Synthesis and anti-hypertensive activity of novel sulphadimidine derivatives

Article abstract of DOI:10.1007/s00044-011-9935-3

A series of novel sulphadimidine derivatives has been synthesized via coupling of sulphadimidine diazonium salt with N-substituted anilines in acetic acid and subjected to evaluate their antihypertensive activity. All the synthesized compounds have similar effects and non-significantly different than the standard drug (Prazosin) and control groups. All newly synthesized dyes were characterized by elemental analyses and spectral data (IR, 1H-NMR, and MS). Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9935-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3902–3906
DOI 10.1007/s00044-011-9935-3
ORIGINAL RESEARCH
Synthesis and anti-hypertensive activity of novel sulphadimidine
derivatives
•
Moustafa A. Gouda Hatem E. Gafer
•
Mohamed Gouda
Received: 1 August 2011 / Accepted: 3 December 2011 / Published online: 13 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of novel sulphadimidine derivatives
has been synthesized via coupling of sulphadimidine dia-
zonium salt with N-substituted anilines in acetic acid and
subjected to evaluate their antihypertensive activity. All the
synthesized compounds have similar effects and non-sig-
nificantly different than the standard drug (Prazosin) and
control groups. All newly synthesized dyes were charac-
terized by elemental analyses and spectral data (IR,
1H-NMR, and MS).
methylphenobarbital (iv) (Eadie and Hooper, 2002) still is
in use as antisepticum.
Some diaminopyrimidines, such as pyrimethamine
(v) (McIntosh, 2001) or trimethoprim (vi) (Joffe et al.,
1989) are powerful antimalaria drugs. Used in combination
with sulphonamides, vi is also a potent antibacteriostati-
cum, whereas minoxidil (vii) (Cash, 1999) is used as anti-
hypertensive. Sulphadiazine (viii) (Petersen and Schmidt,
2003) is one of the chemotherapeutics containing a
pyrimidine moiety.
Keywords Pyrimidine ꢀ Sulphadimidine dyes ꢀ
In view of the above-mentioned findings and as con-
tinuation of our effort (Abu-Hashem et al., 2010), to
identify new candidates that may be of value in designing
new, potent, selective, and less toxic pyrimido[20,10:2,3]-
thiazolo[4,5-b]quinoxaline derivatives as anti-inflamma-
tory and analgesic agents, we report herein the syntheses of
some new pyrimidines starting from sulphadimidine 1.
Anti-hypertensive activity
Introduction
Over the years, the pyrimidine system turned out to be an
important pharmacophore, interacting with the synthesis
and function of nucleic acids [e.g., the cytostaticum fluo-
rouracil (i) (Goette, 1981) or the HIV drug zidovudine (ii)
(Darbyshire et al., 2004)]. Ultrashort-acting barbiturates
such as thiopental sodium (iii) (Dordoni et al., 2004)
(Pentothal) are often used as general anesthetics, whereas,
Results and discussion
The synthetic procedure adopted to obtain the target com-
pounds is depicted in Scheme 1. A solution of sulfadimidine
(1) in conc. HCl/H2O was diazotized with a solution of
NaNO2/H2O, and then coupled to substituted anilines 3 in
acetic acid to afford sulphadimidine dyes 4a–4d.
