Synthesis, characterization, and antimicrobial evaluation of novel 4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5] thieno[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.190

(Chemical Equation Presented) A series of novel 7-alkyl/aryl sulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno[2, 3-d] pyrimidine 6 were synthesized for evaluation of their antibacterial and antifungal activity. The structures were determi

Full text of DOI:10.1002/jhet.190

September 2009
Synthesis, Characterization, and Antimicrobial Evaluation of
Novel 4-Pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]
Thieno[2,3-d]pyrimidine Derivatives
975
Kokila Parmar,a* Bharat Suthar,a Arun Suthar,a and Abhay Mahetab
aDepartment of Chemistry, Hemchandracharya North Gujarat University, Patan,
Gujarat 384 265, India
bEnum Nostrum Remedis, Andheri, Mumbai, Maharashtra 400059, India
*E-mail: drkaparmar@gmail.com
Received January 31, 2009
DOI 10.1002/jhet.190
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of novel 7-alkyl/aryl sulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]thieno[2,3-d]
pyrimidine 6 were synthesized for evaluation of their antibacterial and antifungal activity. The structures
were determined by IR, NMR, mass spectroscopy, and elemental analysis. They were screened for
activities against bacterial and fungal strains.
J. Heterocyclic Chem., 46, 975 (2009).
INTRODUCTION
bacterial [15], antiviral [16], anticancer [17–19], analge-
sic [20], and antimalarial [21] activities. Though many
synthetic strategies have been reported for the prepara-
tion of thienopyrimidine derivatives, most of them
include use of expensive, commercially nonavailable or
hazardous reagents, drastic reaction conditions, longer
reaction time and difficult work-up [22–27]. In the
view of biological importance of thienopyrimidine, we
aimed the synthesis of a series of novel 7-alkyl/aryl sul-
fonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]thieno
[2,3-d]pyrimidine 6.
Fused pyrimidines continue to attract considerable
attention because of their great practical usefulness, pri-
marily, due to a very wide spectrum of biological activ-
ities. This is evident, in particular, from publications of
regular reviews on the chemistry of systems where the
pyrimidine ring is fused to various heterocycles, such
as, purines [1], pteridines [2], quinazolines [3], pyrido-
pyrimidines [4,5], triazolopyrimidines [6], pyrazolopyri-
midines [7], pyrimidoazepines [8], furopyrimidines, and
pyrrolopyrimidines. Thienopyrimidines occupy a special
position among these compounds. Along with some
other pyrimidine systems containing an annulated five-
membered heteroaromatic ring, thienopyrimidines are
structural analogs of biogenic purines and can be con-
sidered as potential nucleic acid antimetabolites. Earlier,
various aspects of the chemistry and biology of isomeric
thienopyrimidines have been reviewed [9,10]. The
chemistry of pyrimidines and its derivatives has been
studied over a century due to their diverse biological
activities [11–14]. Thienopyrimidine possess various
physiological and biological properties, and thus, find
important use in medicine. According to recent literature
survey, thienopyrimidine have been found to have anti-
RESULTS AND DISCUSSION
Chemistry. As shown in synthetic Scheme 1, the
synthetic route involves the Gewald reaction [28] of
boc-piperidone 1 with malononitrile and sulfur in pres-
ence of morpholine in refluxing ethanol to obtain 2-
amino thiophene derivative 2. The formation of 2-amino
1
thiophene 2 was evident from the H NMR spectra and
mass spectrometry.
The cyclization of 2-amino thiophene
2 with
triethyl orthoformate and ammonium acetate at 120ꢀC
led to formation of thienopyrimidine derivative 3. In
C
V
2009 HeteroCorporation

976
K. Parmar, B. Suthar, A. Suthar, and A. Maheta
Vol 46
Scheme 1
1
the 1H NMR spectra of 3, one aromatic proton reso-
nance of pyrimidine ring was observed at 8.85 ddas a
singlet, in addition molecular ion peak (Mþ, 90%) in
mass spectrum was also observed. The compound
3 was further reacted with 2,5-dimethoxy-tetrahydrofu-
ran in refluxing acetic acid furnished pyrrole deriva-
tive 4. The identity of pyrrole 4 was established by
mass spectrometry and 1H NMR spectra, the aromatic
protons resonance of pyrrole ring were observed at
6.32 d, J ¼ 2.1 and 7.34 d, J ¼ 2.0 as two doublet.
