Synthesis of a new series of angiotensin II receptor antagonists and antibacterial agents

Article abstract of DOI:10.1007/s12272-013-0159-6

2-(Arylmethylenehydrazono)-4,4-diphenyl-1H-imidazol-5(4H)-one 3 underwent regioselective cyclization upon treatment with bromine in acetic acid containing sodium acetate to give the respective 3-substituted-6,6-diphenyl-6,7-dihydro- imidazo[2,1-c][1,2,4]triazole-5-one 4 in overall good yields and not the isomeric structure 5. In addition, compound 4 was synthesized by alternative method via reaction of compound 1 with different acids in acetic acid. The synthesized hydrazone derivatives were screened for their angiotensin II receptor antagonists activity and the results showed promising activity. Also, imidazo[2,1-c][1,2,4]triazole-5-ones 4 were screened for the antibacterial activity and the result revealed that two derivatives have excellent activity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12272-013-0159-6

Arch. Pharm. Res.
DOI 10.1007/s12272-013-0159-6
RESEARCH ARTICLE
Synthesis of a new series of angiotensin II receptor antagonists
and antibacterial agents
•
Thoraya A. Farghaly Sobhi M. Gomha
•
Mohamed M. Abdalla
Received: 26 February 2013 / Accepted: 15 May 2013
Ó The Pharmaceutical Society of Korea 2013
Abstract 2-(Arylmethylenehydrazono)-4,4-diphenyl-1H-
imidazol-5(4H)-one 3 underwent regioselective cyclization
upon treatment with bromine in acetic acid containing
sodium acetate to give the respective 3-substituted-6,6-
diphenyl-6,7-dihydro-imidazo[2,1-c][1,2,4]triazole-5-one 4
in overall good yields and not the isomeric structure 5. In
addition, compound 4 was synthesized by alternative
method via reaction of compound 1 with different acids in
acetic acid. The synthesized hydrazone derivatives were
screened for their angiotensin II receptor antagonists
activity and the results showed promising activity. Also,
imidazo[2,1-c][1,2,4]triazole-5-ones 4 were screened for
the antibacterial activity and the result revealed that two
derivatives have excellent activity.
one of the most important classes of organic compounds.
They have cathepsin S inhibitors, analgesic, anticancer,
antitumor, anti-inflammatory, antibacterial, and antifungal
activities (Cywin et al. 2003; El-Gazzar et al. 2008; Gan-
guly et al. 2001; Kandile et al. 2009, Vicini et al. 2009;
Banachiewicz and Kaminska 2001). In addition, substituted
imidazo[2,1-c] [1,2,4]triazoles derivatives have become of
great importance due to their wide range of biological
activity (Pavlov et al. 1998; Harb et al. 1990; Sztanke et al.
2004; Singh 1990). Besides, they were used as antioxidant
(Sayed et al. 2010) and anti-cancer agents (Sztanke et al.
2008). In view of the above mentioned findings and in
continuation of our efforts (Farghaly and Abdalla 2009;
Farghaly et al. 2010, 2012; Abdel Hafez et al. 2010;
Riyadh et al. 2010) to synthesis a new heterocyclic com-
pounds that may have potent biological activities, we
decided in the present work to synthesize new 2-[(substi-
tutedmethylene)hydrazono]-4,4-diphenyl-1H-imidazol-5(4H)-
one used as angiotensin II receptor antagonists and imi-
dazo-[2,1-c][1,2,4]triazoles derivatives as antibacterial
agents.
Keywords Hydrazone Á Imidazo[2,1-c][1,2,4]triazole-5-
one Á Antibacterial activity Á Angiotensin activity
Introduction
Many drugs contain imidazole ring, such as angiotensin II
receptor antagonists (Guo et al. 2008; Roumelioti et al.
2002; Shafiee et al. 2000), antimalarial (Pfaller and
Krogstad 1983), antibacterial (Khabnadideh et al. 2003),
anticancer (Li et al. 2010) and anticytokine agents (Laufer
et al. 2002). On the other hand, hydrazones are known as
Materials and methods
Melting points were determined on a Gallenkamp appara-
tus and are uncorrected. IR spectra were recorded in a Pye-
1
Unicam SP300 instrument in potassium bromide discs. H
and 13C NMR spectra were recorded in a Varian Mercury
VXR-300 spectrometer (300 MHz for 1H NMR and
75 MHz for 13C NMR) in DMSO-d6 and the chemical
shifts were related to that of the solvent. Mass spectra were
recorded in a GCMS-QP 1000 EX Shimadzu Spectrometer,
the ionizing voltage was 70 eV. Elemental analyses were
carried out at the Microanalytical Laboratory of Cairo
T. A. Farghaly Á S. M. Gomha (&)
Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
e-mail: s.m.gomha@hotmail.com
M. M. Abdalla
Saco Pharm, 6th October City, Egypt
123

T. A. Farghaly et al.
University, Giza, Egypt. Antibacterial activities were car-
ried out at the Regional Center for Mycology and Bio-
technology at Al-Azhar University, Cairo, Egypt.
