Vol. 29, No. 6 (2017)
Synthesis of N-[(Substituted 1H-pyrazol-3-yl)amino]-2-(4-methylphenyl)quinazolin-4(3H)-one Derivatives 1377
TABLE-1
PHYSICO-CHEMICAL CHARACTERIZATION
DATA OF FINAL COMPOUNDS 7a-7e
lead to the formation of next intermediate 3-amino-2-(4-methyl
phenyl)quinazolin-4(3H)-one (4). Reaction of compound 4 (0.01
mol) with acetic anhydride (0.01 mol) in presence of hydrated
sodium acetate and HCl resulted in the formation of the N-[2-
(4-methylphenyl)-4-oxoquinazolin-3(4H)-yl]acetamide (5).
Compound 5 was then reacted with substituted benzaldehydes
to obtain the compounds 6a-6e which on further cyclization with
hydrazine hydrate (0.01 mol) yielded the corresponding final
compounds (7a-7e).
Compd.
code
m.p.
(°C)
Yield
(%)
R
m.f.
m.w.
-OH
C24H21N5O2
411.47
425.49
429.91
474.36
413.46
210-215
236-240
234-239
295-300
231-235
68
60
65
70
57
7a
7b
7c
7d
7e
-OCH3 C25H23N5O2
-Cl
-Br
-F
C24H20N5OCl
C24H20N5OBr
C24H20N5OF
Characterization of all the intermediates and final com-
pounds were accomplished by various physico-chemical
and spectral techniques. The melting point of all the final
compounds was recorded on digital melting point apparatus
(Kshitij Innovation) using one end open capillary tubes and
are uncorrected. The progress of the reaction and its purity
was confirmed by the thin layer chromatography on silica gel
G plates. FTIR spectra was recorded on Shimadzu IR affinity
spectrophotometer using KBr disc method. The 1H NMR was
recorded on a Varian AC 400 spectrometer using CDCl3 as a
solvent. TMS was taken as the internal standard. Mass spectra
were on aVarian 1200L mass spectrometer. The data is expressed
as (M+1)+ values. Elemental analysis (C, H, N) was determined
using a Carlo-Erba 1160 elemental analyzer. The physio-
chemical and spectral characterization data of all the final
compounds is presented in Tables 1 and 2, respectively.
Pharmacology: All the experimental procedures were
carried out in accordance to CPCSEAs guidelines and approved
by IAEC of the Institute (1205/c/08/CPCSEA).
Anticonvulsant activity: All the synthesized final com-
pounds (7a-7e) were evaluated for the anticonvulsant activity
using maximal electroshock seizure model. The animals were
divided into three groups consisting of 6 animals each viz. test,
control and standard. All the test compounds were dissolved
in 1 % CMC solution and administrated intra-peritonially to
the animals at three doses of 25, 75 and 150 mg/kg; 30 min
before delivering the seizures. Phenytoin (25 mg/kg) was used
as a reference drug. Control animals were given the 0.9 % saline
solution. Seizures were induced in mice by delivering electro-
shock of 50 mA for 0.2 s by means of electro-convulsiometer
through a pair of ear clip electrodes. The results of the maximal
electroshock seizure model for the synthesized compounds
(7a-7e) is summarized in Table-3.
Neurotoxicity screening: The compounds (7a-7e) were
treated for the neurotoxicity using rotarod apparatus. The animals
were trained to balance on rotating rod (diameter: 3 cm) revolving
at a speed of 6 rpm. The test compounds were considered to be
neurotoxic at a particular dose if the trained animal is unable to
balance itself on the rotating rod for at least 1 min. The animals
were tested at four time intervals viz. 0.5, 1, 2 and 4 h for 1 min,
after drug administration. The results are expressed as animals
toxic/total number of animals used and is summarized in Table-4.
Animals: Swiss albino mice weighing about 18-25 g
were used in the entire study. The animals were kept in
individual cages for one week to acclimatize them at the
laboratory conditions. They were allowed free access to water
and food.