The hydrolysis of carbamate group by TFA furnished
secondary amine derivative 5, which was supported
by molecular ion peak in mass spectrum and 1H
NMR spectra, where a singlet at 1.38 d for nine pro-
tons of boc group was not present. The target com-
The H NMR spectral data of compound 6a revealed
a singlet of CH3SO2 group at 2.97 d, a singlet of pyrim-
idine ring at 8.95 d and two doublet of pyrrole ring at
6.36 d, J ¼ 2.0 Hz and 7.35 d,J ¼ 2.0 Hz. The IR spec-
tra of 6a revealed ASO2 absorptions at 1334 cmꢁ1 and
1159 cmꢁ1. In addition, the EI-MS spectra of 6a showed
a molecular ion peak (Mþ, 90%).
In conclusion, we have developed a facile and efficient
synthetic method for the preparation of novel 7-alkyl/aryl
sulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]
thieno[2,3-d]pyrimidine 6.
Biological activities.
Antibacterial and antifungal activities. The newly
synthesized derivatives were evaluated for their in vitro
antibacterial activity against Gram-positive Staphylococ-
cus aureus and Streptococcus pyogenes, Gram-negative
Escherichia coli and Pseudomonas aeruginosa, and anti-
fungal activity against Candida albicans and Aspergillus
niger by micro broth dilution methods [29–31]. The
standard strains used for screening antibacterial and anti-
fungal activities were procured from Institute of Micro-
bial Technology (IMTECH), Chandigarh, India. The MIC
values are given in Table 2. The standard drugs used for
antibacterial activity were ampicillin and ciprofloxacin,
pounds
7-alkyl/aryl
sulfonyl-4-pyrrol-1-yl-5,6,7,8-
tetrahydro-pyrido[40,30:4,5]thieno[2,3-d]pyrimidine 6a–j
were obtained with excellent yield, by reacting sec-
ondary amine 5 with various aryl or alkyl sulfonyl
chloride in presence of TEA as base.
The structure of all newly synthesized compounds
6a–j were established on the basis of elemental analysis
1
and spectral (IR, H NMR, and mass) data. The physical
characterization data are listed in Table 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis, Characterization, and Antimicrobial Evaluation of Novel
4-Pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5] Thieno[2,3-d]pyrimidine Derivatives
977
Table 1
Physical characterization data.
Analysis (%)
Calcd./found
Physical
state
Yield
(%)
Molecular
formula/M.W.
Compound
R/Ar
Time (h)
3
Mp (ꢀC)
112–115
C
H N
6a
6b
6c
6d
6e
6f
Me
Et
White crystals
93
90
89
91
93
86
91
89
85
88
C14H14N4O2S2
334
50.28
50.14
51.71
51.54
53.02
53.23
53.02
53.23
54.23
54.11
57.56
57.41
58.52
58.61
55.06
55.17
56.32
56.47
51.69
51.55
4.22
4.31
4.63
4.27
5.01
4.86
5.01
5.12
5.35
5.43
4.07
4.22
4.42
4.30
3.65
3.49
4.25
4.11
3.42
3.23
16.75
16.68
16.08
16.21
15.46
15.51
15.46
16.31
14.88
14.72
14.13
14.01
13.65
13.71
13.52
13.64
13.14
13.34
15.86
15.98
White crystals
4
5
4
5
4
5
3
4
3
74–75
77–79
C
C
C
15H16N4O2S2
348
iso-Pr
Off white crystals
White crystals
16H18N4O2S2
362
n-Pr
91–93
16H18N4O2S2
362
n-Bu
Off white crystals
White crystals
113–115
194–196
185–187
269–271
139–141
131–133
C17H20N4O2S2
376
C6H5
C19H16N4O2S2
396
C20H18N4O2S2
410
C19H15FN4O2S2
414
C20H18N4O3S2
426
6g
6h
6i
p-CH3C6H4
p-F-C6H4
p-CH3O-C6H4
p-NO2-C6H4
Pale yellow crystals
Pale yellow crystals
Off white crystals
Yellow crystals
6j
C19H15N5O4S2
441
and nystatin for antifungal activity. Mueller Hinton Broth
was used as nutrient medium for bacteria and Sabouraud
Dextrose Broth for fungal to grow. Inoculums size for
test strain was adjusted to 108 CFU/mL by comparing the
turbidity. The serial dilutions were prepared in primary
and secondary screening. The target compounds and
standard drugs were dissolved in DMSO-water at a con-
centration of 2.0 mg/mL. In primary screening, 500 lg/
mL, 250 lg/mL, and 125 lg/mL concentrations of the
synthesized drugs were taken. Data were not taken for
the initial solution because of the high DMSO concentra-
tion (10%). The actively synthesized drugs found in this
primary screening were further tested in a second set of
dilution against all microorganisms. In secondary screen-
ing, the drugs found active in primary screening were
similarly diluted to obtain 100 lg/mL, 50 lg/mL, 25 lg/
mL, 12.5 lg/mL, and 6.250 lg/mL concentrations. The
inoculated wells were incubated overnight at 37ꢀC in a
humid atmosphere overnight. The highest dilution show-
ing at least 99% inhibition zone is taken as MIC.
