Synthesis and local anaesthetic activities of 2-aminothiazole/thiadiazole analogues of lidocaine

Article abstract of DOI:10.1007/s00044-011-9659-4

Various 2-aminothiazole and 2-aminothiadiazole derivatives viz N-[4-(2-Chloro-4-fluoro-phenyl)-thiazol-2-yl]-2-substituted acetamides (3a, 4a, 5a) and N-[5-(4-substituted aryl)-[1,3,4]thiadiazol-2-yl]-2-acetamides (3b, 3c, 4b, 4c, 5b, 5c) were synthesized from their corresponding properly substituted 2-aminothiazoles and 2-aminothiadiazoles. Structures of all the newly synthesized compounds were established by analytical and spectral data. Synthesized compounds were screened for their local anaesthetic activity using the rat sciatic nerve model. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9659-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1544–1549
DOI 10.1007/s00044-011-9659-4
ORIGINAL RESEARCH
Synthesis and local anaesthetic activities of 2-aminothiazole/
thiadiazole analogues of lidocaine
•
•
•
Naveen P. Badiger Ashraf Khan M. B. Kalashetti
I. M. Khazi
Received: 23 December 2010 / Accepted: 3 May 2011 / Published online: 27 May 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Various 2-aminothiazole and 2-aminothiadiaz-
ole derivatives viz N-[4-(2-Chloro-4-fluoro-phenyl)-thiazol-
2-yl]-2-substituted acetamides (3a, 4a, 5a) and N-[5-(4-
substituted aryl)-[1,3,4]thiadiazol-2-yl]-2-acetamides (3b,
3c, 4b, 4c, 5b, 5c) were synthesized from their corre-
sponding properly substituted 2-aminothiazoles and
2-aminothiadiazoles. Structures of all the newly synthesized
compounds were established by analytical and spectral data.
Synthesized compounds were screened for their local
anaesthetic activity using the rat sciatic nerve model.
The structural requirements (Lofgren, 1948; Takman
et al., 1969) for a local anaesthetic are a lipophilic (aromatic)
head, a hydrophilic end bearing a tertiary amine and an
intermediate substituted alkyl chain. Compounds having an
amino group linked to a heterocyclic nucleus, such as lipo-
philic moiety displays greater activity and less toxicity than
benzene analogues (Bhargava and Chaurasia, 1969; Mat-
tocks and Hutchinson, 1948). Some derivatives of 2-am-
inothiazoles (Bhargava and Singh, 1960; Srivastava and Rai,
1980; Lakhan and Rai, 1986; Bhargava et al., 1978) are
reported to possess local anaesthetic activity. In view of the
significant role played by the heterocyclic rings in interac-
tion with hydrophilic region and to increase the activity and
to evaluate the influence on activity by different heterocyclic
systems, we report herein the synthesis of various 2-ami-
nothiazole/thiadiazole derivatives containing the acetyl-
amino group coupled with various secondary amines.
Keywords 2-aminothiazoles 2-amino[1,3,4]thiadiazoles Á
Chloroacetylation Á Local anaesthetic activity Á
Rat sciatic nerve model
Introduction
Local anaesthetics are the compounds that block nerve
fibre conduction when applied locally to nerve tissue in
appropriate concentrations. They block the voltage-sensi-
tive sodium channels of every type of nerve fibre blocking
sodium entry into neuron thereby eliminating their action
potential (Catterall and Mackie, 2001). The great practical
advantage of the local anaesthetics is that their action can
be reversed when they are removed from the nerve tissue.
In this case, there is a complete recovery of the nerve
function and the action potential, with no evidence of
structural damage to nerve fibre or cells (Catterall and
Mackie, 2001).
Results and discussion
Chloroacetylation of 2-amino[1,3]thiazoles (1a–c) with
chloroacetylchloride in the presence of glacial acetic acid
leads to the formation of substituted thiazole/thiadiazole
acetamide derivatives (2a–c) in excellent yields (Scheme 1).