M. A. Gouda (&)
Chemistry Department, Faculty of Science,
Mansoura University, Mansoura 35516, Egypt
e-mail: dr_mostafa_chem@yahoo.com
The structures 4a–4d were established on the basis of
elemental analyses and spectral data. The UV–Visible
spectra displayed the maximum absorption (kmax) within
516–474 nm region. The IR spectra showed characteristic
absorption bands within the m = 3,270–3,220 cm-1 corre-
sponding to stretching vibration of NH. The bands within
m = 1,519–1,492 cm-1 were due to the symmetric vibra-
tions of the azo group. Absorption bands within the
m = 1,166–1,155 and 1,083–1,079 cm-1 were attributed to
H. E. Gafer ꢀ M. Gouda
Textile Research Division, National Research Center,
Dokki, Cairo, Egypt
Present Address:
M. A. Gouda
Department of Chemistry, Faculty of Science and Arts, Ulla,
Taibah University, Medina, Kingdom of Saudi Arabia
123

Med Chem Res (2012) 21:3902–3906
3903
Scheme 1 Synthesis of
sulphadimidine derivatives
4a–4d
R2
R1
N
N
Cl
N2
NH2
N
R2
N
R1
NaNO2
HCl
3
O S O
NH
O S O
NH
O S O
NH
N
N
N
N
N
N
H3C
CH3
H3C
CH3
H3C
CH3
1
2
4a, R1= R2= Et
4b, R1= R2= Me
4c, R1= H, R2= Et
4d, R1= CH2Ph, R2= Et
SO2 of the coupling component. The 1H-NMR spectrum of
4a displayed signals at d 1.12 (br., t, 6H, 2CH3), 3.36 (br.,
q, 4H, 2CH2), 6.75 (s, 1H, C5–H, pyrimidine), and
12.0 ppm (br., s, 1H, NH–SO2). Also, 4b showed signals at
d 3.10 (br., s, 6H, N–(CH3)2), 6.78 (s, 1H, C5–H, pyrimi-
dine), and 12.10 ppm (br., s, 1H, NH–SO2). Furthermore,
4c revealed signals at d 1.21 (br., t, 3H, CH3), 3.34 (br., q,
2H, CH2), 4.36 (br., s, 1H, NH), 6.76 (s, 1H, C5–H,
pyrimidine), and 11.8 ppm (br., s, 1H, NH–SO2). Finally,
4d displayed signals at d 1.14 (br., t, 3H, CH3), 3.34 (br., q,
2H, CH2), 4.30 (s, 2H, CH2–Ph), 6.77 (s, 1H, C5–H,
pyrimidine), and 11.90 ppm (br., s, 1H, NH–SO2).
level, when the pulse rate is within the normal range.
‘‘STRAT’’ switch is put on and the recorder records the
blood pressure as systolic blood pressure (SBP) and dia-
stolic blood pressure (DBP), which is displayed on moni-
tor. The pressure can be easily read from the pre-calibrated
monitor. Once all the values are displayed the recorder is
switched off and for next measurement. All results were
expressed throughout as mean SEM. For comparison of
responses with control group, means were analyzed by one-
way analysis of variance (ANOVA). Statistical significance
was determined at P \ 0.05. The results depicted in
Table 1 revealed that the hypertensive rats showed signif-
icant reduction in BP level when treated with sulphadimi-
dine derivatives. By comparing the results obtained from
the anti-hypertensive activity of the investigated com-
pounds to their structures, the following structure–activity
relationships (SAR’s) were postulated: (i) Compounds 4a–
4d have similar activity as antihypertensive effect, and
non-significantly different from standard drug (Prazosin)
which may be attributed to the presence of pyrimidine ring
system (Fig. 1) and amino group. (ii) Compound 4c is more
potent than 4a, 4b, and 4d which may be attributed to the
presence of (NH) group (Fig. 2).