The MIC values revealed that some of the newly syn-
thesized compounds showed moderate to good
Table 2
Antibacterial and antifungal activity of compound 6a–j.
Antibacterial
MIC (lg/mL)
Antifungal
MIC (lg/mL)
E. coli
MTCC 443
P. aeruginosa
MTCC 1688
S. aureus
MTCC 96
S. pyogenes
MTCC 442
C. albicans
MTCC 227
A. niger
MTCC 282
Compounds
Ampicillin
Ciprofloxacin
100
25
100
25
250
50
100
50
–
–
–
–
Nystatin
6a
6b
6c
6d
6e
6f
6g
–
–
–
–
100
100
500
1000
1000
1000
500
1000
500
1000
200
100
500
62.5
125
200
25
62.5
250
200
250
500
500
250
125
100
62.5
62.5
25
125
50
62.5
250
125
100
250
500
62.5
500
250
100
500
250
500
500
500
250
500
500
1000
500
50
62.5
100
100
200
62.5
>1000
1000
1000
1000
500
6h
6i
6j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

978
K. Parmar, B. Suthar, A. Suthar, and A. Maheta
Vol 46
evaporated to dryness. The residue was purified on a silica gel
column, packed in hexane. Elution of the column with hexane:
ethyl acetate (80:20 v/v) gave the pure compound 4 as off
white solid, 4.88 g (56%), 1H NMR (DMSO-d6): d 1.38 (s,
9H), 2.61 (t, 2H, J ¼ 5.6 Hz), 2.98 (t, 2H, 5.6 Hz), 4.19 (s,
2H), 6.32 (d, 2H, J ¼ 2.1 Hz), 7.34 (d, 2H, J ¼ 2.0 Hz), 8.86
(s, 2H); ms: m/z 357 (M þ 1). Anal. Calcd. for C18H20N4O2S:
C, 60.65; H, 5.66; N, 15.72. Found: C, 60.68; H, 5.63; N,
15.69.
inhibition. Compounds 6a, 6d, and 6j exhibited good ac-
tivity against all the four bacterial strains. Compounds
6d, 6e, 6h, and 6f showed good activity against E .coli
and S. aureus bacterial strains. The MIC values of anti-
fungal activity revealed that compound 6a exhibited
good activity against C. albicans fungal strain. Rest of
all compounds did not exhibit comparable activity
against both the fungal strains.
4-Pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]thieno[2,3-d]
pyrimidine (5). A solution of compound 4 (4.8 g, 0.013 mol)
and TFA (3.2 mL, 0.040 mol) in DCM (20 mL) was stirred at
10ꢀC for 1.5 h. Reaction mixture was charged into saturated
NaHCO3 (50 mL) and DCM layer was separated, aqueous
layer was washed with DCM (100 mL). Combined DCM layer
was washed with water (2 ꢂ 50 mL), dried on anhydrous so-
dium sulfate and evaporated to dryness gave compound 5 as
EXPERIMENTAL
Melting points were determined with Buchi B-545 melting
point apparatus and are uncorrected. IR spectra were recorded
1
on a PerkinElmer PE-1600 FTIR spectrometer in KBr disk. H
NMR spectra were recorded on a Varian 400 spectrometer in
DMSO-d6 as a solvent and TMS as an internal standard. Peak
values are shown in d ppm. EI-MS spectra were measured on
a Waters Mass Spectrometer. All of the solvents and materials
were reagent grade and purified as required.