Appearance of an absorption band at 1676 cm-1 due to
amide carbonyl in IR and chemical shifts at 10.71(2a),
1
12.51(2b, 2c) d ppm in H NMR confirms –NH proton
which is attached to the carbonyl carbon. Appearance of
peak at d 4.43 ppm (–COCH2) further confirms formation
of these compounds (2a–c). Finally, the target compounds
have been synthesized by the condensation of 2a–c with
different secondary amines like diethylamine, piperidine,
and morpholine in dioxan as solvent to get compounds
(3a–c), (4a–c) and (5a–c), respectively (Scheme 1). The
N. P. Badiger Á A. Khan Á M. B. Kalashetti Á I. M. Khazi (&)
Department of Chemistry, Karnatak University,
Dharwad 580003, India
e-mail: drimkorgchem@gmail.com
123

Med Chem Res (2012) 21:1544–1549
1545
R1
X
N
NH2
R2
S
( 1a-1c )
i
R1
N
X
NHCOCH2Cl
R2
S
( 2a-2c )
ii
iv
iii
R1
R1
X
N
C2H5
C2H5
N
X
NHCOCH2
R2
S
N
NHCOCH2
( 5a-5c )
R2
R1
S
O
( 3a-3c )
X
N
N
NHCOCH2
R2
S
( 4a-4c )
Reagents and conditions:
i = Glacial AcOH, Chloroacetyl chloride reflux. ii =Diethylamine,1,4dioxan reflux.
iii = Piperidine, 1,4 dioxan reflux.
iv = Morpholine, 1,4 dioxan reflux.
Where.
a, X= C
b, X= N
c, X= N
R1 = 2-chloro-4-fluorophenyl
R2 =
H
R1 =
R1 =
R2 = p-methoxybenzyl-
R2 = p-fluorobenzyl-
------
-------
Scheme 1
structures of all the newly synthesized compounds were
established by their spectral and analytical data.
have been conducted along with rat sciatic nerve block assay
in comparison with the reference drug Lidocaine (Table 2).
When a 2% solution was used, several compounds (Table 1)
exhibited better activity in blocking the rat sciatic nerve with
respect to Lidocaine (160, 160, 150, 210 and 180 min for
motor activity recovering, respectively, versus 117 min for
lidocaine). It has been confirmed that reducing the size of the
ring structure results in improvement of anaesthetic activity.
Analogues with a terminal diethylamino or piperidine sub-
stitutions displayed higher activity.
These 2-amino thiazole/thiadiazole analogues of lido-
caine (3a–c), (4a–c) and (5a–c) were tested in vivo for their
local anaesthetic activity by rat sciatic nerve block anaes-
thesia (Fig. 1; Table 1). For all the tested compounds, it
appears that the position and the nature of the side chain
affect surface and infiltration activities. Thus, in order to
evaluate local anaesthetic activity, additional investigations
(Rabbit corneal and mouse tail anaesthetic activities) also
123

1546
Med Chem Res (2012) 21:1544–1549
Table 2 Rabbit corneal and mouse tail anaesthetic activities
160
Compound
Corneal anaesthsiaa
Mouse tail anaesthesiab
134
140
120
100
80
118
115
112
2.3 ( 0.32)10-2
3.6 ( 0.28)10-2
1.7 ( 0.44)10-2
0.72 ( 0.26)10-2
2.4 ( 0.32)10-2
0.66 ( 0.41)10-2
3.2 ( 0.21)10-2
4.7 ( 0.31)10-2
1.23 ( 0.43)10-2
0.92 ( 0.29)10-2
109
3a
44.3 3.2
54.2 4.3
88.3 4.3
42.6 3.3
34.8 5.5
92.6 6.2
25.6 5.3
40.2 6.8
72.1 4.3
100
91
3b
82
67
3c
57
56
60
4a
40
4b
20
4c
0
5a
5b
Compounds
5c
Lidocaine HClc
Fig. 1 In vivo duration of local anaesthetic activity (rat sciatic nerve
block) of lidocaine and newly synthesized compounds. Each rat
received 0.2 ml of the 2% anaesthetic solution. The values are
means SE of three determinations
a
All compounds were in aqueous solution at 2% concentration. The
values expressed as % of the anaesthetic activity of lidocaine (=100)
are means SE of three determinations
IC50 values expressed as mol l-1
b
c
Lidocaine hydrochloride was used for comparison
Table 1 Duration of local anaesthetic activity in rat sciatic nerve
block
Compound
Duration* (min)
1%
instruments at University Scientific Instruments centre
(USIC), Karnatak University Dharwad, India.