Anti-hypertension activity
Albino rats weighing 150–200 g were used for screening
all the synthesized sulphadimidine derivatives for antihy-
pertensive activity. A suspension of tested compound was
prepared using dimethylsulfoxide (DMSO) 0.1 ml and
administered at a dose level of ‘‘0.3 mg/kg’’ animal body
weight to different six rats in each group. Animals were
divided into seven groups (six rats each); the first group
was a control (0.1 ml DMSO, i.p.). The second group,
hypertensive animals (positive control) (0.1 ml DMSO,
i.p.), the third group was given Prazosin (standard drug:
0.3 mg/kg in 0.1 ml DMSO, i.p.). The fourth group was
given the same dose of Prazosin from the tested com-
pounds. After administration of dose to animal, blood
pressure was measured by non-invasive tail cuff method
(Fatehi-Hassanabad et al., 2004) using pressure meter
(Riva Rocci Sphygmomanometer, 58500 UGO BASILE,
Italy). Measurement was done after 1 h. One hour after
administration of drug sample, animal was shifted to the
restrainers, which restricts the movement of animal. The
tail was cleaned with moist cotton to remove the dirty,
matter and talcum powder was sprayed on tail to make its
surface smooth. A tail cuff and pulse transducer was fixed
around the tail. Initially, animal shows particular pulse
Table 1 Mean systolic blood pressure of hypertensive rats treated
with tested compounds
Control SHR
Prazosin 4a/SBP 4b/SBP 4c/SBP 4d/SBP
1
104
102
106
108
107
105
141
142
139
138
136
135
106
107
103
105
103
104
102
108
106
110
104
103
104
106
108
101
110
102
100
104
105
100
102
106
101
104
106
105
107
104
2
3
4
5
6
X
SE
105.33 138.5 104.67 105.5
0.88 1.12 0.67 1.26
105.17 102.83 104.5
1.42 1.38 1.4
123

3904
Med Chem Res (2012) 21:3902–3906
Fig. 1 Structure of some
biologically active compounds
incorporated pyrimidine ring
system
O
N
CH3
O
O
O
HN
C2H5
F
H3C
HN
HN
N
O
C6H5
O
N
H
i
S
N
H
O
O
N
H
iv
O
O
HO
iii
N3
ii
OCH3
OCH3
H3CO
Cl
NH2
N
N
O O
S
NH2
N
N
N
N
H
C2H5
N
NH2
NH2
H2N
N
vii
NH2
viii
v
H2N
N
NH2
vi
Fig. 2 Structure–activity
relationships (SAR’s) of the
investigated compounds
N
N
R2
N
NH2
N
R1
O
O
N
O S O
NH
N
N
N
N
O
O
CH3
H3C
Prazosin
4a, R1= R2= Et; 4b, R1= R2= Me
4c, R1= H, R2= Et; 4d, R1= CH2Ph, R2= Et
1
All results were expressed throughout as mean SEM.
For comparison of responses with control group, means
were analyzed by one-way analysis of variance (ANOVA).
Statistical significance was determined at P \ 0.05. The
results depicted in Table 1 revealed that the hypertensive
rats showed significant reduction in BP level when treated
with sulphadimidine dyes 4a–4d. Compounds 4a–4d have
similar activity as antihypertensive effect, and non-signif-
icantly different from standard drug (Prazosin) and control
groups.
Mansoura University). The H-NMR spectra were deter-
mined on a Varian XL 200 MHz (Faculty of Science, Cairo
University) in DMSO solvent using tetramethylsilane
(TMS) as internal standard. Mass spectra were recorded on
GCMS-QP 1000 EX Shimadzu Japan (Gas Chromatogra-
phy-Mass spectrometer). Elemental analyses (C, H, and N)
were carried out at the Faculty of Science, Cairo Univer-
sity; the results were found to be in good agreement
( 0.12%) with the calculated values.
General procedure for the synthesis of sulphadimidine
dyes 4a–4d
Experimental
A well-stirred solution of sulphadimidine 1 (2.78 g,
0.01 mol) in 3 ml conc. HCl and 4 ml H2O was cooled in
ice-bath and diazotized with the solution of 0.7 g NaNO2
(0.01 mol) in 2 ml H2O. The cold diazonium solution was
added slowly to a well-stirred solution of N-substituted
anilines 3a (1.49 g, 0.01 mol), 3b (1.21 g, 0.01 mol), 3c
(1.21 g, 0.01 mol), or 3d (2.11 g, 0.01 mol) in 20 ml acetic
acid at (0–5°C). The reaction mixture was stirred for
All melting points are in degree centigrade and are
uncorrected. Thin layer chromatography (TLC) analysis
was carried out on silica gel 60 F254-precoated aluminum
sheets. The UV–Visible spectra were recorded with a
Perkin-Elmer Lambda 551 S spectrometer, using dichlo-
romethane as the solvent. The Infrared spectra were
recorded on Mattson 5000 spectrometer (t, cm-1) using
potassium bromide wafer technique (Faculty of Science
123

Med Chem Res (2012) 21:3902–3906
3905
another 2 h. The crude product was filtered off, dried well,
(br., t, 3H, CH3), 2.30 (br., s, 6H, C4–CH3, C6–CH3,
pyrimidine), 3.34 (br., q, 2H, CH2), 4.30 (s, 2H, CH2–Ph),
6.77 (s, 1H, C5–H, pyrimidine), 6.87–8.11 (m, 13H, Ar–H),
11.90 (br., s, 1H, NH–SO2). MS (m/z, %): 500 (0.6), 291
(8.5), 264 (15.7), 263 (60.6), 259 (23.0), 200 (34.5), 196
(54.5), 150 (23.6), 98 (32.7), 72 (50.3), 57 (100.0). Anal.
Calcd for C27H28N6O2S (500.62): C, 64.78; H, 5.64; N,
16.79. Found: C, 64.83; H, 5.71; N, 16.82.
and recrystallized from ethanol–benzene to give 4a–4d.
4-((4-(Diethylamino)phenyl)diazenyl)-N-(4,6-
dimethylpyrimidin-2-yl)benzene-sulfonamide (4a)
Orange red powder, Yield, 82%, mp: 181°C, UV–Visible,
DMF; (kmax): 504 nm; IR (KBr): mmax, cm-1: 3234 (NH),
1515 (N=N), 1162, 1079 (SO2), 1515 (Ar); 1H NMR
(DMSO-d6): d 1.12 (br., t, 6H, 2CH3), 2.26 (br., s, 6H, C4–
CH3, C6–CH3, pyrimidine), 3.36 (br., q, 4H, 2CH2), 6.75 (s,
1H, C5–H, pyrimidine), 6.86–8.10 (m, 8H, Ar–H), 12.0
(br., s, 1H, NH–SO2). MS (m/z, %): 438 (0.3), 240 (2.4),
200 (11.5), 167 (14.5), 150 (35.8), 126 (24.2), 110 (230),
94 (41.2), 85 (59.4), 70 (71.0), 55 (100.0). Anal. Calcd for
C22H26N6O2S (438.55): C, 60.25; H, 5.98; N, 19.16.
Found: C, 60.34; H, 6.06; N, 19.22.
Anti-hypertensive activity
Male Sprague-Dawley rats (purchased from animal house,
National Research Centre, Dokki, Cairo, Egypt) weighing
between 180 and 200 g were used. Animals were housed in
temperature and humidity-controlled, light-cycled quarters
and randomly divided into two groups. One group received
saline injection (0.5 ml/kg, twice weekly, for 5 weeks,
S.C., n = 25) whereas the other group were injected with
deoxycorticosterone acetate (DOCA)-salt (20 mg/kg, twice
weekly, for 5 weeks, S.C., n = 25) and NaCl (1%) was
added to their drinking water. Using this protocol for
producing spontaneously hypertensive rats (SHR), hyper-
tension was induced in the second group of rats. This
model of hypertension (DOCA-salt-induced hypertension)
has been used by several investigators (Fareh et al., 2000;
Somers et al., 2000; Bunag, 1973).
4-((4-(Dimethylamino)phenyl)diazenyl)-N-(4,6-
dimethylpyrimidin-2-yl)benzene-sulfonamide (4b)
Scarlet red powder, Yield, 76%, mp: 198°C, UV–Visible,
DMF; (kmax): 516 nm; IR (KBr): mmax, cm-1: 3228 (NH),
1
1500 (N=N), 1162, 1081 (SO2); H NMR (DMSO-d6): d
2.28 (br., s, 6H, C4–CH3, C6–CH3, pyrimidine), 3.10 (br., s,
6H, N–(CH3)2), 6.78 (s, 1H, C5–H, pyrimidine), 6.80–8.12
(m, 8H, Ar–H) and 12.10 (br., s, 1H, NH–SO2). MS (m/z,
%): 410 (M?, 0.6), 257 (6.0), 200 (7.2), 167 (6.7), 150
(6.8), 126 (13.3), 110 (14.0), 86 (21.8), 81 (33.3), 70
(100.0). Anal. Calcd for C20H22N6O2S (410.49): C, 58.52;
H, 5.40; N, 20.47. Found: C, 58.59; H, 5.46; N, 20.53.
References
Abu-Hashem AA, Gouda MA, Badria FA (2010) Synthesis of some
new pyrimido[20,10:2, 3]thiazolo[4,5-b]quinoxaline derivatives
as anti-inflammatory and analgesic agents. Eur J Med Chem
45:1976–1981
N-(4,6-Dimethylpyrimidin-2-yl)-4-((4-
(ethylamino)phenyl)diazenyl)benzene-sulfonamide (4c)
Bunag RD (1973) Validation in the awake rats of a tailcuff method for
measuring systolic pressure. J Appl Physiol 34:279–282
Cash TF (1999) The psychosocial consequences of androgenetic
alopecia: a review of the research literature. Br J Dermatol
141(3):398–405
Darbyshire J, Foulkes M, Peto R, Duncan W, Babiker A, Collins R,
Hughes M, Peto T, Walker A (2004) The Cochrane library, Issue
2. Wiley, Chichester
Dordoni PL, Frassanito L, Bruno MF, Proietti R, de Cristofaro R,
Ciabattoni G, Ardito G, Crocchiolo R, Landolfi R, Rocca B
(2004) In vivo and in vitro effects of different anaesthetics on
platelet function. Br J Haematol 125(1):79–82
Eadie MJ, Hooper WD (2002) Other barbiturates methyl-phenobar-
bital. In: Levy EH, Mattson R, Meldrum BS, Perucca E (eds)
Antiepileptic drugs, Chap. 55. Lippincott-Williams and Wilkins,
Philadelphia, PA
Orange powder, Yield, 72%, mp: 166°C, UV–Visible,
DMF; (kmax): 474 nm; IR (KBr): mmax, cm-1: 3320, 3270
(NH), 1492 (N=N), 1155, 1083 (SO2); H NMR (DMSO-
1
d6): d 1.21 (br., t, 3H, CH3), 2.26 (br., s, 6H, C4–CH3, C6–
CH3, pyrimidine), 3.34 (br., q, 2H, CH2), 4.36 (br., s, 1H,
NH), 6.76 (s, 1H, C5–H, pyrimidine), 6.80–8.10 (m, 8H,
Ar–H), 11.8 (br., s, 1H, NH–SO2). MS (m/z, %): 410 (1.8),
292 (23.0), 263 (100.0), 261 (76.3), 197 (39.4), 108 (22.9),
76 (29.7). Anal. Calcd for C20H22N6O2S (410.49): C,
58.52; H, 5.40; N, 20.47. Found: C, 58.58; H, 5.46; N,
20.51.
4-((4-(Benzyl(ethyl)amino)phenyl)diazenyl)-N-(4,6-
dimethylpyrimidin-2-yl)benzenesulfon-amide (4d)
Fareh J, Touyz RM, Schiffrin EL, Thibault G (2000) Altered cardiac
endothelin receptors and protein kinase C in deoxycorticoster-
one-salt hypertensive rats. J Mol Cell Cardiol 32:665–676
Fatehi-Hassanabad Z, Fatehi M, Shahidi MI (2004) Endothelial
dysfunction in aortic rings and mesenteric beds isolated from
deoxycorticosterone acetate hypertensive rats: possible involve-
ment of protein kinase C. Eur J Pharmacol 494:199–204
Red powder, Yield, 76%, mp: 178°C, UV–Visible, DMF;
(kmax): 506 nm; IR (KBr): mmax, cm-1: 3276 (NH), 1516
1
(N=N), 1166, 1083 (SO2); H NMR (DMSO-d6): d 1.14
123

3906
Med Chem Res (2012) 21:3902–3906
Goette DK (1981) Topical chemotherapy with 5-fluorouracil. A
review. J Am Acad Dermatol 4:633–649
Petersen E, Schmidt DR (2003) Sulfadiazine and pyrimethamine in
the postnatal treatment of congenital toxoplasmosis: what are the
options? Expert Rev Anti Infect Ther 1:175–182
Somers MJ, Mavromatis K, Galis ZS, Harrison DG (2000) Vascular
superoxide production and vasomotor function in hypertension
induced by deoxycorticosterone acetate-salt. Circulation 101:
1722–1728
Joffe AM, Farley JD, Linden D, Goldsand G (1989) Trimethoprim-
sulfamethoxazole-associated aseptic meningitis: case reports and
review of the literature. Am J Med 87:332–338
McIntosh HM (2001) The Cochrane library, Issue 4. Update Software
Ltd.
123