1
off white solid, 2.05 g (59%), H NMR (DMSO-d6): d 2.65 (t,
2H, J ¼ 5.7 Hz), 3.01 (t, 2H, J ¼ 5.8 Hz), 4.19 (s, 2H), 5.56–
5.58 (m, 1H), 6.33 (d, 2H, J ¼ 2.0 Hz), 7.36 (d, 2H, J ¼ 2.1
Hz), 8.89 (s, 2H); ms: m/z 257 (M þ 1). Anal. Calcd. for
C13H12N4S: C, 60.92; H, 4.72; N, 21.86. Found: C, 60.90; H,
4.75; N, 21.83.
2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyridine-
6-carboxylic acid tert-butyl ester (2). To a stirred solution
of (10.0 g, 0.050 mol) of 1-Boc-4-piperidone (1), malononitrile
(3.97 g, 0.060 mol) and sulfur (1.92 g, 0.060 mol) in ethanol
(70 mL), morpholine (5.71 mL, 0.065 mol) was added over
period of 15 min at room temperature. The reaction mixture
was heated at 82ꢀC with stirring for 1 h and cooled at room
temperature. Water (200 mL) was charged to a reaction mix-
ture and stirred at room temperature for 30 min. Product was
separated by filtration and washed with water (50 mL), hexane
(50 mL), and dried. Recrystallization from ethanol gave com-
pound 2 as pale yellow solid, 11.2 g (80%), mp 193–195ꢀC;
1H NMR (DMSO-d6) d 1.39 (s, 9H), 2.62 (t, 2H, J ¼ 5.6 Hz),
3.02 (t, 2H, J ¼ 5.7 Hz), 4.21 (s, 2H), 5.84 (bs, 2H); ms: m/z
280 (M þ 1). Anal. Calcd. for C13H17N3O2S: C, 55.89; H,
6.13; N, 15.04. Found: C, 55.92; H, 6.10; N, 15.06.
4-Amino-5,8-dihydro-6H-pyrido[40,30:4,5]thieno[2,3-d]py-
rimidine-7-carboxylic acid tert-butyl ester (3). A solution
of compound 2 (11.0 g, 0.039 mol), ammonium acetate (9.1 g,
0.118 mol) in triethyl orthoformate (50 mL) was heated at
120ꢀC with stirring for 6 h and cooled at room temperature.
Water (150 mL) was added to reaction mixture and stirred at
room temperature for 15 min. Solid product was filtered,
washed with water (50 mL), hexane (50 mL), and dried. Solid
was recrystallized from ethanol gave compound 3 as off white
General procedure for preparation of 7-alkyl/aryl sulf
onyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido[40,30:4,5]thieno
[2,3-d]pyrimidine (6). All of these reactions were carried
out under a nitrogen atmosphere. To a stirred and cooled
(5ꢀC) solution of Compound 5 (0.781 mmol), dimethyl amino
pyridine (0.0781 mmol) and triethylamine (1.56 mmol) in dry
THF (15 mL), alkyl/aryl sulfonyl chloride (0.859 mmol) was
added and the reaction mixture was allowed to warm at
room temperature and stirred at room temperature for 3–5 h.
Reaction mixture was evaporated under vacuum gave an oily
residue. The residue was dissolved in ethyl acetate (50 mL)
and washed with 5% aqueous HCl (50 mL), saturated aque-
ous NaHCO3 (50 mL), and water (50 mL). Ethyl acetate
layer was dried and evaporated under vacuum gave solid res-
idue which was washed with hexane (10 mL) and dried,
gave 6a–j. The yield, reaction time, and physical properties
are reported in Table 1.
7-Methanesulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido
[40,30:4,5]thieno[2,3-d]pyrimidine (6a). IR: ASO2 1334,
1159 cmꢁ1
;
1H NMR: d 2.64 (t, 2H, J ¼ 5.4 Hz), 2.97 (s,
3H), 2.98 (t, 2H, J ¼ 6.0 Hz), 4.66 (s, 2H), 6.36 (d, 2H, J ¼
2.0 Hz), 7.35 (d, 2H, J ¼ 2.0 Hz), 8.95 (s, 1H); ms: m/z 335
(Mþ).
7-Ethanesulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido
[40,30:4,5]thieno[2,3-d]pyrimidine (6b). IR: ASO2 1336, 1163
1
solid, 7.6 g (63%), H NMR (DMSO-d6): d 1.40 (s, 9H), 2.64
1
cmꢁ1; H NMR: d 1.31 (t, 3H, J ¼ 6.5), 2.61 (t, 2H, J ¼ 6.0
(t, 2H, J ¼ 5.7 Hz), 2.99 (t, 2H, J ¼ 5.8 Hz), 4.24 (s, 2H),
5.75 (bs, 2H), 8.85 (s, 1H); ms: m/z 307 (M þ 1). Anal. Calcd.
for C14H18N4O2S: C, 54.88; H, 5.92; N, 18.29. Found: C,
54.91; H, 5.89; N, 18.32.
