Triazole incorporated pyridazinones as a new class of antihypertensive agents: Design, synthesis and in vivo screening

Article abstract of DOI:10.1016/j.bmcl.2010.12.028

A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5- dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol.

Full text of DOI:10.1016/j.bmcl.2010.12.028

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1023–1026
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triazole incorporated pyridazinones as a new class of antihypertensive
agents: Design, synthesis and in vivo screening
Anees A. Siddiqui a, Ravinesh Mishra a, , Mohammad Shaharyar a, Asif Husain a, Mohd. Rashid a, Palash Pal b
⇑
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110 062, India
b Pharmacy Department, Faculty of Technology and Engineering, The M.S. University of Baroda, Vadodara 390 001, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reac-
tions starting from respective aryl hydrocarbons. The final compounds (4a–4u) were evaluated for anti-
hypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k
showed appreciable antihypertensive activity comparable with that of standard hydralazine and
propranolol.
Received 21 September 2010
Revised 8 November 2010
Accepted 4 December 2010
Available online 10 December 2010
Keywords:
Pyridazinone
Ó 2010 Elsevier Ltd. All rights reserved.
1,2,4-Triazole
Antihypertensive activity
Non-invasive method
The chemistry of pyridazinones has been an interesting field of
study since decade. The synthesis of novel pyridazinone deriva-
tives and investigation of their chemical and biological behavior
have gained more importance in recent decades for biological,
medicinal, and agricultural reason. Living organism finds difficulty
in construction of N–N bonds that limits the natural abundance of
compounds having such bonds. The pharmacological activity of
4,5-dihydro-6-phenyl-3(2H)-pyridazinones has been extensively
studied and is known for its cardiovascular effects.1–3 In this field
several compounds such as zardaverine or imazodan have been
developed as PDE III inhibitors in the search for new antiplatelet
or cardiotonic agents.4,5
A survey of literature revealed that substituted pyridazinones
have received much attention during recent years on account of
their prominent potential as antidepressant,6 antihypertensive,7–9
antithrombotic,10 anticonvulsant,11 cardiotonic,12 antibacterial,13
diuretics,14 antiHIV,15 and anticancer.16 Pyridazinone causes direct
relaxation of arteriolar smooth muscle by reducing arterial tone
without affecting autonomic nervous system. The molecular mech-
anisms mediating this action are not clear, but may ultimately
involve a fall in intracellular calcium concentrations. While a vari-
ety of changes in cellular signaling pathways are influenced by
arteriolar vasodilators like hydralazine, precise molecular targets
that explain its capacity to dilate arteries remain uncertain. The
current work describes the synthesis of novel 4,5-dihydro-3(2H)-
pyridazinone moiety with encouraging antihypertensive activity
by non-invasive method using Tail Cuff method.
The synthesis of novel pyridazinone derivatives has been car-
ried out according to the steps shown in Figure 1. In the initial
step, b-aroyl propionic acids (1a–1g) were synthesized by Fri-
edel–Crafts acylation of appropriate hydrocarbons with succinic
anhydride in the presence of anhydrous aluminum chloride.17
The intermediates (2a–2g) were synthesized by reacting b-aroyl
propionic acids with carbohydrazide in absolute ethanol.18 The
thiosemicarbazides (3a–3u) conveniently synthesized by refluxing
carbohydrazide derivatives (2a–2g) with aryl isothiocyanate in
ethanol. Intermediate thiosemicarbazide (0.05 M) was refluxed in
2 M sodium hydroxide solution (reaction time varies from 4 to
5 h), cooled, and poured into excess of water containing crushed
ice. Acidification with glacial acetic acid yielded a solid which
was collected by filtration and crystallized from ethanol to give fi-
nal compounds (4a–4u).19 Purity of compounds was checked by
single-spot TLC. Two different solvent systems: toluene:ethyl ace-
tate:formic acid (5:4:1) and petroleum ether:toluene:acetic acid
(5:4:1), were used to run the TLC and spots were located under io-
dine vapors/UV light. Compounds were characterized on the basis
of spectral data (IR, 1H NMR, mass and elemental analysis). Spec-
tral data of all the newly synthesized compounds were in full
agreement with proposed structures.20 In general, Infra Red Spec-
tra (IR) revealed NH, CH, C@S, C@O and C@N peak at 3323, 2926,
2368, 1685 and 1607 cmꢀ1, respectively. In the Nuclear Magnetic
Resonance Spectra (1H NMR) the signals of the respective protons
of the prepared titled compounds were verified on the basis of
their chemical shifts, multiplicities, and coupling constants. The
⇑
Corresponding author. Tel.: +91 9990031907; fax: +91 11 27048685.