2%
3a
25 ( 10.5)
77 ( 6.8)
90 ( 3.6)
40 ( 15.0)
35 ( 11.0)
40 ( 12.0)
75 ( 7.0)
117 ( 8.0)
25 ( 12.3)
65 ( 10.7)
45 ( 17.0)
72 ( 6.9)
Synthesis of 4-(2-chloro-4-fluorophenyl)-1,3-thiazol-2-
amine (1a)
3b
3c
210 ( 16.9)
160 ( 18.2)
160 ( 15.3)
180 ( 20.3)
150 ( 17.2)
63 ( 6.8)
4a
This compound was prepared as per the literature method
(Renuka and Shipra, 1997).
4b
4c
Yield 95%; mp 130°C. Lit. (131–132°C) (Renuka and
Shipra, 1997).1H NMR (CDCl3) d; 5.32 (2H, s, NH2), 6.64
(1H, s, H5), 7.0–7.77 (3H, m, Ar–H). IR tmax cm-1 (KBr):
3475, 3292, 3113, 2977, 2762. Anal. Calcd. for: C9 H6 Cl F
N2 S; C, 47.27; H, 2.64; N, 12.25%. Found: C, 47.25; H,
2.61; N, 12.23%.
5a
5b
5c
50 ( 6.5)
Lidocaine HCl
117 ( 11.0)
* In vivo duration of local anaesthetic activity in rat sciatic nerve
block (each rat received 0.2 mL of 1% and 2% anaesthetic solution).
The values are means of SE of three determinations
Synthesis of 5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine
(1b)
Experimental
A
mixture of 4-methoxyphenylacetic acid (1.67 g;
Chemistry
10 mmol) and thiosemicarbazide (0.92 g; 10 mmol) in
phosphorous oxychloride (30 ml) was refluxed gently for
45 min. The reaction mixture was cooled and quenched
(highly exothermic) with cold water (90 ml). The resulting
solution was refluxed for additional 4 h and filtered hot. The
filtrate was cooled and basified with aqueous potassium
hydroxide solution. The solid that separated was filtered,
washed with water, dried and recrystallized from ethanol.
Yield 90%; mp 195–197°C. (Lit. 196°C) (Giri and
Singh, 1964). 1H NMR (CDCl3) d; 3.81(3H, s, OCH3), 4.17
(2H, s, CH2), 5.1(2H, s, NH2), 6.86–7.28 (4H, m, Ar–H).
IR tmax cm-1 (KBr): 3257, 3105, 2972, 2927. Anal. Calcd.
for: C10 H11 N3 O S; C, 54.28; H, 5.01; N, 18.99%. Found:
C, 54.26; H, 5.01; N, 18.96%.
All chemicals and reagents were purchased from Sigma-
Aldrich Chemicals Pvt. Ltd India. Melting points were
determined in open capillaries and are uncorrected. The IR
spectra of samples were recorded on Nicolet Impact-FT-IR
spectrophotometer, (Model-410, USA) using KBr pellet
technique. 1H NMR experiments were performed on a
300 MHz Bruker AC-300F spectrometer (Model RX-300,
Switzerland) using TMS as an internal standard in CDCl3.
All chemical shifts were reported as d (ppm) values. All the
newly synthesized compounds were analyzed for C, H and
N, and results were found to be within the range of 0.4%
of the theoretical value. These data were obtained from the
123

Med Chem Res (2012) 21:1544–1549
1547
Synthesis of 5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-amine
(1c)
1574. Anal. Calcd. for: C11 H9 Cl F N3 O S; C, 46.24; H,
3.17; N, 14.71%. Found: C, 46.20; H, 3.15; N, 14.70%.
Compound (1c) is synthesized by employing the same
procedure as for (1b) using 4-fluorophenylacetic acid.
Yield 90%; mp 212–213°C (Lit. 210°C) (Giri and Singh,
1964). 1H NMR(CDCl3) d; 4.17(2H, s, CH2), 5.1(2H,s,
NH2), 6.86–7.28 (4H, m, Ar–H). IR tmax cm-1 (KBr): 3257,
3105, 2972, 2927. Anal. Calcd. for: C9 H8 F N3 S; C, 51.66;
H, 3.85; N, 20.08%. Found: C, 51.65; H, 3.83; N, 20.05%.