Hz), 3.01 (t, 2H, J ¼ 6.2 Hz), 3.01 (q, 2H, J ¼ 6.0 Hz), 4.63
(s, 2H), 6.32 (d, 2H, J ¼ 1.9 Hz), 7.32 (d, 2H, J ¼ 2.0 Hz),
8.89 (s, 1H); ms: m/z 349 (Mþ).
4-Pyrrol-1-yl-5,8-dihydro-6H-pyrido[40,30:4,5]thieno[2,3-d]
pyrimidine-7-carboxylic acid tert-butyl ester (4). A solution
of compound 3 (7.5 g, 0.025 mol), 2,5-dimethoxy-tetrahydro-
furan (3.5 mL, 0.027 mol) in acetic acid (50 mL) was heated
at 100ꢀC with stirring for 3 h and cooled at room temperature.
Reaction mixture was charged in ice water (100 mL) and
stirred for 15 min. Product was extracted with ethyl acetate
(2 ꢂ 100 mL), combined ethyl acetate layer was washed with
water (2 ꢂ 50 mL), dried on anhydrous sodium sulfate and
7-(Propane-2-sulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyri-
do[40,30:4,5]thieno[2,3-d]pyrimidine (6c). IR: ASO2 1332,
1
1160 cmꢁ1; H NMR: d 1.13 (d, 6H, J ¼ 6.4 Hz), 2.63 (t, 2H,
J ¼ 6.1 Hz), 2.99 (t, 2H, J ¼ 5.9 Hz), 3.32 (m, 1H, J ¼ 6.1
Hz), 4.67 (s, 2H), 6.32 (d, 2H, J ¼ 2.0 Hz), 7.34 (d, 2H, J ¼
2.0 Hz), 8.91 (s, H); ms: m/z 363 (Mþ).
7-(Propane-1-sulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyri-
do[40,30:4,5]thieno[2,3-d]pyrimidine (6d). IR: ASO2 1330,
1152 cmꢁ1; 1H NMR: d 1.01 (t, 3H, J ¼ 6.3 Hz), 1.93 (m, 2H, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis, Characterization, and Antimicrobial Evaluation of Novel
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979
[6] Hermecz, I. Adv Heterocycl Chem 1995, 63, 103.
¼ 5.7 Hz), 2.67 (t, 2H, J ¼ 6.1 Hz), 2.92 (t, 2H, J ¼ 6.1 Hz),
3.10 (t, 2H, J ¼ 6.1 Hz), 4.68 (s, 2H), 6.38 (d, 2H, J ¼ 2.1 Hz),
7.37 (d, 2H, J ¼ 2.1 Hz), 8.90 (s, 1H); ms: m/z 363 (Mþ).
7-(Butane-1-sulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido
[40,30:4,5]thieno[2,3-d]pyrimidine (6e). IR: ASO2 1334, 1159
[7] Hermecz, I. Adv Heterocycl Chem 1999, 73, 178.
[8] Mohammed, A. E.; Shaban, E. A.; Morgaan, A. E. Adv
Heterocycl Chem 2000, 77, 345.
[9] Elnagdi, M. H.; Elgemeie, G. H.; Elmoghayar, M. R. Adv
Heterocycl Chem 1987, 41, 319.
1
cmꢁ1; H NMR: d 0.97 (t, 3H, J ¼ 6.2 Hz), 1.45 (m, 2H, J ¼
[10] Hermecz, I. Adv Heterocycl Chem 1987, 42, 83.
[11] Varvounis, G.; Giannopoulos, T. Adv Heterocycl Chem
1996, 66, 193.
5.7 Hz), 2.13 (q, 2H, J ¼ 6.0 Hz), 2.64 (t, 2H, J ¼ 5.8 Hz),
2.98 (t, 2H, J ¼ 6.0 Hz), 3.55 (t, 2H, J ¼ 6.1 Hz), 4.66 (s,
2H), 6.35 (d, 2H, J ¼ 2.1 Hz), 7.36 (d, 2H, J ¼ 2.0 Hz), 8.95
(s, 1H); ms: m/z 377 (Mþ).
