Design, synthesis, and pharmacological evaluation of some 2-[4-morpholino]-3-aryl-5-substituted thiophenes as novel anti-inflammatory agents: Generation of a novel anti-inflammatory pharmacophore

Article abstract of DOI:10.1016/j.bmc.2004.06.028

We report the synthesis and pharmacological evaluation of some novel 2-morpholino-3-aryl-5-substituted thiophenes, as possible anti-inflammatory leads. The studies culminate in the generation of a novel pharmacophore, which will enable the designing of be

Full text of DOI:10.1016/j.bmc.2004.06.028

Bioorganic & Medicinal Chemistry 12 (2004) 4667–4671
Design, synthesis, and pharmacological evaluation of some
2-[4-morpholino]-3-aryl-5-substituted thiophenes as novel
anti-inflammatory agents: generation of a novel anti-inflammatory
pharmacophore
Ajay D. Pillai,a Parendu D. Rathod,b Franklin P. Xavier,b Kamala K. Vasu,b,
*
Harish Padhc and Vasudevan Sudarsanamb
aDepartment of Pharmaceutical Chemistry, M.S. Ramaiah college of Pharmacy, M.S. Ramaiah Nagar, Mathikere,
Bangalore 560 054, Karnataka, India
bDepartment of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development Centre,
Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India
cDepartment of Biotechnology, B.V. Patel Pharmaceutical Education and Research Development Centre,
Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India
Received 4 June 2004; accepted 22 June 2004
Available online 24 July 2004
Abstract—Compounds incorporating a thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of re-
search interest owing to the therapeutic utility of the template as useful drug molecular scaffolding. Recently we reported the anti-
inflammatory activity profile exhibited by two thiophene analogs, AP84 and AP82 in acute and chronic models of inflammation.
The good activity profile exhibited by AP84, a 3-(substituted aryl)-2-(4-morpholino)-5-heteroaryl substituted analog of thiophene,
in the formalin induced rat paw edema chronic model as compared to a weak activity in acute carrageenin induced rat paw edema,
and the slightly better protection exhibited in the acute model by AP82 (27%), the 5-aroyl analog provided an impetus for a proper
exploration of their structural types. In this paper we report the synthesis and pharmacological evaluation of some novel, 2-(4-mor-
pholino)-3-(substituted aryl)-5-substituted thiophenes, as possible anti-inflammatory leads. The 3-(4-chlorophenyl)-2-(4-morpho-
lino) thiophene analogs AP49, AP158, and AP88 provided a protection of 20%, 23%, and 20%, respectively, when screened for
anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, comparable to that of AP82, at a dose
level of 100mg/kg body weight p.o. compared to ibuprofen as standard. The replacement of the 3-(4-chlorophenyl) moiety with the
3-phenyl moiety gave rise to AP50 (30%), AP159 (38%), AP27 (0%), and AP92 (38%), with three analogs being more active in the
acute model. Alteration of the group para to the phenyl ring at third position, from chloro, to methyl mercapto gave rise to the 3-(4-
methylmercapto-phenyl) analogs AP54 (20%), AP160 (0%), and AP73 (52%), with only one analog appearing to be better than
AP82. These results indicate that 4-methane sulfonyl aroyl group at 5-position and other substituents of different quadrants of Craig
plot on the phenyl moiety at the third position could lead to more potent candidates. However, alteration of aroyl to substituted
pyridyl at 5-position with a phenyl group at the third position as in AP26 gave rise to much better protection (66%) again reinforcing
the importance of the heteroaryl ring at the fifth position and implying its utility in the composition of a novel pharmacophore for
designing better trisubstituted thiophenes as anti-inflammatory agents.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
ditions including osteoarthritis. In an effort to develop
novel drug designing strategies in anti-inflammatory re-
search, we came up with a molecule AP84;1 Figure 1,
which we proposed, could have a possible dual inhibi-
tory action along the inflammatory cascade. Even
though the molecule exhibited weak activity in acute
anti-inflammatory screening, and gave only 17% protec-
tion in carrageenin induced rat paw edema model, in the
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
widely used to treat pain, fever, and inflammatory con-
Keywords: Thiophene; Pharmacophore; Carrageenin; Rat paw edema.
*
Corresponding author. Tel.: +91-079-7439375; fax: +91-079-
7450449; e-mail: perd@wilnetonline.net
0968-0896/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2004.06.028

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A. D. Pillai et al. / Bioorg. Med. Chem. 12 (2004) 4667–4671
Cl
The biological activities of various analogs were AP54
(20%), AP160 (0%), and AP73 (52%).
H
In order to clarify the structural requirement for these 2-
morpholino derivatives, we synthesized some 2-morpho-
lino derivatives with phenyl ring at the third position of
the thiophene with other substituents being the same.
The resulting compounds AP50 (30%), AP159 (38%),
AP27 (0%), and AP92 (38%) were comparable to the
above series or marginally better in eliciting the anti-
inflammatory effect.
Cl
O
N
S
O
H
CH3
N
H3CO
N
AP82
S
AP84
O
H3CO2S
H3C
Figure 1. Trisubstituted thiophene AP82 and AP84 designed and
synthesized as anti-inflammatory agents. AP82 had an aroyl substitu-
tion at the fifth position of the thiophene and AP84 had a pyridyl
substitution at the fifth position.
One plausible reason for the lesser activity shown by
AP27 could be that, it undergoes an aromatic hydroxyl-
ation followed by a glucoronide conjugation to get elim-
inated rapidly compared to its counterparts and also this
is not possible in 3-(4-thiomethyl phenyl) and 3-(4-
chloro phenyl) analogs of thiophene since the para-posi-
tion of the phenyl is blocked.
chronic model of the formalin induced paw edema it
gave protection of 54% on day one and 77% on day five
and had a similar profile to dexamethasone in this model.
On the other hand its counterpart AP82, with an aroyl
substitution at the fifth position of the thiophene gave
better protection (27%) in the acute model but not in
the chronic model. We wanted to probe into this out-
come, as this seemed unusual. Hence, we synthesized a
series of trisubstituted thiophenes with incorporation
of aroyl substitution at the fifth position with an N-(4-
morpholino) group at second position as in AP82, with
substituents on the 3-aryl group of the thiophene. A few
analogs with substituted 2-pyridyl moiety at 5-position
were also made for anti-inflammatory evaluation to as-
sess its utility.
From the SAR studies it appears that the phenyl series
has a marginal edge over all the compounds except
AP27 in exhibiting a better biological profile compared
to AP82. To delineate the importance of the phenyl ring
at the third position and the ketone bridge at the fifth
position toward the biological activity, further studies
were done. The fact that the counter part of AP84 that
is, AP26 was the most active compound in the whole ser-
ies with phenyl substitution at the third position of the
thiophene, give a clue that a ketone bridge might not
be preferred at the fifth position as compared to pyridyl
(heteroaryl moiety). The morpholine at the second posi-
tion, the phenyl ring at the third position and a hetero-
cyclic ring like pyridyl at the fifth position can be
considered as a good pharmacophore for designing bet-
ter anti-inflammatory agents.
In this report, we describe the synthesis of a series of 2-
morpholino thiophene derivatives as possible leads for
anti-inflammatory research. In an attempt to study the
structure–activity relationship of these trisubstituted
thiophenes we could propose a novel pharmacophore
for designing better anti-inflammatory agents laying
down the optimum requirements at the third and fifth
position of the trisubstituted thiophene analogs with a
conformationally restricted morpholine at the second
position, synthesized for eliciting better anti-inflamma-
tory activity.
The fact that AP26 like AP84 neither had the features of
a COX-1 inhibitory (ester/acid as in mefenamic acid)
nor a COX-2 inhibitory pharmacophore of two adjacent
aromatic or heteroaromatic moieties helps in the deline-
ation of a novel structural feature to identify developa-
ble drug like candidates to treat conditions of
inflammations. If this is true, we see a novel class of
compounds, which should act somewhere other than
COX-1 or COX-2 inhibition along the inflammatory
cascade to avoid the serious side effects implicated by
COX-1 and COX-2 inhibitors clinically.
2. Results and discussion
The anti-inflammatory activity exhibited by the three
compounds AP49 (20%), AP158 (23%), and AP88
(20%) was not significantly better than that of AP82
(27%) in the acute anti-inflammatory screening model.
The (4-chlorophenyl) substitution at the third position
of the thiophene was not helping the candidates to im-
prove the pharmacological profile. The third position
of thiophene was substituted with 4-thiomethyl phenyl
group where thiomethyl is not as electron withdrawing
(rp=0.00) as chlorine (rp=0.23). However it can revers-
ibly undergo metabolic oxidation to sulfoxide (rp=0.49)
and subsequently irreversible oxidation to sulfone
(rp=0.72). The only compound, which was superior to
AP82 was AP73, wherein a sulfone was attached to
the benzene ring at the fifth position of the thiophene.
3. Conclusion
A series of 2-morpholino thiophene derivatives were
synthesized, characterized and evaluated for their anti-
inflammatory activity in carrageenin induced rat paw
edema model––an acute in vivo model. The 4-chloro-
phenyl, 4-thiomethyl phenyl, and phenyl substitution
at the third position of the thiophene were evaluated
for their modulation of pharmacological activity. From
the SAR studies it appears that the phenyl series has a
marginal edge over all the compounds. The fact that
the counter part of AP84 that is, AP26 was the most
active compound in the whole series with phenyl substi-

A. D. Pillai et al. / Bioorg. Med. Chem. 12 (2004) 4667–4671
4669
tution at the third position of the thiophene, give a clue
that a ketone bridge might not be preferred at the fifth
position as compared to pyridyl (heteroaryl moiety).
The structure–activity relationship studies explore
morpholine at the second position, the phenyl ring at
the third position, and a heterocyclic ring like pyridyl
at the fifth position as a good pharmacophore for
designing better anti-inflammatory agents. The results
disclose a new class of anti-inflammatory agents de-
signed and synthesized for the first time wherein the util-
ity of a pyridyl function at the fifth position of the
thiophene is reconfirmed. If this were true then it is
worth considering this novel pharmacophore in design-
ing new experimental candidates and to further explore
their full potential particularly in inflammatory diseases.
Synthesis of trisubstituted thiophenes: The synthetic
sequence (Scheme 1) we utilized for preparing thiophene
analogs, were analogs to the method reported in the lit-
erature.3 The reaction was brought about by reacting
equimolar amount of thioacrylic acid morpholide inter-
mediate (III) with a-halo carbonyl compound (HI-HIV)
or halomethylene compound HV to yield trisubstituted
thiophenes (I–XIII) (Table 1).
Carrageenin induced rat paw edema:4 Sprague–Dawley
(male/female) rats weighing 150–250g were used for
the edema test. Animals were divided into six rats per
group. Rats were put on fast for 18h prior to the exper-
iment. The standard drug, ibuprofen (100mg/kg body
weight) and the test drugs (100mg/kg body weight) were
given orally as a suspension, in 0.1% sodium CMC as
vehicle (Table 2). One hour later, 0.1mL of 1% carragee-
nin solution in saline was injected in the sub plantar re-
gion of the right hind paw of each rat. After 3h of the
carrageenin injection, the reduction in the paw volume
compared to vehicle control was measured using plet-
hysmometer. The institutional ethics committee, consti-
tuted by the Ministry of Social Justice and
Empowerment, Government of India, approved the
experimental protocol.
4. Experimental
a-Haloketones (HI-HV) were synthesized using reported
procedure.2 2-Chloromethyl-3,5-dimethyl-4-methoxy-
pyridine (HV), was a gift sample from Dishman Phar-
maceuticals Ltd. Carrageenin was purchased from
Qualigen Mumbai. Ibuprofen was a gift sample from
AVIK Pharmaceuticals Ltd Mumbai.
X
X
X
B
A
S
S
O
CH3
II
N
O
I
N
O
N
X = H,Cl, SCH3
O
III
X
III
+
RCOCH2Br
C
H
O
N
S
X
COMPOUNDS
I-XIII
O
R
CH3
H
H3CO
H3C
CH3
Cl
H3CO
H3C
III
+
C
N
N
S
O
N
Br
Br
Br
RCOCH2Br
SCH3
Cl
SO2CH3
O
O
O
CH3
HIII
HI
HII
Br
H3CO
H3C
Cl
NHCOCH3
AND
N
HV
O
HIV
A = S, Morpholine B = Triethyl ortho formate, Morpholine C = acetonitrile
Scheme 1. Synthesis of trisubstituted thiophenes. The adduct III was reacted with various haloketones of the formula (HI-HIV) and 2-chloromethyl-
3,5-dimethyl-4-methoxy-pyridine (HV) to yield the desired products of the formula (I–XIII).

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A. D. Pillai et al. / Bioorg. Med. Chem. 12 (2004) 4667–4671
Table 1. Structure of trisubstituted thiophenes designed and synthe-
sized
Table 2. A and B represent the paw volume and the % protection given
by the standard and test drugs in carrageenin induced rat paw edema,
an acute in vivo model for screening anti-inflammatory drugs
H
R2
Experimental
candidate
A (B)
R
N
S
O
Control
Ibuprofen
AP49 (I)
2.25 0.08
0.89 0.13 (60)
1.80 0.19 (20)
1.73 0.14 (23)
1.64 0.11 (27)
1.80 0.14 (20)
1.80 0.17 (20)
2.30 0.14 (0)
1.08 0.02 (52)
2.55 0.10 (0)
1.57 0.12 (30)
1.40 0.01 (38)
2.45 0.11 (0)
1.40 0.18 (38)
0.77 0.18 (66)
Experimental
candidate
R
R2
AP158 (II)
AP82 (III)
AP88 (IV)
AP54 (V)
Cl
AP49 (I)
Cl
Cl
Cl
Cl
O
AP160 (VI)
AP73 (VII)
AP75 (VIII)
AP50 (IX)
AP159 (X)
AP27 (XI)
AP92 (XII)
AP26 (XIII)
SCH3
AP158 (II)
AP821 (III)
AP88 (IV)
AP54 (V)
O
O
SO2CH3
NHCOCH3
Cl
O
The test drugs were dosed at 100 mg/kg body weight p.o. The standard
used was ibuprofen, which was dosed at 100 mg/kg body weight.
SCH3
O
O
m/z=418, 1H NMR (CDCl3, d, ppm)=3.04–3.09 (m,
4H), 3.74–3.78 (m, 4H), 7.2–7.7 (m, 9H).
SCH3
AP160 (VI)
AP73 (VII)
SCH3
SCH3
4.1.2. 5-(p-Methyl mercapto benzoyl)-2-(4-morpholino)-3-
p-chloro phenyl-thiophene. AP158 (II). Molecular for-
mula C22H20ClNO2S2, MW 429.5, mp 165–66°C,
Rf =0.79 mobile phase toluene–acetonitrile (7:3), %
yield––99%, IR (KBr, cmÀ1)=1608 (C@O stretching at
SO2CH3
O
OCH3
N
CH3
H3C
AP75 (VIII)
AP50 (IX)
SCH3
1
fifth position), mass-(LC–MS)––M+1 at m/z=430, H
NMR (CDCl3, d, ppm)=2.5 (s, 3H), 3.04–3.07 (d,
4H), 3.74–3.77 (m, 4H), 7.2–7.4 (m, 4H), 7.50–7.55 (m,
3H), 7.77 (d, 2H).
Cl
O
4.1.3. 5-(p-Methyl sulfonyl benzoyl)-2-(4-morpholino)-3-
p-chloro phenyl-thiophene. AP82 (III). Molecular for-
mula C22H20ClNO4S2, MW 461.5, mp 222–23°C,
Rf =0.43 mobile phase toluene–acetonitrile (7:3), %
yield––68%, IR (KBr, cmÀ1)=1600 (C@O stretching of
ketone), 1352 (S(@O) asymmetrical stretching), 1276
(C–N cyclic amine), 1144 (S@(O), symmetrical stretch-
ing), mass-(LC–MS)––M+1 at m/z=463, 1H NMR
(CDCl3, d, ppm)=3.08–3.11 (s, 8H), 3.75–3.79 (s, 3H),
7.2–7.55 (m, 5H), 7.94–8.08 (m, 4H).
SCH3
AP159 (X)
AP27 (XI)
AP92 (XII)
O
O
SO2CH3
NHCOCH3
CH3
O
OCH3
H3C
AP26 (XIII)
4.1.4. 5-(p-Acetyl amino benzoyl)-2-(4-morpholino)-3-p-
chloro phenyl-thiophene. AP88 (IV). Molecular formula
C23H21ClN2O3S, MW 440.5, mp 148–49°C, Rf =0.67
mobile phase toluene–acetonitrile (7:3), % yield––54%,
IR (KBr, cmÀ1)=3230 (aryl NH stretching), 1724
(C@O stretching), 1624 (C@O stretching of amide),
1558 (NH bending of amide), mass-(LC–MS)––M+1
at m/z=441, M+2 at m/z=443, H NMR (CDCl3, d,
ppm)=2.225 (s, 3H), 3.0–3.07 (d, 4H), 3.7–3.78 (d,
4H), 7.2–7.6 (m, 9H), 7.8–7.83 (s, 1H).
N
All the synthesized analogs were characterized by IR, 1H NMR, and
mass spectra.
1
4.1. Physical properties of novel synthesized trisubstituted
thiophenes (I–XIII)
4.1.1. 5-(p-Chloro benzoyl)-2-(4-morpholino)-3-p-chloro
phenyl-thiophene. AP49 (I). Molecular formula
C21H17Cl2NO2S, MW 417, mp 202–3°C, Rf =0.76 mo-
bile phase toluene–acetonitrile (7:3), % yield––66, IR
(KBr, cmÀ1)=1632 (C@O stretching at fifth position),
1312 (C–N cyclic amine), mass-(LC–MS)––M+1 at
4.1.5. 5-(p-Chloro benzoyl)-2-(4-morpholino)-3-p-methyl-
thio phenyl-thiophene. AP54 (V). Molecular formula
C22H20ClNO2S, MW 429, mp 153°C, Rf =0.54 mobile
phase toluene–acetonitrile (7:3), % yield––62.5, IR
(KBr, cmÀ1)=1632 (C@O stretching at fifth position),

A. D. Pillai et al. / Bioorg. Med. Chem. 12 (2004) 4667–4671
4671
mass-(LC–MS)––M+1 at m/z=430, M+2 at m/z=432,
1H NMR (CDCl3, d, ppm)=2.5 (s, 3H), 3.06–3.10 (m,
4H), 3.74–3.78 (m, 4H), 7.2 (m, 9H).
ppm)=2.5 (s, 3H), 3.04–3.09 (m, 4H), 3.7–3.77 (m,
4H), 7.26–7.79 (m, 10H).
4.1.11. 5-(p-Methyl sulfonyl benzoyl)-2-(4-morpholino)-3-
phenyl-thiophene. AP27 (XI). Molecular formula
C22H21NO4S2, MW 427.6, mp 220–22°C, Rf =0.43 mo-
bile phase toluene–acetonitrile (7:3), % yield––85, IR
(KBr, cmÀ1)=1620 (C@O stretching of ketone), 1352
(S(@O) asymmetrical stretching), 1300 (C–N cyclic
amine), 1168 (S@(O), symmetrical stretching), mass-
(LC–MS)––M+1 at m/z=428, 1H NMR (CDCl3, d,
ppm)=3.1–3.13 (br s, 3H, morpholine and 3H SO2CH3),
3.27–3.29 (br s, 1H, morpholine) 3.75–3.78 (br s, 3H),
4.02–4.05 (s, 1H), 7.2–7.55 (m, 6H), 7.94–7.97 (d, 2H),
8.05–8.08 (d, 2H).
4.1.6. 5-(p-Methyl mercapto benzoyl)-2-(4-morpholino)-3-
p-methylthio phenyl-thiophene. AP160 (VI). Molecular
formula C22H23NO2S3, MW 430, mp 56–57°C,
Rf =0.64 mobile phase toluene–acetonitrile (7:3), %
yield––29, IR (KBr, cmÀ1)=1604 (C@O stretching at
1
fifth position), mass-(LC–MS)––M+1 at m/z=431, H
NMR (CDCl3, d, ppm)=2.50–2.53 (br s, 6H), 3.05–
3.09 (m, 4H), 3.74–3.78 (m, 4H), 7.23–7.73 (m, 7H),
7.77 (d, 2H).
4.1.7. 5-(p-Methyl sulfonyl benzoyl)-2-(4-morpholino)-3-
p-methylthio phenyl-thiophene. AP73 (VII). Molecular
formula C23H23NO4S3, MW 473, mp 210–11°C,
Rf =0.6 mobile phase toluene: methanol (7:3), %
yield––78, IR (KBr, cmÀ1)=1608 (C@O stretching of
ketone), 1304 (S(@O) asymmetrical stretching), 1156
(S@(O), symmetrical stretching), mass-(LC–MS)––
4.1.12. 5-(p-Acetyl amino benzoyl)-2-(4-morpholino)-3-
phenyl-thiophene. AP92 (XII). Molecular formula
C23H22N2O3S, MW 406, mp 215–16 °C, Rf =0.46 mobile
phase toluene–acetonitrile (7:3), % yield––90, IR (KBr,
cmÀ1)=3250 (aryl NH stretching), 1712 (C@O stretch-
ing of ketone), 1612 (C@O stretching of amide), 1540
(NH bending of amide), mass-(LC–MS)––M+1 at m/
1
M+1 at m/z=474, H NMR (CDCl3, d, ppm)=2.5 (s,
3H), 3.1–3.2 (m, 7H), 3.74–3.79 (m, 4H), 7.24–7.28 (m,
9H).
1
z=407, H NMR (CDCl3, d, ppm)=2.8 (s, 3H), 3.73–
3.8 (m, 4H), 3.9–4.0 (m, 4H), 7.2–7.8 (m, 10H), 9.7 (s,
1H).
4.1.8.
5-(3,5-Dimethyl-4-methoxy-2-pyridyl)-2-(4-mor-
pholino)-3-p-thiomethyl phenyl-thiophene. AP75 (VIII).
Molecular formula C23H26N2O2S2, MW 426, mp 140–
41°C, Rf =0.7 mobile phase toluene–acetonitrile (6:4),
% yield––30, IR (KBr, cmÀ1)=2976 (aliphatic CH
stretching), 2850 (aliphatic CH stretching), 1644 (C@C
aromatic stretching), 1604 (C@C aromatic stretching),
4.1.13. 5-(3,5-Dimethyl-4-methoxy-2-pyridyl)-2-(4-mor-
pholino)-3-phenyl-thiophene. AP26 (XIII). Molecular
formula C22H24N2O2S, 42%, MW 380.6, mp 136–
37°C, Rf =0.2 mobile phase benzene–methanol (7:3), %
yield––42, IR (KBr, cmÀ1)=2940 (aliphatic CH stretch-
ing), 2850, 1580, 1476, 1432, 1224, 1100, 1000, 988,
mass-(LC–MS)––M+1 at m/z=381, H NMR (CDCl3,
d, ppm)=2.25 (s, 3H), 2.492 (s, 3H), 2.9–3.02 (br s,
3H), 3.75–3.79 (m, 8H), 7.25–7.75 (m, 5H), 8.2 (s, 1H).
1
mass-(LC–MS)––M+1 at m/z=427, H NMR (CDCl3,
1
d, ppm)=2.23 (s, 3H), 2.25 (s, 3H), 2.5 (s, 3H), 3.0 (s,
3H), 3.05–3.08 (d, 4H, morpholine), 3.75–3.78 (d, 4H,
morpholine), 7.2–7.8 (m, 6H).
4.1.9. 5-(p-Chloro benzoyl)-2-(4-morpholino)-3-phenyl-
formula
Acknowledgements
thiophene.
AP50
(IX).
Molecular
C21H18ClNO2S, MW 383, 152–54°C, Rf =0.8 mobile
phase toluene–acetonitrile (7:3), % yield––56, IR (KBr,
cmÀ1)=1624 (C@O stretching at fifth position), mass-
(LC–MS)––M+1 at m/z=384, M+2=386, 1H NMR
(CDCl3, d, ppm)=3.0–3.1 (m, 4H), 3.73–3.77 (m, 4H),
7.24–7.78 (m, 10H).
The IC grant provided by the industrial commission of
Gujarat for carrying out this work is acknowledged.
References and notes
1. Pillai, A. D.; Rathod, P. D.; Franklin, P. X.; Patel, M.;
Manish, N.; Vasu, K. K.; Padh, H.; Sudarsanam, V. J.
Biochem. Biophys. Res. Commun. 2003, 301, 183–186.
2. Pillai, A. D. Ph.D. Dissertation, Bhavngar University,
2002.
3. Rolfs, A.; Liebscher, J. Org. Synth. 1973, 74, 257–263.
4. Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc. Soc. Exp.
Biol. Med. 1962, 111, 544–547.
4.1.10. 5-(p-Methyl mercapto benzoyl)-2-(4-morpholino)-
3-phenyl-thiophene. AP159 (X). Molecular formula
C22H21NO2S2, MW 395, mp 131–32°C, Rf =0.86 mobile
phase toluene–acetonitrile (7:3), % yield––46, IR (KBr,
cmÀ1)=1604 (C@O stretching at fifth position),
1288 (C–N cyclic amine), mass-(LC–MS)––M+1 at
m/z=396, M+Na=417.9, 1H NMR (CDCl3, d,