Synthesis of (3a–c)
A mixture of 2-chloro-N-[4-(2-chloro-4-fluorophenyl)-1,3-
thiazol-2-yl]acetamide (3.05 g, 10 mmol) (2a) and dieth-
ylamine (1.6 g, 20 mmol) in 1,4-dioxan (40 ml) refluxed in
an oil bath for 4 h. The reaction mixture was cooled,
poured into ice cold water (100 ml). The solid that sepa-
rated was filtered, washed with water, dried and recrys-
tallized from ethanol to obtain brown coloured solid (3a).
Similarly, 3b and 3c were prepared from the corresponding
2-chloro-N-[5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-yl]
acetamide (2b) and 2-chloro-N-[5-(4-fluorobenzyl)-1,3,4-
thiadiazol-2-yl]acetamide (2c).
Synthesis of 2-chloro-N-[substituted thiazol/thiadiazol-
2-yl]acetamides (2a–c)
To a suspension of 4-(2-chloro-4-fluorophenyl)-1,3-thia-
zol-2-amine (2.28 g, 10 mmol) (1a) in glacial acetic acid
(50 ml) was added chloroacetylchloride (1.70 g, 10 mmol)
dropwise with stirring. The reaction mixture was then
heated on steam bath for 3 h, cooled, and poured into ice
water (100 ml). The solid that separated was filtered,
washed with water, dried and recrystallized from ethanol
to get (2a). Similarly 2b and 2c were prepared from
the corresponding 5-(4-methoxybenzyl)-1,3,4-thiadiazol-
2-amine (1b) and 5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-
amine (1c), respectively.
N-[4-(2-chloro-4-fluorophenyl)-thiazol-2-yl]-2-
diethylamino acetamide (3a)
Yield 69%; mp189–190°C. 1H-NMR (CDCl3) d; 10.64
(1H, s, NH), 1.11–1.14 (6H, t, N–CH2––CH3), 2.67–2.69
(4H, t, N–CH2–CH3), 3.29 (2H, s, COCH2), 7.08 (1H,
s,Thiazole-H5), 7.11–7.82(3H, m, Ar–H). IR tmax cm-1
(KBr): 3236, 3171, 2988, 1641, 1571. Anal. Calcd. for: C15
H17 Cl F N3 OS; C, 52.70; H, 5.01; N, 12.29%. Found: C,
52.68; H, 5.00; N, 12.26%.
2-Chloro-N-[4-(2-chloro-4-fluorophenyl)-1,3-thiazol-2-
yl]acetamide (2a)
1
Yield 95%; mp 167–168°C. H-NMR (CDCl3) d; 10.71
(1H, s, NH), 4.21 (2H, s, CH2), 7.09 (1H, s, Thiazole-H5),
7.12–7.81 (3H, m, Ar–H). IR tmax cm-1 (KBr): 3241,
3180, 2996, 1647, 1575. Anal. Calcd. for: C11 H7 Cl2 F N2
O S; C, 43.30; H, 2.31; N, 9.18%. Found: C, 43.28; H,
2.30; N, 9.15%.
2-Diethylamino-N-[5-(4-methoxybenzyl)-[1,3,4]thiadiazol-
2-yl]acetamide (3b)
1
Yield 72%; mp 229–231°C. H-NMR (CDCl3) d; 12.54
(1H, s, NH), 1.10–1.12 (6H, t, N–CH2–CH3), 2.56–
2.60(4H, t, N–CH2–CH3), 4.1 (2H, s, COCH2), 3.83(3H, s,
OCH3), 3.21(2H, s, CH2),6.91–7.28(4H, m, Ar–H). IR
tmax cm-1 (KBr): 3215, 3170, 2988, 2854, 1696, 1572.
Anal. Calcd. for: C16 H22 N4 O2S; C, 57.46; H, 6.63; N,
16.75%. Found: C, 57.45; H, 6.60; N, 16.73%.
2-Chloro-N-[5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-
yl]acetamide (2b)
Yield 95%; mp 219–220°C. 1H-NMR (CDCl3) d; 12.52 (1H,
s, NH), 4.43 (2H, s, COCH2), 4.31 (2H, s, CH2), 3.81 (3H, s,
OCH3), 6.87–7.28 (4H, m, Ar–H). IR tmax cm-1 (KBr):
3207, 3105, 1645, 1575. Anal. Calcd. for: C12 H12 Cl N3 O2
S; C, 48.40; H, 4.06; N, 14.11%. Found: C, 48.38; H, 4.01; N,
14.10%.