Anal. Calcd. for C22H17ClN4O (388.86) C, 67.95; H, 4.41;
N, 14.41. Found: C, 67.69; H, 4.26; N, 14.35 %.
2-[(2-Chlorophenylmethylene)hydrazono]-4,4-diphenyl-
1H-imidazol-5(4H)-one (3d)
Preparation of hydrazones 3a–n
A mixture of hydrazine 1 (2.5 mmol) and the appropriate
aldehyde 2 (2.5 mmol) in acetic acid (20 mL) and few
drops of conc. hydrochloric acid (&1 mL) was heated
under reflux for 3 h. The reaction mixture was then cooled
and diluted with water. The so-formed solid product was
then collected by filtration, dried and recrystallized from
the proper solvent to afford the corresponding hydrazones
3a–n.
White solid (76 %) mp. 204–206 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.59 (br s, 1H, NH), 7.19–7.78 (m,
14H, ArH), 8.15 (s, 1H, =CH), 9.20 (s, 1H, NH). IR m
cm-1: 3,444, 3,163 (2NH), 1,755 cm-1. Ms m/z (%) 390
(M??2, 10), 389 (M??1, 11), 388 (M?, 34), 247 (57), 182
(36), 180 (34), 165 (55), 138 (26), 115 (26), 111 (21), 104
(60), 89 (68), 78 (45), 77 (100). Anal. Calcd. for
C22H17ClN4O (388.86) C, 67.95; H, 4.41; N, 14.41. Found:
C, 67.69; H, 4.26; N, 14.35 %.
4,4-Diphenyl-2-[(phenylmethylene)hydrazono]-1H-
imidazol-5(4H)-one (3a) (Kottke and Kuhmstedt 1978)
2-[(4-Bromophenylmethylene)hydrazono]-4,4-diphenyl-
1H-imidazol-5(4H)-one (3e)
¨
White solid (81 %) mp. 240–242 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.89 (br s, 1H, NH), 7.29–7.87 (m,
15H, ArH), 8.20 (s, 1H, =CH), 9.33 (s, 1H, NH). IR m
cm-1: 3,341, 3,150 (2NH), 1,735 (CO) cm-1. Ms m/z (%)
355 (M??1, 9), 354 (M?, 34), 249 (24), 248 (100), 182
(25), 165 (28), 106 (53), 104 (71), 90 (37), 77 (78). Anal.
Calcd. for C22H18N4O (354.41) C, 74.56; H, 5.12; N,
15.81. Found: C, 74.29; H, 5.08; N, 15.74 %.
White solid (83 %) mp. 238–240 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.81 (br s, 1H, NH), 7.05 (d, J = 8 Hz,
2H, Ar–H), 7.14–7.52 (m, 10H, Ar–H), 8.01 (d, J = 8 Hz,
2H, Ar–H), 8.23 (s, 1H, = CH), 9.781 (s, 1H, NH). IR m
cm-1: 3,405, 3,215 (2NH), 1,742 (CO) cm-1. Ms m/z (%)
435 (M??2, 5), 434 (M??1, 14), 433 (M?, 10), 432 (15),
248 (100), 182 (18), 165 (25), 104 (45), 77 (38). Anal.
Calcd. for C22H17BrN4O (433.31) C, 60.98; H, 3.95; N,
12.93. Found: C, 60.78; H, 3.86; N, 12.91 %.
4,4-Diphenyl-2-[(4-methylphenylmethylene)hydrazono]-
1H-imidazol-5(4H)-one (3b)
4,4-Diphenyl-2-[(2-hydroxyphenylmethylene)hydrazono]-
1H-imidazol-5(4H)-one (3f) (Kottke and Kuhmstedt 1978)
White solid (85 %) mp. 244–246 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 2.33 (s, 3H, CH3), 3.57 (br s, 1H, NH),
7.22 (d, J = 8 Hz, 2H, Ar–H), 7.31-7.41 (m, 10H, Ar–H),
7.76 (d, J = 8 Hz, 2H, Ar–H), 8.17 (s, 1H, = CH), 9.51 (s,
1H, NH). IR m cm-1: 3,225, 3,210 (2NH), 1,745 (CO)
cm-1. Ms m/z (%) 369 (M??1, 24), 368 (M?, 72), 367
(23), 248 (69), 180 (31), 165 (31), 120 (63), 118 (48), 104
(100), 91 (38), 88 (33), 77 (83). Anal. Calcd. for
C23H20N4O (368.44) C, 74.98; H, 5.47; N, 15.21. Found:
C, 74.85; H, 5.38; N, 15.14 %.