[12] Litvinov, V. P. Russ Chem Bull 2004, 53, 487.
[13] Waterson, A. G.; Petrova, K. G.; Hornbergera, K. R.; Hub-
barda, R. D.; Sammonda, D. M.; Smitha, S. C.; Dicksona, H. D. Bio-
org Med Chem Lett 2009, 19, 1332.
7-Benzenesulfonyl-4-pyrrol-1-yl-5,6,7,8-tetrahydro-pyrido
[40,30:4,5]thieno[2,3-d]pyrimidine (6f). IR: ASO2 1342, 1168
1
cmꢁ1; H NMR: d 2.50 (t, 2H, J ¼ 5.6 Hz), 3.29 (t, 2H, J ¼
[14] Tu, S.; Zhang, J.; Jia, R.; Jiang, B.; Zhang, Y.; Jiang, H.
Org Biomol Chem 2007, 5, 1450.
5.1 Hz), 4.55 (s, 2H), 6.33 (d, 2H, J ¼ 2.1 Hz), 7.20 (d, 2H, J
¼ 2.1 Hz), 7.60–7.71 (m, 3H), 7.83–7.85 (m, 2H), 8.92 (s,
1H); ms: m/z 397 (Mþ).
[15] Hafez, H. N.; El-Gazzara, A. B. A. Bioorg Med Chem Lett
2008, 18, 5222.
[16] Alagarsamy, V.; Meena, S.; Ramseshu, K. V.; Solomon, V.
R.; Thirumurugan, K.; Dhanabal, K.; Murugan, M. Eur J Med Chem
2006, 41, 1293.
4-Pyrrol-1-yl-7-(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-pyrido
[40,30:4,5]thieno[2,3-d]pyrimidine (6g). IR: ASO2 1345, 1171
1
cmꢁ1; H NMR: d 2.35 (s, 3H), 2.60 (t, 2H, J ¼ 5.4 Hz), 3.33
[17] Chambharea, R. V.; Khadseb, B. G.; Bobdeb, A. S.; Bahe-
kar, R. H. Eur J Med Chem 2003, 38, 89.
(t, 2H, J ¼ 5.3 Hz), 4.61 (s, 2H), 6.36 (d, 2H, J ¼ 2.0 Hz),
7.25 (d, 2H, J ¼ 2.0 Hz), 7.35 (d, 2H, J ¼ 7.5 Hz), 7.87 (d,
2H, J ¼ 7.6 Hz), 8.89 (s, 1H); ms: m/z 411 (Mþ).
[18] Rashad, A. E.; Ali, M. A.; Nucleosides Nucleotides Nucleic
Acids 2006, 25, 17.
7-(4-Fluoro-benzenesulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetrahydro
-pyrido[40,30:4,5]thieno[2,3-d]pyrimidine (6h). IR: ASO2 1341,
[19] Kidwai, M.; Venkataramanan, R.; Garg, R. K.; Bhushan, K.
R. J Chem Res 2000, 12, 586.
1
1161 cmꢁ1; H NMR: d 2.62 (t, 2H, J ¼ 5.4 Hz), 3.37 (t, 2H,
[20] Dai, Y.; Guo, Y.; Frey, R. R.; Ji, Z.; Curtin, M. L.; Ahmed,
A. A.; Albert, D. H.; Arnold, L.; Arries, S. S.; Barlozzari, T.; Bauch,
J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Guo,
J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Pease, L. J.;
Stewart, K. D.; Stoll, V. S.; Tapang, P.; Wishart, N.; Davidsen, S. K.;
Michaelides, M. R. J Med Chem 2005, 48, 6066.
J ¼ 5.3 Hz), 4.64 (s, 2H), 6.33 (d, 2H, J ¼ 2.0 Hz), 7.31 (d,
2H, J ¼ 2.0 Hz), 7.25 (d, 2H, J ¼ 7.7 Hz), 7.82 (d, 2H, J ¼
7.8 Hz), 8.91 (s, 1H); ms: m/z 415 (Mþ).
7-(4-Methoxy-benzenesulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetra-
hydro-pyrido[40,30:4,5]thieno[2,3-d]pyrimidine (6i). IR: ASO2
1
1352, 1167 cmꢁ1; H NMR: d 2.63 (t, 2H, J ¼ 5.2 Hz), 3.40 (t,
[21] Schroeder, M. C.; Hamby, J. M.; Connolly, C. J.; Grohar,
P. J.; Winters, R. T.; Barvian, M. R.; Moore, C. W.; Boushelle, S. L.;
Crean, S. M.; Kraker, A. J.; Driscoll, D. L.; Vincent, P. W.; Elliott,
W. L.; Lu, G. H.; Batley, B. L.; Dahring, T. K.; Major, T. C.; Panek,
R. L.; Doherty, A. M.; Showalter, H. D. J Med Chem 2001, 44, 1915.
[22] Wardakhan, W. W.; Abdel-Salam, O. M.; Elmegeed, G. A.