2-Diethylamino-N-[5-(4-fluorobenzyl)-[1,3,4]thiadiazol-2-
yl]acetamide (3c)
1
Yield 71%; mp 245–247°C. H-NMR (CDCl3) d; 12.45
2-Chloro-N-[5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-
yl]acetamide (2c)
(1H, s, NH), 1.10–1.12 (6H, t, N–CH2–CH3), 2.56–2.60
(4H, t, N–CH2–CH3), 4.2 (2H, s, COCH2), 3.16(2H, s,
CH2),6.91–7.28(4H, m, Ar–H). IR tmax cm-1 (KBr): 3170,
1
Yield 95%; mp 236°C. H-NMR (CDCl3) d; 12.52 (1H, s,
NH), 4.42 (2H, s, COCH2), 4.36 (2H, s, CH2), 7.02–7.28
3065, 2980, 2864, 1688, 1555. Anal. Calcd. for: C15 H19
F
N4 OS; C, 55.88; H, 5.94; N, 17.38%. Found: C, 55.86; H,
5.92; N, 17.35%.
(4H, m, Ar–H). IR tmax cm-1 (KBr): 3202, 3178, 1648,
123

1548
Med Chem Res (2012) 21:1544–1549
Synthesis of N-[substituted thiazol/thiadiazol-2-yl]-2-
piperidin-1-yl-acetamides (4a–c)
morpholine (1.74 g, 20 mmol) in 1,4-dioxan (40 mL)
refluxed in an oil bath for 4 h. The reaction mixture was
cooled, poured into ice cold water (100 ml).The solid that
separated was filtered, washed with water, dried and re-
crystallized from ethanol to obtain colourless needles (5a).
A similar reaction of compounds 2-chloro-N-[5-(4-methoxy-
benzyl)-1,3,4-thiadiazol-2-yl]acetamide (2b) and 2-chloro-
N-[5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-yl]acetamide (2c)
with morpholine resulted target compounds 5b and 5c,
respectively.
A mixture of 2-chloro-N-[4-(2-chloro-4-fluorophenyl)-1,3-
thiazol-2-yl]acetamide (3.05 g, 10 mmol) (2a) and piperi-
dine (1.7 g, 20 mmol) in 1,4 dioxan (40 ml) was refluxed in
an oil bath for 4 h. The reaction mixture was cooled, poured
into ice cold water (100 ml).The solid that separated was
filtered, washed with water, dried and recrystallized from
ethanol to obtain pale yellow solid (4a). Similarly, 4b and
4c were prepared by employing the same procedure from
the corresponding 2-chloro-N-[5-(4-methoxybenzyl)-1,3,4-
thiadiazol-2-yl]acetamide (2b) and 2-chloro-N-[5-(4-fluo-
robenzyl)-1,3,4-thiadiazol-2-yl] acetamide (2c).
N-[4-(2-chloro-4-fluorophenyl)-thiazol-2-yl]-2-morpholin-
4-yl-acetamide (5a)
1
Yield 78%; mp 212–213°C. H-NMR (CDCl3) d; 10.54
(1H, s, NH), 2.55 (4H, t, Morpholine-H3,5), 3.73 (4H, t,
Morpholine-H2,6), 7.01–7.74 (3H, m, Ar–H). IR tmax cm-1
(KBr): 3235, 3171, 3068, 2993, 1643, 1575. Anal. Calcd.
for : C15H15 Cl F N3O2S; C, 50.63; H, 4.25; N, 11.81%.
Found: C, 50.60; H, 4.22; N, 11.80%.
N-[4-(2-Chloro-4-fluorophenyl)-thiazol-2-yl]-2-piperidin-
1-yl-acetamide (4a)
Yield 65%; mp 201–203°C. 1H-NMR (CDCl3) d; 10.49 (1H,
s, NH), 1.26–1.69 (6H, t, Piperidine-H3,4,5), 2.56 (4H, t,
Piperidine-H2,6), 3.21 (2H, s, COCH2), 7.09 (1H, s, Thia-
zole-H5), 7.12–7.79 (3H, m, Ar–H). IR tmax cm-1 (KBr):
3173, 3069, 2931, 2994, 1643, 1575. Anal. Calcd. for : C16
H17 Cl F N3 O S; C, 54.31; H, 4.84; N, 11.88%. Found: C,
54.30; H, 4.82; N, 11.85%.