¨
1
White solid (78 %) mp. 216–218 °C (Dioxane) H NMR
(DMSO-d6) d ppm: 3.65 (br s, 1H, NH), 6.99–7.95 (m,
14H, ArH), 8.23 (s, 1H, =CH), 9.39 (s, 1H, NH), 13.50 (s,
1H, OH). IR m cm-1: br 3,200, 3,166 (2NH and OH), 1,755
(CO) cm-1. Ms m/z (%) 371 (M??1, 47), 370 (M?, 38),
248 (47), 182 (38), 165 (88), 122 (59), 115 (41), 105 (44),
103 (31), 77 (91). Anal. Calcd. for C22H18N4O2 (370.41) C,
71.34; H, 4.90; N, 15.13. Found: C, 71.25; H, 5.01; N,
15.10 %.
2-[(4-Chlorophenylmethylene)hydrazono]-4,4-diphenyl-
1H-imidazol-5(4H)-one (3c) (Kottke and Kuhmstedt 1978)
4,4-Diphenyl-2-[(3-hydroxyphenylmethylene)hydrazono]-
1H-imidazol-5(4H)-one (3g)
¨
1
White solid (79 %) mp. 280–282 °C (Dioxane) H NMR
(DMSO-d6) d ppm: 3.80 (br s, 1H, NH), 7.21 (d, J = 8 Hz,
2H, Ar–H), 7.29–7.58 (m, 10H, Ar–H), 7.85 (d, J = 8 Hz,
2H, Ar–H), 8.20 (s, 1H, =CH), 9.61 (s, 1H, NH). IR m
cm-1: 3,250, 3,163 (2NH), 1,747 (CO) cm-1. Ms m/z (%)
390 (M??2, 6), 389 (M??1, 2), 388 (M?, 17), 387 (32),
248 (100), 247 (57), 207 (28), 182 (42), 180 (51), 165 (49),
139 (47), 138 (26), 111 (32), 90 (21), 77 (64), 76 (89).
White solid (74 %) mp. 208–210 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.78 (br s, 1H, NH), 7.08–7.77 (m,
14H, ArH), 8.05 (s, 1H, =CH), 9.48 (s, 1H, NH), 14.26 (s,
1H, OH). IR m cm-1: br 3,225, 3,154 (2NH and OH), 1,759
(CO) cm-1. Ms m/z (%) 371 (M??1, 12), 370 (M?, 35),
248 (17), 181 (42), 180 (56), 165 (68), 142 (24), 141 (68),
138 (90), 77 (95). Anal. Calcd. for C22H18N4O2 (370.41) C,
123

Synthesis of a new series of angiotensin
71.34; H, 4.90; N, 15.13. Found: C, 71.18; H, 5.15; N,
15.32 %.
C24H20N4O (380.44) C, 75.77; H, 5.30; N, 14.73. Found:
C, 75.54; H, 5.20; N, 14.89 %.
2-[(3,4-Dimethoxyphenylmethylene)hydrazono]-4,4-
diphenyl-1H-imidazol-5(4H)-one (3h)
4,4-Diphenyl-2-[methylenehydrazono]-1H-imidazol-
5(4H)-one (3l)
1
White solid (81 %) mp. 260–262 °C (Dioxane) H NMR
White solid (80 %) mp. 168–170 °C (EtOH). 1H NMR
(DMSO-d6) d ppm: 3.34 (br s, 1H, NH), 7.15–7.58 (m,
12H, Ar-H and =CH2), 9.32 (s, 1H, NH). IR m cm-1: 3,231,
3,187 (2NH), 1,728 (CO) cm-1. Ms m/z (%) 278 (M?, 23),
252 (29), 180 (100), 165 (47), 77 (78). Anal. Calcd. for
C16H14N4O (278.31) C, 69.05; H, 5.07; N, 20.13. Found:
C, 69.18; H, 5.0; N, 20.01 %.
(DMSO-d6) d ppm: 3.58, 3.61 (s, 6H, 2OCH3), 4.05 (br s,
1H, NH), 6.94–7.58 (m, 13H, ArH), 8.12 (s, 1H, =CH),
10.0 (s, 1H, NH). IR m cm-1: br 3,209 (2NH), 1,759 (CO)
cm-1. Ms m/z (%) 414 (M?, 55), 413 (23), 249 (32), 248
(62), 180 (40), 167 (68), 166 (75), 165 (94), 104 (43), 77
(100), 76 (49). Anal. Calcd. for C24H22N4O3 (414.47) C,
69.55; H, 5.35; N, 13.52. Found: C, 69.34; H, 5.31; N,
13.46 %.
2-[Ethylenehydrazono]-4,4-diphenyl-1H-imidazol-5(4H)-
one (3m)
4,4-Diphenyl-2-[(3,4,5-trimethoxyphenylmethylene)
hydrazono]-1H-imidazol-5(4H)-one (3i)
1
White solid (80 %) mp. 112–114 °C (EtOH/Dioxane) H
NMR (DMSO-d6) d ppm: 1.87 (d, 3H, CH3), 3.38 (br s, 1H,
NH), 7.11–7.50 (m, 11H, Ar–H and =CH), 9.20 (s, 1H,
White solid (75 %) mp. 236–238 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.58, 3.61 (s, 9H, 3OCH3), 3.95 (br s,
1H, NH), 7.11–7.80 (m, 12H, ArH), 8.11 (s, 1H, =CH),
9.58 (s, 1H, NH). IR m cm-1: 3,210, 3,170 (2NH), 1,755
(CO) cm-1. Ms m/z (%) 445 (M??1, 26), 444 (M?, 63),
443 (39), 267 (23), 248 (79), 238 (31), 196 (74), 180 (100),
167 (42), 165 (99), 104 (97), 90 (31), 77 (88), 76 (77).
Anal. Calcd. for C25H24N4O4 (444.48) C, 67.55; H, 5.44;
N, 12.60. Found: C, 67.47; H, 5.31; N, 12.50 %.
NH). IR m cm-1: 3,225, 3,160 (2NH), 1,725 (CO) cm-1
.
Ms m/z (%) 292 (M?, 10), 248 (37), 223 (20), 180 (80), 179
(51), 165 (41), 104 (100), 77 (92). Anal. Calcd. for
C17H16N4O (292.31) C, 69.85; H, 5.52; N, 19.17. Found:
C, 69.74; H, 5.32; N, 19.09 %.
4,4-Diphenyl-2-[(2-thionylmethylene)hydrazono]-1H-
imidazol-5(4H)-one (3n)
1
4,4-Diphenyl-2-[(3-methoxy-4-hydroxyphenylmethylene)
hydrazono]-1H-imidazol-5(4H)-one (3j)
White solid (83 %) mp. 240–242 °C (EtOH/Dioxane) H
NMR (DMSO-d6) d ppm: 3.33 (br s, 1H, NH), 7.12–7.44
(m, 13H, Ar–H), 8.39 (s, 1H, =CH), 9.30 (s, 1H, NH). IR m
cm-1: 3,429, 3,228 (2NH), 1,700 (CO) cm-1. Ms m/z (%)
361 (M??1, 15), 360 (M?, 39), 248 (100), 180 (26), 165
(49), 112 (49), 111 (43), 104 (75), 96 (78), 77 (64). Anal.
Calcd. for C20H16N4OS (360.43) C, 66.65; H, 4.47; N,
15.54. Found: C, 66.42; H, 4.20; N, 15.22 %.
1
White solid (82 %) mp. 250–252 °C (EtOH/Dioxane) H
NMR (DMSO-d6) d ppm: 1.78 (s, 1H, OH), 3.58 (br s, 1H,
NH), 3.83 (s, 3H, OCH3), 6.80–7.43 (m, 13H, Ar–H), 8.08
(s, 1H, =CH), 9.40 (s, 1H, NH). IR m cm-1: br 3,250, 3,167
(2NH and OH), 1,747 (CO) cm-1. Ms m/z (%) 400 (M?,
48), 399 (41), 248 (100), 247 (49), 206 (24), 180 (43), 165
(54), 163 (14), 104 (73), 77 (99). Anal. Calcd. for
C23H20N4O3 (400.44) C, 68.99; H, 5.03; N, 13.99. Found:
C, 68.78; H, 5.15; N, 13.86 %.
Synthesis of 3-substituted-6,6-diphenyl-6,7-dihydro-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4b, c, f, h–j, l, m)
Method A Bromine (0.052 g, 1 mmol) in acetic acid
(5 mL) was added dropwise to a stirred solution of the
appropriate hydrazone 3a–m (1 mmol of each) in acetic
acid (10 mL) and sodium acetate (0.5 g). The reaction
mixture was then poured onto ice cold water, and the solid
that precipitated was filtered off, washed with sodium
bicarbonate solution and then with water, dried and crys-
tallized from EtOH\DMF to give the respective compounds
4b, c, f, h–j, l, m but the other derivatives 4a, d, e, g,
k can’t cyclized.
