,
n ¼ 5) with the purpose of comparing mean effective dose
(ED50) with experimental compounds. The doses were admin-
istered every five minutes allowing for the hypotensive effect
to take place.
Figs. 12e15 show efficacy and potency on systolic, dia-
stolic and mean arterial pressure and on heart rate of all tested
compounds as well as captopril, losartan and omapatrilat. Cap-
topril was the most potent and effective, LQM303 exhibited
some similarity with captopril in diastolic and mean arterial
pressure, but they differed in systolic arterial pressure and po-
tency, as shown in Figs. 13 and 14. LQM301, LQM302,
LQM304 and LQM305 exhibited similar effects to losartan
and omapatrilat. This observation was made based only on
the behavioral tendencies of the curves representing the
doseeeffect % relationship, Figs. 13 and 14.
4. Statistical analysis
The data were analyzed using Excel and Statistica Soft-
ware, the values appear as average (n ¼ 5) ꢂ SEM. The com-
parison of the results of both curves was conducted by
Student’s t-test and ANOVA *P < 0.05.
5. Results and discussion
First step: The arterial pressure model was used to deter-
mine the hypotensive effect of all compounds. The results
are shown in Figs. 2e9. The values are plotted as follows:
A: mean arterial pressure (MAP) vs. dose; B: systolic arterial
pressure (SAP) vs. dose; C: diastolic arterial pressure (DAP)
vs. dose.
On the other hand, captopril, losartan and omapatrilat
did not have a significant effect on heart rate, whereas
LQM303eLQM305 induced a significant decrease in heart
The black dotted line is the extension of the initial value of
the arterial pressure (Basal t0); the blue line1 indicates pressure
values before the addition of each dose (Basal); and the pink
line indicates pressure values after compound addition (effect).
For the case of losartan effect, in Fig. 8 we can observe its hy-
potensive effect, because there is a difference between the
basal pressure and the final pressure after the administration
of the drug of reference. The change in mean arterial pressure
after administering 10.0 mg/kg of losartan is 41.31 mmHg; for
the systolic arterial pressure, it is 43.62 mmHg; for the dia-
stolic arterial pressure it is 45.64 mmHg, therefore, losartan
does exhibit hypotensive effect in the experiment with the
anesthetized rat model.
Doseeeffect curves were used to calculate the ED50 of
compounds LQM301eLQM305, and captopril, losartan and
omapatrilat. The results are shown in Figs. 10 and 11. In these
figures, we can also observe the mathematical models used for
the ED50 calculations.
Fig. 12. Doseeeffect (%) curves of five thiomorpholine compounds, captopril,
losartan and omapatrilat (antihypertensive drugs). The graph shows their effi-
cacy and potency on systolic arterial pressure. The captopril was more
effective in reducing systolic arterial pressure than LQM303 > losar-
tan > omapatrilat ¼ LQM304 > LQM305 ¼ LQM302 > LQM301 at 1 mg/kg.
1
For interpretation of the references to colour in text, the reader is referred
to the web version of this article.

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495
Fig. 13. Doseeeffect (%) curves of five thiomorpholine compounds, captopril,
losartan and omapatrilat (antihypertensive drugs). The graph shows their
efficacy and potency on diastolic arterial pressure. Captopril was more
effective in reducing diastolic arterial pressure than LQM303 > losar-
tan ¼ LQM304 > omapatrilat > LQM302 > LQM305 > LQM301 at 1 mg/kg.
Fig. 15. Doseeeffect (%) curves of five thiomorpholine compounds, captopril,
losartan and omapatrilat (antihypertensive drugs). The graph shows their effi-
cacy and potency on heart rate. LQM303 was more effectivein reducing
heart rate than LQM304 > captopril > losartan ¼ LQM305 ¼ omapatrilat >
LQM301 ¼ LQM302 at 1 mg/kg.
each compound of the experimental series and of the reference
antihypertensives during the 2.0 h that the experiment lasted,
for the spontaneous hypertensive rat experimental model.
Figs. 16e22 show the graphs of the tendencies in these
experiments.
Based on the findings of the experiment with the conscious
spontaneous hypertensive rat model, where the change in sys-
tolic arterial pressure was of 82.3 mmHg, 80 min after admin-
istering 1.0 mg/kg of losartan, and change in diastolic pressure
was of 66.35 mmHg, also 80 min after administering losartan,
it was confirmed that losartan exhibits the hypotensive effect
that has been known until now, as can be observed in Table 3.
rate, this may occur because LQM compounds have a depress-
ing effect on the Sino auricular node, which controls the car-
diac rhythm, therefore decreasing heart rate.