N-[5-(4-methoxybenzyl)-[1,3,4]thiadiazol-2-yl]-2-
morpholin-4-yl-acetamide (5b)
1
Yield 80%; mp 259–260°C. H-NMR (CDCl3) d; 12.49
(1H, s, NH), 2.62 (4H, t, Morpholine-H3,5), 3.75 (4H, t,
Morpholine-H2,6), 3.80 (3H, s, OCH3), 4.30 (2H, s,
COCH2), 3.29(2H, s, CH2), 6.88–7.27 (4H, m, Ar–H). IR
tmax cm-1 (KBr): 3154, 2924, 2860, 1697, 1553. Anal.
Calcd. for : C16H20 N4 O3S; C, 55.15; H, 5.79; N, 16.08%.
Found: C, 55.12; H, 5.75; N, 16.06%.
N-[5-(4-Methoxybenzyl)-[1,3,4]thiadiazol-2-yl]-2-
piperidin-1-yl-acetamide (4b)
1
Yield 65%; mp 245–246°C. H-NMR (CDCl3) d; 12.02
(1H, s, NH), 1.52–1.60 (6H, t, Piperidine-H3,4,5), 2.43–2.45
(4H, t, Piperidine-H2,6), 4.30 (2H, s, COCH2), 3.17 (2H, s,
CH2), 3.80(3H, s, OCH3), 6.88–7.27 (4H, m, Ar–H). IR
tmax cm-1 (KBr): 3100, 2920, 2854, 1696, 1558. Anal.
Calcd. for : C17 H22 N4O2S; C, 58.94; H, 6.40; N, 16.17%.
Found: C, 58.91; H, 6.40; N, 16.14%.
N-[5-(4-fluorobenzyl)-[1,3,4]thiadiazol-2-yl]-2-morpholin-
4-yl-acetamide (5c)
1
Yield 80%; mp 281–282°C. H-NMR (CDCl3) d; 12.45
(1H, s, NH), 2.61-2.64 (4H, t, Morpholine-H3,5), 3.77-3.80
(4H, t, Morpholine-H2,6), 4.35 (2H, s, COCH2), 3.28(2H, s,
CH2), 7.01–7.28 (4H, m, Ar–H). IR tmax cm-1 (KBr):
N-[5-(4-fluorobenzyl)-[1,3,4]thiadiazol-2-yl]-2-piperidin-
1-yl-acetamide (4c)
3162, 2949, 2917, 1696, 1565. Anal. Calcd. for : C15 H17
F
1
Yield 69%; mp 269–270°C. H-NMR (CDCl3) d; 12.05
N4 O2 S; C, 53.56; H, 5.09; N, 16.66%. Found: C, 53.55; H,
5.07; N, 16.64%.
(1H, s, NH), 1.54–1.60 (6H, t, Piperidine-H3,4,5), 2.43–2.47
(4H, t, Piperidine-H2,6), 4.26 (2H, s, COCH2), 3.11 (2H, s,
CH2),6.92–7.23 (4H, m, Ar–H). IR tmax cm-1 (KBr): 3151,
2937, 2854, 1694, 1555. Anal. Calcd. for : C16 H19 F N4 O
S; C, 57.47; H, 5.73; N, 16.75%. Found: C, 57.45; H, 5.72;
N, 16.73%.
Pharmacology
Rat sciatic nerve block
Synthesis of N-[substituted thiazol/thiadiazol-2-yl]-2-
morpholin-4-yl-acetamides (5a–c)
Triplicate sets of three groups of three male Wistar rats
(weighing 180–200 g) were used (Caliendol et al., 1995)
for the experiment. Aqueous solution of the test compound
(2%, 0.2 ml) was injected in each rat into the posterior
aspect of the femur head. A complete loss of motor control
A mixture of 2-chloro-N-[4-(2-chloro-4-fluorophenyl)-
1,3-thiazol-2-yl]acetamide (3.05 g, 10 mmol) (2a) and
123

Med Chem Res (2012) 21:1544–1549
1549
References
of the injected limb indicates a positive effect of the drug.