4,4-Diphenyl-2-[styrylmethylenehydrazono]-1H-imidazol-
5(4H)-one (3k)
White solid (74 %) mp. 284–286 °C (EtOH) 1H NMR
(DMSO-d6) d ppm: 3.61 (br s, 1H, NH), 5.62 (d,
J = 12 Hz, 1H, = CH), 6.98–7.33 (m, 15H, Ar–H), 7.50
(d, J = 12 Hz, 1H, =CH), 8.27 (s, 1H, =CH), 9.87 (s, 1H,
NH). IR m cm-1: 3,440, 3,067 (2NH), 1,755 (CO) cm-1
.
Ms m/z (%) 381 (M??1, 21), 380 (M?, 16), 268 (42), 248
(81), 207 (49), 196 (51), 179 (51), 164 (56), 132 (56), 119
(51), 104 (88), 103 (49), 89 (23), 77 (86). Anal. Calcd. for
Method B General procedure: A mixture of compound 1
(0.266 g, 10 mmol) and the appropriate acid (10 mmol of
123

T. A. Farghaly et al.
6,6-Diphenyl-6,7-dihydro-3-(3,4,5-trimethoxyphenyl)-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4i)
each) in glacial acetic acid (20 mL) was refluxed for 6 h.
After cooling, the precipitate was collected by filtration and
crystallized from EtOH\DMF to afford products which
were found to be identical in all respects (mp. mixed mp.
and IR) with products 4.
1
White solid (67 %) mp. 266 °C. H NMR (DMSO-d6) d
ppm: 3.78, 3.86, 3.92 (3 s, 9H, 3OCH3), 7.17 (s, 1H, Ar–
H), 7.24 (s, 1H, Ar–H), 7.28–7.73 (m, 10H, Ar–H), 9.28 (s,
1H, NH). IR m cm-1: 3,406 (NH), 1,710 (CO) cm-1. Ms m/
z (%) 443 (M??1, 100), 442 (M?, 37), 250 (26), 230 (33),
181 (41), 165 (78), 104 (78), 77 (52). Anal. Calcd. for
C25H22N4O4 (442.48) C, 67.86; H, 5.01; N, 12.66. Found:
C, 67.68; H, 4.95; N, 12.42 %.
6,6-Diphenyl-6,7-dihydro-3-(4-methylphenyl)-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4b)
1
Yellow solid (60 %) mp. 214 °C. H NMR (DMSO-d6) d
ppm: 2.49 (s, 3H, CH3), 7.31–8.05 (m, 14H, Ar–H), 9.18 (s,
1H, NH). IR m cm-1: 3,166 (NH), 1,751 (CO) cm-1. Ms m/
z (%) 367 (M??1, 21), 366 (M?, 100), 104 (70), 92 (70),
77 (38). Anal. Calcd. for C23H18N4O (366.43) C, 75.39; H,
4.95; N, 15.29. Found: C, 75.12; H, 4.70; N, 15.05 %.
6,6-Diphenyl-6,7-dihydro-3-(3-methoxy-4-hydroxyphenyl)-
pyrazolo[2,1-c][1,2,4] triazole-5-one (4j)
White solid (65 %) mp. 270–272 °C. 1H NMR (DMSO-d6)
d ppm: 1.73(s, 1H, OH), 3.87 (s, 3H, OCH3), 7.20–7.62 (m,
13H, Ar–H), 9.34 (s, 1H, NH). IR m cm-1: 3,282–3,154
(NH andOH), 1,720 (CO) cm-1. Ms m/z (%) 398 (M?, 16),
397 (29), 290 (18), 91 (41), 90 (100), 77 (77). Anal. Calcd.
for C23H18N4O3 (398.41) C, 69.34; H, 4.55; N, 14.06.
Found: C, 69.20; H, 4.35; N, 14.28 %.
3-(4-Chlorophenyl)-6,6-diphenyl-6,7-dihydro-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4c)
1
White solid (63 %) mp. 260 °C. H NMR (DMSO-d6) d
ppm: 7.21–7.58 (m, 14H, Ar–H), 9.25 (s, 1H, NH). 13C
NMR (DMSO-d6) d ppm: 81.02, 122.32, 126.12, 129.01,
130.04, 135.24, 136.11, 142.05, 149.36, 150.24, 157.19,
170.02. IR m cm-1: 3,409 (NH), 1,700 (CO) cm-1. Ms m/
z (%) 389 (M??2, 13), 388 (M??1, 24), 387 (M?, 25),
248 (100), 180 (27), 165 (58), 111 (9), 104 (74), 89 (70), 77
(42). Anal. Calcd. for C22H15ClN4O (386.84) C, 68.31; H,
3.91; N, 14.48. Found: C, 68.10; H, 4.05; N, 14.34 %.
6,6-Diphenyl-6,7-dihydro-pyrazolo[2,1-c][1,2,4] triazole-
5-one (4l)
1
Yellow solid (61 %) mp. 262–264 °C. H NMR (DMSO-
d6) d ppm: 7.13–7.43 (m, 10H, Ar–H), 8.68 (s, 1H, triazole-
CH) 9.52 (s, 1H, NH). IR m cm-1 3,265 (NH), 1,714 (CO)
cm-1. Ms m/z (%) 276 (M?, 7), 252 (32), 223 (40), 180
(100), 165 (34), 104 (88), 77 (99). Anal. Calcd. for
C16H12N4O (276.30) C, 69.55; H, 4.38; N, 20.28. Found:
C, 69.43; H, 4.18; N, 20.07 %.
6,6-Diphenyl-6,7-dihydro-3-(2-hydroxyphenyl)-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4f)
1
6,6-Diphenyl-6,7-dihydro-3-methyl-pyrazolo[2,1-c][1,2,4]
triazole-5-one (4m)
Yellow solid (66 %) mp. 170–172 °C. H NMR (DMSO-
d6) d ppm: 6.94–7.87 (m, 14H, Ar–H), 9.20 (s, 1H, NH),
13.42 (s, 1H, OH). IR m cm-1: br 3,220, 3,160 (NH and
OH), 1,720 (CO) cm-1. Ms m/z (%) 368 (M?, 28), 248
(58), 180 (27), 165 (69), 104 (100), 77 (85). Anal. Calcd.
for C22H16N4O2 (368.39) C, 71.73; H, 4.38; N, 15.21.
Found: C, 71.56; H, 4.15; N, 15.08 %.
1
Yellow solid (68 %) mp. 290–292 °C. H NMR (DMSO-
d6) d ppm: 2.05 (s, 3H, CH3), 7.27–7.62 (m, 10H, Ar–H),
8.27 (s, 1H, NH). IR m cm-1: 3,231 (NH), 1,718 (CO)
cm-1. Ms m/z (%) 290 (M?, 48), 287 (27), 286 (41), 180
(59), 165 (41), 142 (72), 103 (100), 89 (46), 77 (64). Anal.
Calcd. for C17H14N4O (290.33) C, 70.33; H, 4.86; N,
19.30. Found: C, 70.19; H, 4.72; N, 19.18 %.
6,6-Diphenyl-6,7-dihydro-3-(3,4-dimethoxyphenyl)-
pyrazolo[2,1-c][1,2,4]triazole-5-one (4h)
Determination of the angiotensin II receptor antagonists
in vivo
1
White solid (69 %) mp. 240 °C. H NMR (DMSO-d6) d
ppm: 3.50, 3.58 (s, 6H, 2OCH3), 6.98–7.78 (m, 13H, ArH),
9.54 (s, 1H, NH). IR m cm-1: 3,421 (NH), 1,728 (CO)
cm-1. Ms m/z (%) 412 (M?, 47), 248 (30), 180 (22), 179
(100), 165 (73), 149 (32), 104 (58), 77 (78). Anal. Calcd.
for C24H20N4O3 (412.44) C, 69.89; H, 4.89; N, 13.58.
Found: C, 69.77; H, 4.71; N, 13.30 %.
Male Sprague-Dawley rats are anesthetized with 100 mg/
kg i.p. InactinÒ and placed on servo-controlled heating
pads to maintain body temperature between 37 and 38 °C.
PE50 catheters are implanted in the femoral artery and vein
to measure arterial blood pressure and administer
123

Synthesis of a new series of angiotensin
compounds, respectively. A catheter is placed in the tra-
chea to ensure airway patency.
azomethine and 2NH protons at d = 8.39–8.08, 9.61–9.20
and 3.89–3.38 ppm, respectively.
Arterial pressure is measured continuously by connect-
ing the arterial catheter to transducer coupled to a Gould
pressure transducer. The output is recorded on a polygraph.
Mean arterial pressure is derived electronically.
Oxidative cyclization of the hydrazone derivatives 3a–
n with bromine in acetic acid in the presence of sodium
acetate at room temperature yields in each case one iso-
lable product 4 (Scheme 1), while the other isomeric
structure 5 was discarded on the basis of 13C NMR spectra
of the isolated products. The 13C NMR of compound 4c,
taken as a model example of the series prepared, revealed
the signal for the carbonyl carbon resonance at
d = 170.02 ppm. This chemical shift value suggested that
N(4) near C=O is sp3 hybridized nitrogen atom and differ
from the sp2 hybridized nitrogen which appear at
184–189 ppm (Chande et al. 2007; SaC¸ maci et al. 2005;
Abbiati et al. 2001; Allouche et al. 2004). Based on the
above finding we conclude that the isolated product has
structure 4 and not the isomeric structure 5. In addition,
compound 4 was synthesized by alternative method via
reaction of compound 1 with different acids in acetic acid.
Due to many drugs for angiotensin II receptor antago-
nists have imidazole moiety, such as Eprosartan, Losartan,
Canesartan and Irbesartan (Chart 1), we screened some
representative examples of the imidazole derivatives 3 for
this property.
After a 30–45 min stabilization period, autonomic trans-
mission is blocked by treatment with mecamylamine (3 mg/
kg i.v.) and atropine (0.4 mg/kg i.v.). After arterial pressure
has stabilized, angiotensin is infused i.v.in isotonic saline
with a syringe pump. When the pressure response to angio-
tensin has stabilized, angiotensin II receptor antagonists are
given in increasing doses. The doses are given intravenously
in a cumulative fashion, i.e., the next highest dose is given at
the time of maximum response to the prior dose.
Data are presented as percent inhibition of the angio-
tensin pressor response to each dose of the antagonists and
plotted against the log of the cumulative doses of antago-
nist. Linear regression is used to calculate the dose at
which the response to angiotensin is inhibited 50 % (ID50)
for each rat. Mean SEM are calculated.
Antibacterial activity
Agar diffusion well method to determine the antibacterial
activity
Evaluation of the angiotensin II receptor antagonists
activities in vivo
The microorganism inoculums were uniformly spread
using sterile cotton swab on a sterile Petri dish containing
nutrient agar (for bacteria). Each sample (100 lL) was
added to each well (6 mm diameter holes cut in the agar
gel, 20 mm apart from one another). The systems were
incubated for 24–48 h at 37 °C for bacteria. After incu-
bation, microorganism growth was observed. Inhibition of
the bacterial growth were measured in mm. Tests were
performed in triplicate (Smania et al. 1999).
The effect of angiotensin II receptor antagonists on blood
pressure has been measured in anesthetized normotensive
and hypertensive rats. From Table 1 we found that, all the
tested compounds showed potent angiotensin II receptor
antagonists activities in vivo and the ascending order of
activities was 3n, 3d, 3m, 3b, 3g, 3e, 3f, 3c, 3l, 3h, 3j, 3i,
and 3a. From the results in Table 1, it was found that the
best results were obtained by compounds bearing unsub-
stituted phenyl group (3a) and substituted phenyl group
with electron donating groups such as trimethoxy (3i),
methoxy, hydroxyl group (3j) dimethoxy (3h). On the other
hand, derivatives 3n which contain thiophene ring showed
poor activity.
Results and discussion
2-Hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one (1) was
prepared as previously reported (Gomha and Hassaneen
2011). Condensation of 2-hydrazinyl-4,4-diphenyl-1H-imi-
dazol-5(4H)-one (1) with different aldehydes 2a–n in acetic
acid containing few drops of conc. hydrochloric acid gave
the corresponding hydrazone derivatives 3a–n (Scheme 1).
The mass spectra of the isolated products 3a–n showed the
molecular ion peaks at the expected m/z values. Their IR
spectra showed the disappearance of the NH2 group, and
revealed in each case a carbonyl band in the region
1,759–1,700 cm-1 and two bands at 3,444–3,200 and
Antibacterial activity
In vitro antimicrobial screening of compounds 4b, c, h, i, j,
l, m prepared in this study was carried out using cultures of
eight bacteria species, namely, Gram positive Bacteria,
Staphylococcus aureus (RCMB 000106) (S. aureus),
Bacillus subtilis (RCMB 000108) (B. subtilis), Entero-
coccus faecalis (RCMB010068) (E. faecalis), Staphylo-
coccus pyogenes (RCMB 010015) (S. pyogenes) and Gram
negative Bacteria, Pseudomonas aeruginosa (RCMB
1
3,170–3,067 cm-1 assignable for 2NH groups. Also, H
NMR spectra showed, in each case, the presence of the
123

T. A. Farghaly et al.
Scheme 1 Synthesis of
compounds 3 and 4
010043) (P. aeruginosa), Escherichia coli (E. coli) (RCMB
010052), Salmonella typhimurium (RCMB 010072) (S.
typhimurim) and Klebsiella pneumoniae (RCMB 0010093)
(K. pneumonia). Ampicillin as an antibacterial agent for
gram (?) bacteria and Gentamicin as an antibacterial agent
for gram (-) bacteria were used as references to evaluate
123

Synthesis of a new series of angiotensin
Chart 1 Drugs for angiotensin
II receptor antagonists have
imidazole moiety
the presence of electron donating groups such as methyl or
trimethoxy groups at position 3 in imidazotriazole system
increase the activity. In contrast to the above result, com-
pounds 4h and 4j (have an electron donating groups
dimethoxy, methoxy and hydroxyl groups) decrease the
activity. Also, the presence of hydrogen and methyl moi-
eties decreases the reactivity as in compound 4l and 4m,
respectively (Table 2). All biological activities done are
preliminary tests and will be completed in due course.
Table 1 Evaluation of ID50 and LD50 of angiotensin II receptor
antagonists activities of compounds 3
Compound No.
ID50 lg/kg (mean SEM)
LD50 lg/kg
3a
3i
0.11 0.0011 9 10-7
0.19 0.0012 9 10-7
0.22 0.0014 9 10-7
0.23 0.0017 9 10-7
0.29 0.0019 9 10-7
0.32 0.0013 9 10-7
0.34 0.0022 9 10-7
0.49 0.0032 9 10-7
0.44 0.0024 9 10-7
0.56 0.0044 9 10-7
0.66 0.0045 9 10-7
0.77 0.0067 9 10-7
0.89 0.007 9 10-7
234.56 2.33
456.44 4.56
576.32 6.43
385.87 6.77
453.56 4.55
387.56 3.66
458.54 5.66
875.48 4.76
573.58 3.46
485.67 5.46
573.56 4.32
485.67 6.44
489.57 3.44
3j
3h
3l
3c
3f
3g
3e
3b
3m
3d
3n
Conclusions
Two series of 2-(arylmethylenehydrazono)-4,4-diphenyl-
1H-imidazol-5(4H)-one and 3-substituted-6,6-diphenyl-
6,7-dihydro-imidazo[2,1-c][1,2,4]triazole-5-one were syn-
thesized. The hydrazone derivatives were screened for their
angiotensin II receptor antagonists activity and the results
showed promising activity. Also, it was found that the best
results were obtained by compounds bearing unsubstituted
phenyl group and substituted phenyl group with electron
donating groups such as trimethoxy, methoxy, hydroxyl
and dimethoxy. Imidazo[2,1-c][1,2,4]triazole-5-ones were
screened for the antibacterial activity and the result
revealed that two derivatives with electron donating groups
the potency of the tested compounds under the same con-
ditions. The results of antibacterial activities for some of
the newly synthesized compounds showed promising effect
with respect to control drugs (see Table 2). Compounds 4b
and 4i have high potency as antibacterial reagent except for
S. pyogenes and P. aeruginosa. This result indicated that
123

T. A. Farghaly et al.
Table 2 Antimicrobial activity expressed as inhibition diameter zones in millimeter (mm) of compounds against the pathological strains based
on well diffusion as assay
Comp. No. Gram positive bacteria
S. aureus B. subtilis
22.8 ( 0.28) 26.3 ( 0.58) 18.4 (0.44)
Gram negative bacteria
E. faecalis
S. pyogenes
P. aeruginosa E. coli
S. typhimurim K. pneumonia
4b
NA
NA
NA
NA
NA
NA
NA
NA
19.8 ( 0.28) 20.1 ( 0.37)
16.1 ( 0.28) 16.8 ( 0.58)
22.6 ( 0.58)
4c
16.9 ( 0.28) 18.2 ( 0.19) 15.1 ( 0.19) NA
17.4 ( 0.44) 19.6 ( 0.58) 16.2 ( 0.37) NA
21.6 ( 0.28) 23.7 ( 0.44) 17.2 ( 0.44) NA
12.9 ( 0.28) 14.6 ( 0.44) 12.1 ( 0.44) NA
18.1 ( 0.28)
18.9 ( 0.44)
20.8 ( 0.19)
15.9 ( 0.37)
16.3 ( 0.44)
16.9 ( 0.58)
NA
4h
18.2 ( 0.58) 19.3 ( 0.44)
18.4 ( 0.19) 18.9 ( 0.58)
14.3 ( 0.28) 15.3 ( 0.19)
13.5 ( 0.28) 15.2 ( 0.58)
15.2 ( 0.44) 16.1 ( 0.28)
4i
4j
4l
12.6 ( 1.58) 15.8 ( 0.28) 13.4 (0.37)
13.7 ( 0.58) 15.4 ( 0.44) 14.7 ( 0.19) NA
27.4 ( 0.18) 33.1 ( 0.3)
NA
NA
4m
Ampicillin
20.4 ( 0.11) 26.4 ( 0.34) NA
NA NA 17.3 ( 0.15)
NA
NA
Gentamicin NA
28.8 ( 0.24) 22.3 ( 0.18)
26.3 ( 0.15)
The experiment was carried out in triplicate and average zone of inhibition was calculated;(100 lL was tested) (NA = no activity), data are
expressed in the form of mean SD
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