E-mail address: ravi_kcp@rediffmail.com (R. Mishra).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.028

1024
A. A. Siddiqui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1023–1026
O
OH
O
Anhydrous AlCl
O
O
3
+
O
R
R
(1a-g)
Aromatic hydrocarbon Succinic anhydride
NH NHCONHNH
2
2
R
O
N N
O
1
S
NH
R C H NC=S
6
5
R
O
NH
NH
N
N
O
NH
NH
2
(2a-g)
1
R
Intermediates
(3a-u)
NaOH
R
O
N N
N
N
H
1
R
R = H, CH3, OCH3, C2H5, CH2CH(CH3)2, C6H5, Cl
R1 = H, Cl, CH3
N
S
(4a-u)
Figure 1. Synthesis of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives.
two triplets at about d 2.54, J = 7.8 and 2.99, J = 7.8 confirmed the
presence of methylene group at 4- and 5-position of pyridazinone
ring, respectively. For the compounds 4m, 4n, and 4o the men-
tioned peaks were shifted at about d 2.9 and 3.3 ppm, respectively.
The multiplets at d 7.13–7.93 are indicative of aromatic protons.
The singlet at d 10.78 is due to CSNH group flanked by two nitro-
gen atoms. The mass spectra show the presence of peak at definite
m/z value in accordance to the molecular formula. The elemental
analysis results were within 0.4% deviation from the theoretical
values.
The final compounds (4a–4u) were evaluated for antihyperten-
sive activity by non-invasive method using Tail Cuff method. The
results were shown in Table 1 and compared with standard drug,
hydralazine and propanolol. Compounds 4e, 4i, and 4k were found
to show highly significant reduction in mean arterial blood pres-
sure but at higher dose in comparison to standard drugs.21
Albino rats (body weight 200–250 g) were supplied by Central
Animal House Facility, Hamdard University and kept under stan-
dard laboratory conditions in 12 h light/dark cycle at 25 2 °C. Ani-
mals were provided with pellet diet (Lipton, Calcutta, India) and
water ad libitum. They were marked for easy identification. All
the experimental protocols were carried out with the permission
from Institutional Animal Ethics Committee (IAEC) and the guide-
lines provided by the Committee for the Purpose of Control and
Supervision of Experiments in Animal (CPCSEA). Animals were ob-
tained from Central Animal House Facility, Hamdard University,
New Delhi 62. Registration number and date of registration is
173/CPCSEA, 28 January, 2000.
After recording the initial BP of rats, the animals were divided
into groups of five animals each. One group was taken as control.
Hypertension was induced in the remaining groups by subcutane-
ous injection of methyl prednisolone acetate (20 mg/kg/wk) for 2
weeks.22
Mean arterial blood pressure was measured in conscious rats
using CODA Non-Invasive Blood Pressure Recorder by Tail–Cuff
method (Kent Scientific Corporation, USA). The restrainer carrying
the rat was placed in the BP instrument with tail protruding out.
The tail was gently placed in contact with a transducer membrane,
which was connected to the digital BP display panel. The instru-
ment was then turned on and allowed to stabilize until steady
pulse rate was observed. Once the ‘pulse level ready’ signal ap-
peared, the BP recording button was pressed and the mean arterial
BP was recorded. Albino rats (body weight 200–250 g) were used
in present study. Rats were assigned to groups of five animals in
each. Each compound (20 mg/kg body weight) was injected intra-
peritoneally after suspending in 1% carboxymethyl cellulose
(CMC) solution. The mean arterial blood pressure was recorded
after 1 h.
The statistical analysis was performed using GRAPHPAD INSTAT
3 software (Graph Pad Software Inc., San Diego, CA). Data obtained
from animal experiments were expressed as arithmetic mean
SEM. The comparison between various groups was performed by
one-way analysis of variance (ANOVA), and the effect in treatment
groups were compared with toxic control group by Dunnet multi-
ple comparison test. p <0.05 was considered to be significant (⁄p
<0.05; ⁄⁄p <0.01). The percentage reduction in MABP for all the
treatment groups was also calculated and compared.
For conducting the BP measurement studies, the animals were
kept in a restrainer for 10 min every day for 1 week. This exercise
was done to avoid the fluctuation in blood pressure due to aggres-
sive behavior of animal while keeping into the restrainer for mea-
suring the activity.
It can be observed on the basis of structure–activity relation-
ships that groups like p-CH3, p-OCH3 and p-C2H5 in phenyl ring
at 6-position increases the activity as shown by the compound
4e, 4i and 4k. All compounds possessing substituted aryl moiety

A. A. Siddiqui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1023–1026
1025
Table 1
Mean arterial blood pressure (mm Hg) and substituents of compounds (4a–4u)
Compd (20 mg/kg)
MABP (mean SEM)
% Reduction in MABP
R
R1
Control
101.33 4.64
162.33 4.02**
95.12 4.68**
96.16 4.70**
113.6 7.78**
122 4.85**
Toxic control
Propranolola
41.40
41.76
30.01
24.84
38.83
27.30
41.84
31.25
32.48
16.09
40.98
38.88
42.11
32.97
30.51
15.85
12.50
10.67
14.37
13.13
12.52
11.29
11.53
Hydralazineb
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
H
H
CH3
CH3
CH3
OCH3
OCH3
OCH3
C2H5
C2H5
C2H5
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
C6H5
C6H5
C6H5
Cl
Cl
H
Cl
CH3
H
Cl
CH3
H
Cl
CH3
H
Cl
CH3
H
Cl
CH3
H
Cl
CH3
H
Cl
107.4 5.54**
118 7.56**
94.41 7.32**
111.6 10.28**
109.6 6.17**
136.2 2.9**
95.8 3.93**
4j
99.2
2.57**
4k
4l
93.96 6.61**
108.8 5.02**
112.8 3.92**
136.6 1.75**
142 4.19*
4m
4n
4o
4p
4q
4r
4s
4t
145 3.61**
139 4.27**
141 3.10**
142 3.98**
144 4.41**
143.6 4.13**
4u
Cl
CH3
All values were expressed as mean SEM (⁄p 60.05), each group comprised of four animals (i.e., n = 4).
Toxic control group was compared with control group. All the treatment groups were compared with toxic control group and p <0.05 was
considered to be significant.
⁄
p <0.05.
a
Dose of propanolol was taken as 14 mg/kg.
b
Dose of hydralazine was taken as 2.6 mg/kg.
** p <0.01.
at C-6 of pyridazin-3(2H)-one ring showed significant percent
reduction in comparison to the compounds possessing unsubsti-
tuted aryl ring. It indicated that substitution on aromatic ring is
essential for antihypertensive activity. Substitution with methyl,
methoxy and ethyl group at para position of phenyl ring on pyrid-
azinone moiety increases the antihypertensive activity signifi-
cantly. The compounds substituted with group like isobutyl,
biphenyl, chloro at para position of phenyl ring on pyridazinone
moiety did not show appreciable activity.
(RFSMS). The authors are also thankful to Jamia Hamdard, New Del-
hi, India for providing facility for the research work.
References and notes
1. Abouzid, K. A. M.; Khalil, N. A.; Ahmed, E. M. Med. Chem. Res. 2009. doi:10.1007/
s00044-009-9218-4.
2. Bansal, R.; Kumar, D.; Carron, R. Eur. J. Med. Chem. 2009. doi:10.1016/
j.ejmech.2009.06.006.
3. Thota, S.; Bansal, R. Med. Chem. Res. 2009. doi:10.1007/s00044-009-9232-6.
4. Curran, W. V.; Ross, A. J. Med. Chem. 1974, 17, 273–280.
In summary various 6-(substituted phenyl)-2-(4-substituted
phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydro-
pyridazin-3(2H)-one derivatives were prepared. Among these
compounds 6-(4-methylphenyl)-2-[4-(4-chlorophenyl)-5-thioxo-
4,5-dihydro-1H-1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one
(4e), 6-(4-methoxyphenyl)-2-[4-(4-methylphenyl)-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one
(4i) and 6-(4-ethylphenyl)-2-[4-(4-chlorophenyl)-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one
(4k) showed maximum antihypertensive activity.
Therefore, it was concluded that triazole incorporated 4,5-dihy-
dro-3(2H)-pyridazinone derivatives can be further modified to ex-
hibit better potency than the standard drugs. Further studies to
acquire more information about Quantitative Structure Activity
Relationships (QSAR) are in progress in our laboratory. The 4,5-
dihydro-3(2H)-pyridazinone derivatives discovered in this study
may provide valuable therapeutic intervention for the treatment
of hypertension.
5. Dal Piaz, V.; Cianini, G.; Turco, G.; Giovannoni, P.; Mideli, M.; Pirisino, R.;
Pereeti, M. J. Pharm. Sci. 1991, 80, 341–348.
6. Coelho, A.; Sotelo, E.; Ravina, E. Tetrahedron 2003, 59, 2477.
7. Demirayak, S.; Karaburun, A. C.; Beis, R. Eur. J. Med. Chem. 2004, 39, 1089.
8. Siddiqui, A. A.; Wani, S. M. Indian J. Chem. 2004, 43B, 1574.
9. Archan, S.; Toller, W. Curr. Opin. Anesthesiol. 2008, 21(1), 78.
10. Monge, A.; Parrado, P.; Font, M.; Alvarez, E. F. J. Med. Chem. 1987, 30, 1029.
11. Rubat, C.; Coudert, P.; Refouvelet, B.; Tronche, P.; Bastide, P. Chem. Pharm. Bull.
1990, 38(11), 3009.
12. Sircar, I.; Weishaar, R. E.; Kobylarz, D.; Moos, W. H.; Bristol, J. A. J. Med. Chem.
1987, 30, 1955.
13. Longo, J. G.; Verde, I.; Castro, M. E. J. Pharm. Sci. 1993, 82, 286.
14. Akahane, A.; Katayama, H.; Mitsunaga, T. J. Med. Chem. 1999, 42, 779.
15. Livermone, D. G. H.; Bethell, R. C.; Cammack, N. J. Med. Chem. 1993, 36, 3784.
16. Malinka, W.; Redzicka, A.; Lozach, O. Il Farmaco 2004, 59, 457.
17. Khan, M. S. Y.; Siddiqui, A. A. Indian J. Chem. 2000, 39B, 614.
18. Mishra, R.; Siddiqui, A. A.; Kumar, R.; Kumar, S. Molbank 2010, 1, M652.
19. General method for the synthesis of 6-(substituted phenyl)-2-(4-substituted
phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-
3(2H)-one derivatives (4a–4u): A ethanolic solution of 6-oxo-3-substituted
phenyl-5,6-dihydropyridazine-1(4H)-carbohydrazide (0.01 mol) and aromatic
isothiocyanate (0.01 mol) was refluxed for 4 h. The contents were concentrated
and poured into crushed ice, filtered and dried to crude thiosemicarbazide
intermediates as 6-substituted phenyl-2-(N-phenylthiosemicarbazido)-4,5-
dihydropyridazin-3(2H)-one derivatives (3a–3u). Crude thiosemicarbazide
intermediates (0.005 mol) was refluxed in 2 M sodium hydroxide solution
(20 ml) for 4–5 h, cooled, poured into excess of water containing crushed ice
with continuous stirring and filtered to get the final compound. The filtrate on
acidification with glacial acetic acid yielded the precipitate, which was
collected by filtration. The combined precipitates were recrystallized from
ethanol.
Acknowledgements
One of the authors (Ravinesh Mishra) expresses sincere thanks to
the University Grant Commission (UGC), New Delhi, India, for the
award of Research Fellowship in Science for Meritorious Students

1026
A. A. Siddiqui et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1023–1026
20. Physical and analytical data of the compounds: Compound 4a: Yield: 40%; mp
180–182 °C; Rf 0.42; IR (KBr) tmax (cmꢀ1): 3323 (NH), 2930 (CH), 2368 (C@S),
1685 (C@O), 1607 (C@N), 1030; 1H NMR (300 MHz, CDCl3): d 2.54 (t, J = 7.8, 2H,
C–CH2), 2.99 (t, J = 7.8, 2H, CH2–CO), 7.13–7.93 (m, 10H, Ar–H), 10.78 (s, 1H,
CSNH); Mass (m/z): 349/350 (M+/M++1); Anal. Calcd for C18H15N5OS: C, 61.87;
H, 4.33; N, 20.04. Found: C, 61.82; H, 4.22; N, 19.96.
CH2), 3.02 (t, J = 7.8, 2H, CH2–CO), 7.14–7.92 (m, 8H, Ar–H), 10.72 (s, 1H,
CSNH); Mass (m/z): 411 (M+); Anal. Calcd for C20H18ClN5OS: C, 58.32; H, 4.40;
N, 17.00. Found: C, 58.22; H, 4.32; N, 16.88.
Compound 4l: Yield: 52%; mp 206–208 °C; Rf 0.64; IR (KBr) tmax (cmꢀ1): 3456
(NH), 2936 (CH), 2344 (C@S), 1670 (C@O), 1608 (C@N); 1H NMR (300 MHz,
CDCl3): d 1.14 (t, 3H, CH3), 2.24 (q, 2H, CH2), 2.40 (s, 3H, CH3), 2.56 (t, J = 7.8,
2H, C–CH2), 2.98 (t, J = 7.8, 2H, CH2–CO), 7.20–7.94 (m, 8H, Ar–H), 10.80 (s, 1H,
CSNH); Mass (m/z): 391/392 (M+/M++1); Anal. Calcd for C21H21N5OS: C, 64.43;
H, 5.41; N, 17.89. Found: C, 64.36; H, 5.22; N, 17.82.
Compound 4b: Yield: 46%; mp 148–150 °C; Rf 0.46; IR (KBr) tmax (cmꢀ1): 3330
(NH), 2922 (CH), 2365 (C@S), 1665 (C@O), 1612 (C@N), 1025, 817; 1H NMR
(300 MHz, CDCl3): d 2.48 (t, J = 7.7, 2H, C–CH2), 2.99 (t, J = 7.7, 2H, CH2–CO),
7.13–7.93 (m, 9H, Ar–H), 10.82 (s, 1H, CSNH); Mass (m/z): 383 (M+); Anal.
Calcd for C18H14ClN5OS: C, 56.32; H, 3.68; N, 18.24. Found: C, 56.28; H, 3.56; N,
18.22.
Compound 4m: Yield: 52%; mp 206–208 °C; Rf 0.64; IR (KBr) t
max (cmꢀ1): 3424
(NH), 3092 (CH), 2362 (C@S), 1654 (C@O), 1610 (C@N), 882; 1H NMR
(300 MHz, CDCl3): d 0.89 (d, 6H, 2 ꢁ CH3), 1.64–1.72 (m, 1H, CH), 1.86 (t, 2H,
CH2), 2.96 (t, J = 7.6, 2H, C–CH2), 3.20 (t, J = 7.6, 2H, CH2–CO), 7.20–7.94 (m, 9H,
Ar–H), 10.82 (s, 1H, CSNH); Mass (m/z): 405/406 (M+/M++1); Anal. Calcd for
Compound 4c: Yield: 60%; mp 188–190 °C; Rf 0.46; IR (KBr) tmax (cmꢀ1): 3452
(NH), 2926 (CH), 2360 (C@S), 1648 (C@O), 1600 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.40 (s, 3H, CH3), 2.62 (t, J = 7.8, 2H, C–CH2), 3.2 (t, J = 7.8, 2H, CH2–
CO), 7.2–7.80 (m, 9H, Ar–H), 10.76 (s, 1H, CSNH); Mass (m/z): 363/364 (M+/
M++1); Anal. Calcd for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27. Found: C, 62.78;
H, 4.66; N, 19.02.
C
22H23N5OS: C, 65.15; H, 5.72; N, 17.27. Found: C, 65.08; H, 5.58; N, 17.16.
Compound 4n: Yield: 48%; mp 210–212 °C; Rf 0.56; IR (KBr) tmax (cmꢀ1): 3490
(NH), 2922 (CH), 2362 (C@S), 1632 (C@O), 1560 (C@N), 806; 1H NMR
(300 MHz, CDCl3): d 0.88 (d, 6H, 2 ꢁ CH3), 1.68–1.74 (m, 1H, CH), 1.88 (t, 2H,
CH2), 2.86 (t, J = 7.8, 2H, C–CH2), 3.24 (t, J = 7.8, 2H, CH2–CO), 7.18–7.84 (m, 8H,
Ar–H), 10.84 (s, 1H, CSNH); Mass (m/z): 439 (M+); Anal. Calcd for
Compound 4d: Yield: 40%; mp 192–194 °C; Rf 0.54; IR (KBr) tmax (cmꢀ1): 3426
(NH), 3094 (CH), 2365 (C@S), 1658 (C@O), 1612 (C@N), 809, 699; 1H NMR
(300 MHz, CDCl3): d 2.30 (s, 3H, CH3), 2.44 (t, J = 7.6, 2H, C–CH2), 2.96 (t, J = 7.6,
2H, CH2–CO), 7.21–7.23 (dd, 2H, J = 7.8, H-30, H-50), 7.34–7.40 (m, 5H, Ar–H),
7.61–7.64 (dd, 2H, J = 7.8, H-20, H-60), 10.82 (s, 1H, CSNH); Mass (m/z): 363/364
(M+/M++1); Anal. Calcd for C19H17N5OS: C, 62.79; H, 4.71; N, 19.27. Found: C,
62.74; H, 4.62; N, 19.16.
C
22H22ClN5OS: C, 60.06; H, 5.04; N, 15.92. Found: C, 59.96; H, 4.92; N, 15.86.
Compound 4o: Yield: 56%; mp 218–220 °C; Rf 0.58; IR (KBr) tmax (cmꢀ1): 3442
(NH), 2926 (CH), 2356 (C@S), 1676 (C@O), 1616 (C@N); 1H NMR (300 MHz,
CDCl3): d 0.89 (d, 6H, 2 ꢁ CH3), 1.66–1.74 (m, 1H, CH), 1.86 (t, 2H, CH2), 2.40 (s,
3H, CH3), 2.86 (t, J = 7.8, 2H, C–CH2), 3.22 (t, J = 7.8, 2H, CH2–CO), 7.20–7.94 (m,
8H, Ar–H), 10.86 (s, 1H, CSNH); Mass (m/z): 419/420 (M+/M++1); Anal. Calcd for
Compound 4e: Yield: 38%; mp 196–198 °C; Rf 0.60; IR (KBr) tmax (cmꢀ1): 3215
(NH), 2929 (CH), 2364 (C@S), 1682 (C@O), 1615 (C@N), 760; 1H NMR
(300 MHz, CDCl3): d 2.34 (s, 1H, CH3), 2.48 (t, 2H, CH2), 2.96 (t, J = 7.8, 2H, C–
CH2), 3.20 (t, J = 7.8, 2H, CH2–CO), 7.13–7.93 (m, 8H, Ar–H), 10.74 (s, 1H,
CSNH); Mass (m/z): 397 (M+); Anal. Calcd for C19H16ClN5OS: C, 57.35; H, 4.05;
N, 17.60. Found: C, 57.25; H, 3.96; N, 17.52.
C
23H25N5OS: C, 65.84; H, 6.01; N, 16.69. Found: C, 65.78; H, 5.82; N, 16.54.
Compound 4p: Yield: 56%; mp 174–176 °C; Rf 0.60; IR (KBr) tmax (cmꢀ1): 3210
(NH), 3096 (CH), 2371 (C@S), 1670 (C@O), 1496 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.50 (t, J = 7.7, 2H, C–CH2), 2.96 (t, J = 7.7, 2H, CH2–CO), 7.12–7.94 (m,
14H, Ar–H), 10.82 (s, 1H, CSNH); Mass (m/z): 425/426 (M+/M++1); Anal. Calcd
for C24H19N5OS: C, 67.74; H, 4.50; N, 16.46. Found: C, 67.68; H, 4.38; N, 16.26.
Compound 4q: Yield: 42%; mp 193–195 °C; Rf 0.58; IR (KBr) tmax (cmꢀ1): 3426
(NH), 3094 (CH), 2366 (C@S), 1664 (C@O), 1592 (C@N), 844; 1H NMR
(300 MHz, CDCl3): d 2.46 (t, J = 7.6, 2H, C–CH2), 2.98 (t, J = 7.6, 2H, CH2–CO),
7.04–7.96 (m, 13H, Ar–H), 10.74 (s, 1H, CSNH); Mass (m/z): 459 (M+); Anal.
Calcd for C24H18ClN5OS: C, 62.67; H, 3.94; N, 15.23. Found: C, 62.54; H, 3.88; N,
45.14.
Compound 4f: Yield: 72%; mp 202–204 °C; Rf 0.48; IR (KBr) tmax (cmꢀ1): 3450
(NH), 2924 (CH), 2352 (C@S), 1662 (C@O), 1602 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.30 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.52 (t, J = 7.7, 2H, C–CH2), 2.96 (t,
J = 7.7, 2H, CH2–CO), 7.21–7.23 (dd, 2H, J = 7.8, H-30, H-50), 7.34–7.40 (m, 4H,
Ar–H), 7.61–7.64 (dd, 2H, J = 7.8, H-20, H-60), 10.84 (s, 1H, CSNH); Mass (m/z):
377/378 (M+/M++1); Anal. Calcd for C20H19N5OS: C, 63.64; H, 5.07; N, 18.55.
Found: C, 63.58; H, 4.88; N, 18.46.
Compound 4g: Yield: 42%; mp 170–172 °C, Rf 0.56; IR (KBr) tmax (cmꢀ1): 3471
(NH), 2926 (CH), 2374 (C@S), 1647 (C@O), 1612 (C@N), 1092, 794; 1H NMR
(300 MHz, CDCl3): d 2.58 (t, J = 7.8, 2H, C–CH2), 2.96 (t, J = 7.8, 2H, CH2–CO),
3.67 (s, 3H, CH3O), 7.0–7.94 (m, 9H, Ar–H), 10.86 (s, 1H, CSNH); Mass (m/z):
379/390 (M+/M++1); Anal. Calcd for C19H17N5O2S: C, 60.14; H, 4.52; N, 18.46.
Found: C, 60.02; H, 4.48; N, 18.40.
Compound 4r: Yield: 59%; mp 185–187 °C; Rf 0.62; IR (KBr) tmax (cmꢀ1): 3446
(NH), 2928 (CH), 2374 (C@S), 1678 (C@O), 1610 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.40 (s, 3H, CH3), 2.52 (t, J = 7.7, 2H, C–CH2), 2.96 (t, J = 7.7, 2H, CH2–
CO), 7.12–7.94 (m, 13H, Ar–H), 10.76 (s, 1H, CSNH); Mass (m/z): 439/440 (M+/
M++1); Anal. Calcd for C25H21N5OS: C, 68.32; H, 4.82; N, 15.93. Found: C, 68.14;
H, 4.76; N, 15.86.
Compound 4h: Yield: 38%; mp 178–180 °C; Rf 0.58; IR (KBr) tmax (cmꢀ1): 3499
(NH), 2920 (CH), 2360 (C@S), 1638 (C@O), 1562 (C@N), 801; 1H NMR
(300 MHz, CDCl3): d 2.62 (t, J = 7.6, 2H, C–CH2), 2.94 (t, J = 7.6, 2H, CH2–CO),
3.82 (s, 3H, CH3O), 7.12–7.96 (m, 8H, Ar–H), 10.72 (s, 1H, CSNH); Mass (m/z):
413 (M+); Anal. Calcd for C19H16ClN5O2S: C, 55.14; H, 3.90; N, 16.92. Found: C,
55.02; H, 3.84; N, 16.84.
Compound 4s: Yield: 38%; mp 194–196 °C; Rf 0.64; IR (KBr) tmax (cmꢀ1): 3452
(NH), 2934 (CH), 1680 (C@O), 1612 (C@N), 1093, 846; 1H NMR (300 MHz,
CDCl3): d 2.46 (t, J = 7.8, 2H, C–CH2), 2.90 (t, J = 7.8, 2H, CH2–CO), 7.12–7.88 (m,
9H, Ar–H), 10.82 (s, 1H, CSNH); Mass (m/z): 383 (M+); Anal. Calcd for
C
18H14ClN5OS: C, 56.32; H, 3.68; N, 18.24. Found: C, 56.22; H, 3.54; N, 18.16.
Compound 4t: Yield: 32%; mp 204–206 °C; Rf 0.62; IR (KBr) tmax (cmꢀ1): 3454
(NH), 2924 (CH), 2358 (C@S), 1670 (C@O), 1612 (C@N), 1074, 836; 1H NMR
(300 MHz, CDCl3): d 2.54 (t, J = 7.8, 2H, C–CH2), 2.98 (t, J = 7.8, 2H, CH2–CO),
7.10–7.92 (m, 8H, Ar–H), 10.76 (s, 1H, CSNH); Mass (m/z): 418 (M+); Anal.
Calcd for C18H13ClN5OS: C, 51.68; H, 3.13; N, 16.74. Found: C, 51.56; H, 3.02; N,
16.58.
Compound 4i: Yield: 52%; mp 182–184 °C; Rf 0.54; IR (KBr) tmax (cmꢀ1): 3458
(NH), 2940 (CH), 2372 (C@S), 1672 (C@O), 1618 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.40 (s, 3H, CH3), 2.56 (t, J = 7.6, 2H, C–CH2), 2.96 (t, J = 7.6, 2H, CH2–
CO), 3.67 (s, 1H, CH3O), 7.0–7.94 (m, 8H, Ar–H), 10.84 (s, 1H, CSNH); Mass (m/
z): 393/394 (M+/M++1); Anal. Calcd for C20H19N5O2S: C, 61.05; H, 4.87; N,
17.80. Found: C, 60.98; H, 4.94; N, 17.64.
Compound 4u: Yield: 47%; mp 206–208 °C; Rf 0.66; IR (KBr) tmax (cmꢀ1): 3450
(NH), 2938 (CH), 2356 (C@S), 1682 (C@O), 1614 (C@N); 1H NMR (300 MHz,
CDCl3): d 2.40 (s, 3H, CH3), 2.56 (t, J = 7.7, 2H, C–CH2), 2.98 (t, J = 7.7, 2H, CH2–
CO), 7.12–7.88 (m, 8H, Ar–H), 10.84 (s, 1H, CSNH); Mass (m/z): 397/399 (M+/
M++2); Anal. Calcd for C19H16ClN5OS: C, 57.35; H, 4.05; N, 17.60. Found: C,
57.26; H, 3.95; N, 17.47.
Compound 4j: Yield: 46%; mp 196–198 °C; Rf 0.62; IR (KBr) tmax (cmꢀ1): 3424
(NH), 3096 (CH), 2362 (C@S), 1660 (C@O), 1598 (C@N), 842, 732; 1H NMR
(300 MHz, CDCl3): d 1.66 (t, 2H, CH3), 2.24 (q, 2H, CH2), 2.56 (t, J = 7.7, 2H, C–
CH2), 2.94 (t, J = 7.7, 2H, CH2–CO), 7.20–7.94 (m, 9H, Ar–H), 10.82 (s, 1H,
CSNH); Mass (m/z): 377/378 (M+/M++1); Anal. Calcd for C20H19N5OS: C, 63.64;
H, 5.07; N, 18.55. Found: C, 63.58; H, 4.96; N, 18.42.
21. Borchard, R. E.; Barnes, C. D.; Eltherington, L. G. Drug Dosage in Laboratory
Animals: A Handbook, 3rd ed.; The Telford Press: New Jersey, 1991.
22. Krakoff, L. R.; Selvadurai, R.; Sytter, E. Am. J. Physiol. 1975, 228, 613.
Compound 4k: Yield: 48%; mp 202–204 °C; Rf 0.60; IR (KBr) tmax (cmꢀ1): 3458
(NH), 3028 (CH), 2312 (C@S), 1612 (C@O), 1588 (C@N), 848, 758; 1H NMR
(300 MHz, CDCl3): d 1.16 (t, 3H, CH3), 2.28 (q, 2H, CH2), 2.58 (t, J = 7.8, 2H, C–