The animals were observed to asses the duration of effect,
from the time of onset of the motor paralysis at 5-min
intervals for the first 30 min, and at 15-min intervals after
that up to the first sign of motor activity.
Bhargava PN, Chaurasia MR (1969) New local anesthetics. Deriv-
atives of 5-diethylaminoacetamido-2-arylimino-3-aryl-4-thiazo-
lidones. J Pharm Sci 58:896–898
Bhargava PN, Singh PR (1960) Synthesis of new local anaesthetics II.
J Indian Chem Soc 37:241–243
Bhargava PN, Prakash S, Singh HD (1978) Synthesis of 2-N,N-
dialkyl(oralkylaryl)aminoacetamido-(substituted)-benzothiazoles
or -thiazoles as local anaesthetics. J Indian Chem Soc 55(7):
726–729
Corneal anaesthesia
Male New Zeland rabbits (weighing 2.5–2.7 kg) were used
for this study. Local surface anaesthesia was evaluated by
determining the number of stimuli to the cornea every
3 min (Caliendol et al., 1995). This was affected rhyth-
mically with a Frey’s horse-hair to produce the blink reflex.
Anaesthetic effect was considered total, if the reflex did not
occur after 100 stimulations. Care was taken at the
beginning of the experiment to ascertain that this reflex was
normal in both eyes of the rabbits used. The aqueous
solutions (2%) of the compounds studied were dropped into
the conjunctival sac so that the space between the eyelids
contained a clearly visible film of solution for the set
time of 3 min. Lidocaine solution (2%) was used for
comparison.
Caliendoa G, Fiorinoa F, Griecoa P, Perissuttia E, Santagadaa V,
Melib R, Mattace G, Angelina Zanescoc R, De Nuccic G (1999)
Preparation and local anaesthetic activity of benzotriazinone and
benzoyltriazole derivatives. Eur J Med Chem 34:1043–1051
Caliendol G, Di Carloz R, Grecol G, Griecol P, Meli R, Novellinol E,
Perissuttil E, Santagada V (1995) Synthesis, local anesthetic
activity and QSAR studies for a set of N-[2-(alkylamino)ethyl]
benzotriazol-x-y1 acetamides. Eur J Med Chem 30:603–608
Catterall W, Mackie K (2001) Local anaesthetics. In: Hardman JG,
Limbird LE, Gilman AG (eds) Goodman and Gilman’s the
pharmacological basis of therapeutics, 10th edn. McGraw-Hill,
New York, pp 687–731
Giri S, Singh H (1964) Thiadiazoles. I. Synthesis of substituted
sulfathiadiazoles and related compounds. J Indian Chem Soc
41:295–298
Lakhan R, Rai BJ (1986) Local anaesthetics. IV. Synthesis and activity
of 2-(N-substituted or N,N disubstituted aminoacetamido)-4- or
-4-5-substituted thiazoles. Farmaco Sci 41(10):788–793
Lofgren N (1948) Studies on local anaesthetics: xylocaine a new
synthetic drug. Hoegsstroms, Stockholm
Mouse tail anaesthesia
Mattocks AM, Hutchinson ON (1948) Local anesthetics; N-dial-
kylaminoalkylimides of naphthalic and diphenylmaleic acids.
J Am Chem Soc 70:3474–3475
Renuka J, Shipra (1997) Synthesis, spectral studies and antimicrobial
activity of some fluorinecontaining 2-amino-4-arylthiazoles.
J Indian Chem Soc 74:54–55
Srivastava PN, Rai SK (1980) Some derivatives of 2-aminothiazole as
potent local anaesthetic. Eur J Med Chem Chim Ther 15:274
Takman BH, Camougis G, Lofgren NM (1969) Studies on local
anaesthetics. Hydroxyalkylamioacylanilines as local anaesthet-
ics. Acta Pharm Suec 6(1):25–32
Male Swiss mice (weighing 18–20 g) were used for this
study. The aqueous solution (0.1 ml) of the test compound
is injected SC about 1 cm from the root of the tail (Cali-
endoa et al., 1999). Fifteen minutes after injection, the pain
reflex of all the injected animals was tested by applying a
small artery clip to the zone where the compound was
injected. The proportion of animals which do not show the
usual pain reflex within 30 s was noted for each dose.
Lidocaine solutions were used for comparison.
123