Second step: In the second experimental stage, the con-
scious hypertensive rat model was used to better evaluate hy-
potensive effect, recording systolic and diastolic arterial
pressure, and heart rate.
The administration of the reference antihypertensives and
the compounds of the experimental series was in a dose of
1.0 mg/kg orally. The experimental results show a decrease
in systolic and diastolic pressures and heart rate.
Table 3 shows the results obtained in the maximum de-
crease of systolic and diastolic pressure and heart rate for
6. Conclusion
The synthesis of the experimental LQM compounds is very
simple, and they are easy to purify. The results obtained sug-
gest that LQM compounds have a moderate hypotensive effect
and could be used for chronic patients.
In this research, some of these compounds were compared
with captopril (ACE inhibitors), losartan (antagonist of AT1
Table 3
The results of maximum decrease in systolic pressure, diastolic pressure, and
heart rate, of the compounds that form the experimental series and of the an-
tihypertensive compounds used as reference
Compound
DPmax systolic/
DPmax diastolic/
Dmax heart rate/
time (mmHg/min) time (mmHg/min) time (beat/min/min)
LQM301
LQM302
LQM303
LQM304
LQM305
73.9/100
71.47/100
95.755/90
45.6/60
46.7/100
31.8/60
72.2/110
147.88/100
160.448/100
92.5/120
48.225/90
29.2/60
Fig. 14. Doseeeffect (%) curves of five thiomorpholine compounds, captopril,
losartan and omapatrilat (antihypertensive drugs). The graph shows their effi-
cacy and potency on mean arterial pressure. Captopril and LQM303 were
more effective in reducing mean arterial pressure than losartan ¼ omapatrilat
¼ LQM304 > LQM305 > LQM302 > LQM301 at 1 mg/kg.
28.086/60
12.5875/60
36.45/100
66.35/80
106.566/120
52.04/70
38.37/80
CAPTOPRIL 42.0/50
LOSARTAN 82.3/80

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Fig. 16. Curve effect vs. time of compound LQM301 (AeC). Oral administration: 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experi-
mental conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 73.9 mmHg, 100 min after administration.
(B) Variation of diastolic pressure vs. time. The maximum decrease was 46.7 mmHg. (C) Variation of cardiac frequency vs. time. The maximum decrease was
72.2 beats/min.
receptors) and omapatrilat (inhibitor of neutral endopeptidase
and ACE) in normotensive and hypertensive rat. The results
obtained in the doseeeffect curves in the arterial pressure
model show two important candidate compounds (LQM303
and LQM304), since these have a lower ED50 than the other
synthesized compounds. Also, the doseeeffect curve of
LQM303 shows a similarity in the tendency to decrease sys-
tolic, diastolic and mean arterial pressure. Therefore, it would
be important to analyze the influence of the functional groups
of this molecule (LQM303) in order to determine which of
Fig. 17. Curve effect vs. time of compound LQM302 (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 71.4 mmHg, 100 min after administration. (B) Variation
of diastolic pressure vs. time. The maximum decrease was 31.8 mmHg, 60 min after administration. (C) Variation of heart rate vs. time. The maximum decrease
was 147.88 beats/min, 100 min after administration.

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497
Fig. 18. Curve effect vs. time of compound LQM303 (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 95.755 mmHg, 90 min after administration. (B) Var-
iation of diastolic pressure vs. time. The maximum decrease was 48.225 mmHg, 90 min after administration. (C) Variation of heart rate vs. time. The maximum
decrease was 160.448 beats/min, 100 min after administration.
them is involved in the pharmacological activity. In addition,
we determined that some compounds exist that not only re-
duce arterial pressure but also reduce heart rate. This could
be relevant because, in these compounds, we can find the
groups that influence the decrease in cardiac rhythm and
then test them in a cardiac arrhythmia model. On account of
their characteristics, they are prime candidates to exert possi-
ble anti-arrhythmic activity.
Fig. 19. Curve effect vs. time of compound LQM304 (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 45.6 mmHg, 60 min after administration. (B) Variation
of diastolic pressure vs. time. The maximum decrease was 29.2 mmHg, 60 min after administration. (C) Variation of heart rate vs. time. The maximum decrease
was 92.5 beats/min, 120 min after administration.

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Fig. 20. Curve effect vs. time of compound LQM305 (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 28.086 mmHg, 60 min after administration. (B) Var-
iation of diastolic pressure vs. time. The maximum decrease was 12.558 mmHg, 60 min after administration. (C) Variation of heart rate vs. time. The maximum
decrease was 160.566 beats/min, 120 min after administration.
Considering the ED50 of each tested compound, the scale of
effective pharmacological effect would be captopril >
omapatrilat > losartan > LQM304 > LQM303 > LQM302 >
LQM305 > LQM301.
The hypotensive effect of omapatrilat, losartan and capto-
pril showed a gradual relationship of hypotensive effect vs.
dose (mg/kg IV) in this model; whereas LQM compounds de-
crease blood pressure between 5 and 10 mmHg at a dose of
Fig. 21. Curve effect vs. time of compound captopril (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 42.0 mmHg, 50 min after administration. (B) Variation
of diastolic pressure vs. time. The maximum decrease was 36.45 mmHg, 100 min after administration. (C) Variation of cardiac frequency vs. time. The maximum
decrease was 52.04 beats/min, 70 min after administration.

A.Ma. Vela´zquez et al. / European Journal of Medicinal Chemistry 43 (2008) 486e500
499
Fig. 22. Curve effect vs. time of compound losartan (AeC). Oral administration, 1.0 mg/kg dose. Spontaneous hypertensive rat. Each graph shows experimental
conditions and maximum decrease. (A) Variation of systolic pressure vs. time. The maximum decrease was 82.3 mmHg, 80 min after administration. (B) Variation
of diastolic pressure vs. time. The maximum decrease was 66.35 mmHg, 80 min after administration. (C) Variation of cardiac frequency vs. time. The maximum
decrease was 38.37 beats/min, 80 min after administration.
0.001, 0.01 and 0.01 (mg/kg IV) after the hypotensive effect
becomes gradual, so LQM compounds do not reduce blood
pressure in a sudden manner as in the case of vasodilatations
and b-adrenergic blockers, angiotensin-converting enzyme in-
hibitors (ACE), receptors AT1 antagonists, and neutral endo-
peptidase inhibitors.
Acknowledgements
The authors wish to acknowledge PAPIIT/UNAM Projects
No. IN213606 and IN207705 and ALPHARMA SA de CV, for
partial support of this work. They would like to thank C. Bar-
´
´
ajas, F. Sotres, P. Garcıa, R. Gonzalez, A. Pecina, A. Valencia,
´
D. Jimenez from FESC-UNAM and Rosa I. del Villar M.,
~
Oscar Yanez and Georgina Duarte from USAI-UNAM for
their skillful technical assistance and DGSCA-UNAM for their
Finally, we can say that the development of new antihyper-
tensive drugs is justified because it is necessary to search for
drugs that are able to reduce blood pressure, like monotherapy,
in order to achieve good protection for the majority of hyper-
tensive patients and a reduction of adverse reactions.
As shown in Table 2, the compound that exhibited the high-
est antihypertensive activity in the conscious spontaneous hy-
pertensive rat model was LQM303, confirming what has been
observed in the anesthetized rat model.
The magnitude of the effect of the compounds on systolic
pressure in decreasing order was LQM303 > losartan >
LQM301 > LQM302 > LQM304 > captopril > LQM305.
For diastolic pressure, the magnitude of the effect in
decreasing order was losartan > LQM303 > LQM301 >
captopril > LQM302 > LQM304 > LQM305.
´
support. Catedrade Quımica Medicinal FESC-UNAM.
´
References
[1] C.J.L. Murray, A.D. Lopez, The Global Burden of Disease: In a Compre-
hensive Assessment of Mortality and Disability from Diseases, Injuries,
and Risk Factors in 1990 and projected to 2020, first ed. Harvard Univ.
Press, Cambridge, MA, 1996.
[2] T.S. Kristensen, Occup. Med. 15 (2000) 293e305.
[3] M.H. Alderman, Am. J. Public Health 83 (1993) 313e314.
[4] K.R. Pelletier, Am. J. Health Promot. 13 (1999) 333e345.
[5] M.G. Wilson, P.B. Holman, A. Hammock, Am. J. Health Promot. 10
(1996) 429e435.
And for heart rate, it was: LQM303 > LQM302 > LQM305
> LQM304 > LQM301 > captopril > losartan.
Finally, we observed that of the studied compounds,
LQM303 exhibits the best decreasing effect in both systolic
and diastolic pressure; it also exhibits the best heart rate-
decreasing effect.
[6] G. Sorensen, K. Emmons, M.K. Hunt, D. Johnston, Annu. Rev. Public
Health 19 (1998) 379e416.
[7] N.E. Adler, T. Boyce, M.A. Chesney, S. Cohen, S. Folkman, R.L. Kahn,
Am. Psychol. 49 (1994) 15e24.
[8] S. Wing, E. Barnett, M. Casper, H.A. Tyroler, Am. J. Public Health 82
(1992) 204e209.
[9] S. James, Am. Heart J. 108 (1984) 669e672.

500
A.Ma. Vela´zquez et al. / European Journal of Medicinal Chemistry 43 (2008) 486e500
[10] K.A. Matthews, S.F. Kelsey, E.N. Meilahn, L.H. Kuller, R. Wing, Am. J.
Epidemiol. 129 (6) (1989) 1132e1144.
[19] D.M. Stout, W.L. Matier, C. Barcelon-Yang, R.D. Reynolds, B.S. Brown,
J. Med. Chem. 28 (1985) 295e298.
[11] G.L. Burke, D.E. Bild, J.E. Hilner, A.R. Folsom, L.E. Wagenknecht,
S. Sidney, Ethn. Health 1 (1996) 327e335.
[20] M.L. Glowka, P.W. Codding, J. Med. Chem. 34 (1991) 2678e
2684.
[12] A.R. Dyer, K. Liu, M. Walsh, C. Kiefe, D.R. Jacobs, D.E. Bild, J. Hum.
Hypertens. 13 (1999) 13e21.
[21] Y.L. Zeng, Y.F. Wang, J. Li, J.M. Xu, M. Wang, H. Qiu, Eur. J. Pharma-
col. 183 (1990) 1849.
[22] D. Dai, J. Mol. Cell. Cardiol. 22 (1990) S74.
[13] K.A. Matthews, C.I. Kiefe, C.E. Lewis, K. Liu, S. Sidney, C. Yunis,
Hypertension 39 (2002) 772e776.
[14] A. Fitton, P. Benfield, Drugs 40 (1990) 31e74.
´
[23] I. Martınez-Trejo, Thesis Master’s Degree Facultad de Estudios Superi-
ores UNAM, 2002.
[15] T.S. Foster, S.R. Hamann, V.R. Richards, P.J. Bryant, D.A. Graves,
R.G. McAllister, J. Clin. Pharmacol. 23 (1983) 161e170.
[16] A.V. Chobanian, G.L. Bakris, H.R. Black, W.C. Cushman, L.A. Green,
J.L. Izzo Jr., D.W. Jones, B.J. Materson, S. Oparil, J.T. Wright Jr.,
E.J. Roccella, JAMA, J. Am. Med. Assoc. 289 (2003). doi:10.1001/
jama.289.19.2560.
[24] M. Lin, Y. Liu, Y. Lu, H. Zhang, W. Zheng, Yao Xue Xue Bao 16 (1981)
757e761.
[25] M. Artico, A. Mai, G. Sbardella, S. Massa, G. Lampis, D. Deidda,
R. Pompei, Bioorg. Med. Chem. Lett. 8 (1998) 1493e1498.
[26] M. Biava, R. Fioravanti, G.C. Porretta, D. Deidda, C. Maullu,
M. Pompei, Bioorg. Med. Chem. Lett. 9 (1999) 2983e2988.
´ ´ ´ ´
[27] A. Ma. Velazquez, L.A. Torres, G. Dıaz, A. Ramırez, R. Hernandez,
[17] D.M. Stout, W.L. Matier, C. Barcelon-Yang, R.D. Reynolds, B.S. Brown,
J. Med. Chem. 26 (1983) 808e813.
´
H. Santillan, L. Martınez, I. Martınez, S. Dıaz-Barriga, V. Abrego,
´
´
´
´
M.A. Balboa, B. Camacho, R. Lopez-Castanares, A. Duenas-Gonzalez,
~
~
´
[18] D.M. Stout, W.L. Matier, C. Barcelon-Yang, R.D. Reynolds, B.S. Brown,
J. Med. Chem. 27 (1984) 1347e1350.
G. Cabrera, E. Angeles, ARKIVOC (2006) 150e161.