TABLE-2
SPECTRAL CHARACTERIZATION DATA OF THE FINAL COMPOUNDS 7a-7e
Elemental analysis (%)
Calculated Observed
Compd.
code
Mass (m/e)
IR (KBr, νmax, cm-1)
1H NMR (CDCl3, δ in ppm)
[M+1]+
412.47
3550 (O-H str), 3410 (N-Hstr), 3100 7.4-7.9 (m, 4H, ArH), 7.0 (s, 1H,
(C-H str), 2920 (C-H str) 2917 (C-H N-H), 7.13-7.55 (m, 4H, ArH),
asym str.), 2860 (C-H str), 1690 (C=O 2.3 (s, 1H, N-H), 6.5 (s, 1H, N-
str), 1660 (C=C str), 1516 (C-C str), H), 6.68-6.95 (m, 4H, ArH), 5.0
C (70.06 %)
H (5.14 %)
N (17.02 %)
O (7.78 %)
C (70.13 %)
H (5.19 %)
N (17.10 %)
O (7.83 %)
7a
7b
7c
7d
7e
1470 (C-H bend), 1250 (C-N)
(s, 1H, -OH), 2.35 (s, 3H, -CH3).
3415 (N-Hstr), 3050 (C-H str), 2916 7.2-7.7 (m, 4H, ArH), 7.6 (s, 1H,
(C-H str) 2929 (C-H asym str), 2872 N-H), 7.01-7.45 (m, 4H, ArH),
(C-H str), 2835 (O-CH3 str) 1681 (C=O 2.8 (s, 1H, N-H), 7.0 (s, 1H, N-
str), 1664 (C=C str), 1510 (C-C str), H), 6.72-7.01 (m, 4H, ArH), 3.74
C (70.57 %)
H (5.45 %)
N (16.46 %)
O (7.52 %)
C (70.66 %)
H (5.39 %)
N (16.49 %)
O (7.58 %)
426.49
430.91
475.36
414.46
1472 (C-H bend), 1243 (C-N str)
(s, 1H, -CH3), 2.39 (s, 3H, -CH3)
3425 (N-H str), 3054 (C-H str), 2935 7.8-7.13 (m, 4H, ArH), 9.0 (s, 1H,
(C-H str) 2912 (C-H asym str.), 2867 N-H), 7.09-7.50 (m, 4H, ArH),
(C-H str), 1694 (C=Ostr), 1658 (C=C 3.0 (s, 1H, N-H), 7.4 (s, 1H, N-
str), 1522 (C-C str), 1445 (C-H bend), H), 7.08-7.24 (m, 4H, ArH), 2.4
C (67.05 %)
H (4.69 %)
Cl (8.25 %)
N (16.29 %)
O (3.72 %)
C (67.12 %)
H (4.23 %)
Cl (8.40 %)
N (16.35 %)
O (3.92 %)
1255 (C-N str), 800 (-Cl)
(s, 3H, -CH3)
3422 (N-H str), 3049 (C-H str), 2954 7.7-7.12 (m, 4H, ArH), 8.4 (s, 1H,
(C-H str) 2920 (C-H asym str.), 2866 N-H), 7.14-7.57 (m, 4H, ArH),
(C-H str), 1686 (C=O str), 1659 (C=C 2.0 (s, 1H, N-H), 7.8 (s, 1H, N-
str), 1519 (C-C str), 1475 (C-H bend), H), 7.01-7.17 (m, 4H, ArH), 2.30
C (60.77 %)
H (4.25 %)
Br (16.84 %)
N (14.76 %)
O (3.37 %)
C (60.83 %)
H (4.36 %)
Br (16.75 %)
N (12.62 %)
O (3.43 %)
1243 (C-N str), 1100 (Br)
(s, 3H, -CH3)
3419 (N-H str), 3043 (C-H str), 2926 7.1-7.6 (m, 4H, ArH), 8.1 (s, 1H,
(C-H str)2921 (C-H asym str.), 2867 N-H), 7.0-7.41 (m, 4H, ArH), 2.2
(C-H str), 1693 (C=O str), 1658 (C=C (s, 1H, N-H), 8.0 (s, 1H, N-H),
str), 1520 (C-C str), 1475 (C-H bend), 7.11-7.27 (m, 4H, ArH), 2.40 (s,
C (69.72 %)
H (4.88 %)
F (4.59 %)
N (16.94 %)
O (3.87 %)
C (69.83 %)
H (4.74 %)
F (4.61 %)
N (16.32 %)
O (3.92 %)
1248 (C-N str), 1150 (F)
3H, -CH3)