Acta Pharm 2008, 58, 1.
2H, J ¼ 5.6 Hz), 3.78 (s, 3H), 4.61 (s, 2H), 6.34 (d, 2H, J ¼ 2.0
Hz), 7.23 (d, 2H, J ¼ 2.1 Hz), 7.05 (d, 2H, J ¼ 7.7 Hz), 7.81 (d,
2H, J ¼ 7.6 Hz), 8.90 (s, 1H); ms: m/z 427 (Mþ).
7-(4-Nitro-benzenesulfonyl)-4-pyrrol-1-yl-5,6,7,8-tetrahydro-
pyrido[40,30:4,5]thieno[2,3-d]pyrimidine (6j). IR: ASO2 1345,
1171 cmꢁ1, NO2 1540, 1361 cmꢁ1; 1H NMR: d 2.63 (t, 2H, J ¼
5.8 Hz), 3.38 (t, 2H, J ¼ 5.6 Hz), 4.64 (s, 2H), 6.38 (d, 2H, J ¼
2.0 Hz), 7.26 (d, 2H, J ¼ 2.0 Hz), 8.20 (d, 2H, J ¼ 7.8 Hz),
8.46 (d, 2H, J ¼ 7.7 Hz), 8.93 (s, 1H); ms: m/z 442 (Mþ).
[23] Kikuchi, H.; Yamamoto, K.; Horoiwa, S.; Hirai, S.; Kasa-
hara, R.; Hariguchi, N.; Matsumoto, M.; Oshima, Y. J Med Chem
2006, 49, 4698.
[24] Grunewald, G. L.; Seim, M. R.; Bhat, S. R.; Wilson, M. E.;
Criscione, K. R. Bioorg Med Chem 2008, 16, 542.
[25] Litvinov, V. P. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: New York, 2006; Vol. 92,
p 83.
Acknowledgments. We gratefully acknowledge the most will-
ing help and co-operation shown by CDRI, Lucknow, India for
Spectroscopic Analysis and, Microcare Laboratory and Tubercu-
losis Research Centre, Surat, Gujarat, India for biological activity
acquisition coordinating facility.
[26] Ivachtchenko, A.; Kovalenko, S.; Tkachenko, O. V.; Par-
khomenko, O. J Comb Chem 2004, 6, 573.
[27] Mailavaram, R. P.; Deb, P. K. Chem Pharm Bull 2007, 55,
776.
REFERENCES AND NOTES
[28] Gewald, K.; Schinke, E.; Bottcher, H. Chem Ber 1966, 99,
94.
[1] Rosemeyer, H. Chem Biodivers 2004, 1, 361.
[2] Brown, D. J. The Chemistry of Heterocyclic Compounds;
Wiley: New York, 1988; Vol. 24, p 730.
[29] National Committee for Clinical Laboratory Standards.
Methods for Dilution, Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically Approved Standard, (M7A5), 5th ed.; National
Committee for Clinical Laboratory Standards: Wayne, PA, 2000.
[30] Shadomy, S. In Manual of Clinical Microbiology; Albert,
B., Ed.; ASM Press: Washington, DC, 1991; p 1173.
[31] Rattan, A. Antimicrobials in Laboratory Medicine; BI
Churchill Livingstone: India, 2000; p 85.
[3] Sinha, S.; Srivastava, M. Prog Drug Res 1994, 43, 143.
[4] Guo, Z. Z.; Chin, H. L.; Jhon, K. P.; Richard, J. P.; Mei,
Q. J.; Arthur, G.; Mark, A. M.; Yui, M. Bioorg Med Chem Lett 2001,
11, 2071.
[5] Aleem, G.; Ani, V.; Sherry, F. Q.; Roy, L. K. J Med Chem
1996, 39, 3228.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet