Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin

Article abstract of DOI:10.1016/j.bmc.2010.09.006

A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-methyl-5- (4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125 μg/mL), and a safe profile in terms of cytotoxicity (CC₅₀ of >128 μg/mL) and protection index (>1000). Antitubercular activity and protection index of the new compound are comparable to those found for the current antitubercular drugs streptomycin and rifampin.

Full text of DOI:10.1016/j.bmc.2010.09.006

Bioorganic & Medicinal Chemistry 18 (2010) 8076–8084
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Identification of a novel pyrrole derivative endowed with antimycobacterial
activity and protection index comparable to that of the current
antitubercular drugs streptomycin and rifampin
Mariangela Biava a, , Giulio Cesare Porretta a, Giovanna Poce a, Claudio Battilocchio a, Salvatore Alfonso a,
⇑
Alessandro De Logu b, Nadia Serra b, Fabrizio Manetti c, Maurizio Botta c
a Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università ‘La Sapienza’, piazzale Aldo Moro 5, I-00185 Roma, Italy
b Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Microbiologia Medica, viale Sant’Ignazio 38, I-09123 Cagliari, Italy
c Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via Alcide de Gasperi 2, I-53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 May 2010
Revised 30 August 2010
Accepted 2 September 2010
Available online 19 September 2010
A hit optimization procedure based on isosteric and bioisosteric replacement of decorating groups at both
the N1 and the C5 phenyl rings of 1,5-diarylpyrroles led to identification of 4-((1-(4-fluorophenyl)-2-
methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thiomorpholine that is characterized by a very
high activity toward both Mycobacterium tuberculosis 103471 and H37Rv strains (MIC values of 0.125
l
g/mL), and a safe profile in terms of cytotoxicity (CC50 of >128 lg/mL) and protection index (>1000).
Antitubercular activity and protection index of the new compound are comparable to those found for
the current antitubercular drugs streptomycin and rifampin.
Keywords:
Cytotoxicity
Pharmacophore model
Protection index
Pyrroles
Ó 2010 Elsevier Ltd. All rights reserved.
Tuberculosis
1. Introduction
in the last 40 years. This reflects the inherent difficulties in
developing and clinical testing new agents as well as the lack of
Tuberculosis (TB) has infected man since the birth of civilization
and despite the introduction of TB chemotherapy in the 1950s it
has made a dramatic resurgence in the past decades and it still re-
mains a leading infectious disease worldwide.1 The major factors
explaining the explosion in numbers of infections with Mycobacte-
rium tuberculosis (MTB) are: (i) the deadly synergy with HIV,2,3 (ii)
the development and spread of multidrug-resistant strains of MTB
(MDR-TB),4–6 resistant to all the first-line drugs, and, (iii) more re-
cently, the emergence of extensively drug resistant MTB strains
(XDR-TB),7,8 also resistant to three or more of the six classes of sec-
ond-line drugs and untreatable using currently available anti-TB
drugs. With this background, there have been no new drugs to
treat TB, except fluoroquinolone antibiotics recently introduced,9
pharmaceutical industry research in the area.10 The priority is
the development of a new agent that will shorten the duration of
chemotherapy from the current 6–8 months to two months or less,
although new drugs with activity against MDR- and XDR-TB and
latent TB are also needed.
In the past, we have synthesized several 1,5-diarylpyrrole deriv-
atives with very good activity against MTB and non-tuberculosis
mycobacteria, also showing low cytotoxicity.11–17 Structure–
activity relationship (SAR) studies and a pharmacophore-based
ligand design approach allowed us to identify chemical groups
and their substitution pattern on the pyrrole responsible for the
activity. In particular, a fluoride or a small alkyl group at the
para-position of the phenyl rings at N1 and C5 of the pyrrole and
the thiomorpholinomethyl at C3 were found as the most profitable
assembly for antimycobacterial activity.12–16 As an example, com-
pound 1 (named BM521; Chart 1) bearing this arrangement of sub-
stituents showed a very low MIC value and a protection index of
272.16 (Table 1). On this basis, we report herein the design,
synthesis and evaluation of new pyrrole derivatives (compounds
2–29) obtained by isosteric and bioisosteric replacement of groups
at the phenyl rings, keeping fixed the substituent at the C3 position
of the pyrrole core.
Abbreviations: TB, tuberculosis; MTB, Mycobacterium tuberculosis; MDR-TB,
multidrug-resistant tuberculosis; XDR-TB, extensively drug resistant tuberculosis;
SAR, Structure–activity relationships; MIC, minimum inhibitory concentration;
CC50, 50% cytotoxic concentration; OADC, oleic acid albumin and dextrose complex;
PI, protection index; INH-R, isoniazid-resistant; RMP-R, rifampin-resistant; FCS,
foetal calf serum.
⇑
Corresponding author. Tel.: +39 (0)6 49913812; fax: +39 (0)6 49913133.
E-mail address: mariangela.biava@uniroma1.it (M. Biava).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.09.006

M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
2. Material and methods
2.1. Chemistry
8077
S
N
A Discovery Microwave System apparatus (from CEM) was used
for the Stetter and Paal-Knorr reactions. All chemicals used possess
a purity of >95%. Yields refer to purified products and are not opti-
mized. Melting points were determined in open capillaries on a
Gallenkamp apparatus and are uncorrected. Microanalyses were
conducted on a Perkin-Elmer 240C or a Perkin-Elmer Series II
CHNS/O Analyzer 2400 instrument. Fluka Silica Gel 60 (230–400
mesh) was used for column chromatography. Fluka TLC plates (Sil-
ica Gel 60 F254) were used for thin-layer chromatography (TLC).
Fluka aluminium oxide (activity II–III, according to Brockmann)
N
F
H3C
compound 1 (BM521)
Chart 1. Chemical structure of compound 1 (BM521).
Table 1
Structure, in vitro antimycobacterial activity against M. tuberculosis H37Rv and M. tuberculosis CIP 103471, cytotoxicity (CC50), and protection index (PI) of the new pyrrole
derivatives 2–29 and reference compounds
S
N
N
R'
R
1-29
Compound
R
R0
MIC (l
g/mL) M. tuberculosis H37rv
MIC (
lg/mL) M. tuberculosis 103471
CC50
(l
g/mL)
PIa
1 (BM521)
2
3
4
5
6
7
8
4-F
4-F
2-CF3
4-F
4-CF3
4-F
2-OCH3
4-F
4-OCH3
4-F
4-CH3
2-CF3
4-F
4-CF3
4-F
2-OCH3
4-F
4-OCH3
4-F
2-SCH3
4-F
4-SCH3
4-F
4-CH3
4-OCH3
4-C2H5
4-OCH3
4-C3H7
4-OCH3
4-i-C3H7
4-OCH3
4-CH3
4-SCH3
4-C2H5
4-SCH3
4-C3H7
4-SCH3
4-i-C3H7
4-SCH3
0.125
ND
ND
ND
ND
ND
ND
ND
ND
16
0.25
>16
4
1
8
>16
>16
0.25
4
16
8
68.04
5.21
2.58
8.46
2.37
272.16
—
0.65
8.46
0.29
—
—
>480
5.32
1.39
10.82
10.40
>120
21.30
22.27
33.99
>128
>128
13.13
11.55
18.03
15.76
>128
12.28
4.88
10.22
69.06
18.40
25.74
17.18
89.92
25.25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Sb
Rc
2-SCH3
4-F
8
4.20
<0.125
1
1
0.125
1
2
>1000
>128
6.57
46.20
36.06
63.04
>512
49.12
9.76
40.88
69.06
73.60
102.96
68.72
359.68
202.00
229.90
286.24
>2000
828.12
4-SCH3
4-OCH3
4-CH3
4-OCH3
4-C2H5
4-OCH3
4-C3H7
4-OCH3
4-i-C3H7
4-SCH3
4-CH3
4-SCH3
4-C2H5
4-SCH3
4-C3H7
4-SCH3
4-i-C3H7
0.50
0.50
0.50
0.50
0.25
0.50
0.25
1
0.25
0.50
0.25
0.25
0.25
0.50
0.25
1
0.25
0.25
0.25
0.25
0.125
0.50
0.125
0.50
0.25
0.25
1
0.25
0.50
0.50
0.50
0.50
0.50
0.25
114.95
37.58
>1000
207.03
ND: not determined.
a
PI: protection index, expressed as CC50/MIC ratio.
S: streptomycin.
R: rifampin.
b
c

8078
M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
was used for chromatographic purifications. Fluka Stratocrom alu-
minium oxide plates with a fluorescent indicator were used for TLC
to check the purity of the compounds. HPLC Analysis was con-
ducted using a Waters Alliance 2695 instrument, using a UV–vis
Waters PDA 996 detector and working at 333 nm. Millennium Em-
suspension adjusted to yield a multiplicity of infection of 20 bacte-
ria per macrophage. Cells were then treated with the tested com-
pound and lysed after 3 and 7 days of incubation by addiction of
0.25% of sodium lauryl sulphate in PBS. Lysates were neutralized
by the addition of 15% bovine serum albumin in saline and aliquots
of 10-fold dilutions were plated onto 7H10 agar. CFU of M. tubercu-
losis were counted after 28 days incubation at 37 °C.
power with Windows XP was used. A Phenomenex LUNA C8, 5 lm
(150 ꢀ 4.6 mm) column (code 00F-4249-E0), at 40 °C, was used as
the chromatographic column at a flow rate of 1.0 mL/min. All the
synthesized compounds were P95% pure. 13C NMR and 1H NMR
spectra were recorded with a Bruker AC 400 spectrometer in the
indicated solvent (TMS as the internal standard). The values of
the chemical shifts are expressed in parts per million.
Compounds 2–29 were prepared as shown in Scheme 1. Briefly,
1,4-diketones 32a–k were obtained by reacting the suitable benz-
aldehyde 30a–k with methyl vinyl ketone 31 in the Discovery
Microwave System apparatus. Compounds 32a–k cyclized, in the
presence of the appropriate amine, to yield the expected
1,5-diarylpyrroles 33a–b0. Finally, reacting compounds 33a–b0
with formaldehyde and thiomorpholine, following Mannich reac-
tion conditions, final compounds 2–29 were obtained.
The cytotoxicity was evaluated on Vero cells grown and
maintained in RPMI 1640 medium supplemented with 2 mM
L-glutamine and 10% FCS. Cells were seeded in 96-well plates at a
density of 1 ꢀ 104 cells/well. After 24 h, medium was replaced with
fresh medium containing decreasing concentrations of the tested
compound and incubated at 37 °C in 5% CO2. Cells were observed
for morphological changes at 24, 48 and 72 h of incubation. After
72 h the effects on the proliferation of Vero cells were determined
by tetrazolium-based colorimetric MTT assay. The 50% cell-inhibi-
tory concentration (CC50) reduced by 50% the optical density values
(OD540,690) with respect to control no-drug treated cells.
Protection index (PI) is CC50/MIC ratio (considering M. tubercu-
losis 103471).
2.2. Microbiology
3. Results and discussion
Antimycobacterial activity and cytotoxic activity assays were
performed following a protocol previously reported.14,16 Com-
pounds 2–9 were preliminarily assayed against to freshly isolated
clinical strains, M. furtuitum CA10 and M. tuberculosis B814, accord-
ing to the dilution method in agar. Growth media were Mueller-Hil-
ton (Difco) containing 10% of OADC (oleic acid, albumin and
dextrose complex) for M. furtuitum and Middlebrook 7H11 agar
(Difco) with 10% of OADC for M. tuberculosis. Substances were tested
Initially, on the basis of previous results we synthesized new
analogs of 1, in which the methyl group on the phenyl ring was re-
placed with the isosteric trifluoromethyl one placed at para- and
ortho-positions (compounds 2–5). However, they did not show a
good antimycobacterial activity. In fact, only 4 proved to be active
against M. tuberculosis (MIC 1
lg/mL) even if it is slightly cytotoxic
(CC50 g/mL, Table 1). Next, to further explore the substitution
8
l
requirements of the phenyl ring, the trifluoromethyl substituent
was replaced with a methoxyl one (compounds 6–9). Only 8
at single dose of 100 lg/mL. The active compounds were then
assayed for inhibitory activity against a panel of mycobacteria
(M. tuberculosis CIP 103471, M. tuberculosis H37Rv ATCC 27294, iso-
niazid-resistant M. tuberculosis ATCC and rifampin-resistant
M. tuberculosis ATCC) in Middlebrook 7H11 agar by a standard two-
fold dilution method. Plates were incubated at 37 °C for 3 or 28 days.
BM521, rifampin and streptomycin were used as reference com-
pounds. After cultivation, MICs were read as minimal concentra-
tions of drugs completely inhibiting visible growth of mycobacteria.
The murine macrophage-like cell line J774.A1 was maintained
in Dulbecco’s modified Eagle’s medium supplemented with 10%
foetal calf serum (FCS). Cells were plated at density of 0.5 ꢀ 106
cells per well in 24-well plates and overlaid with a M. tuberculosis
proved to be active against M. tuberculosis (MIC 0.25 lg/mL) and
to have low cytotoxicity (CC50 higher than 120). By using 8 as tem-
plate, 10–13 were designed and synthesized by replacing the
methoxyl substituent with the bioisosteric methylsulfanyl group.
Notably, 12 (named BM579), bearing a N1 p-F phenyl group al-
ready found as the optimal substituent for enhancing the antimy-
cobacterial activity of 1,5-diarylpyrrole derivatives,22 showed an
activity against M. tuberculosis 103471 (<0.125 lg/mL) better than
those shown by the currently available antitubercular drugs strep-
tomycin and rifampin, as well as better than that of previous par-
ent compounds 1 and 8. Although the antimycobacterial activity of
12 was slightly ameliorated with respect to that found for previous
S
N
O
O
c
a
b
O
H
N
N
+
R'
R'
R'
R'
O
30a-k
31
R
R
32a-k
33a-b'
2-29
Scheme 1. Synthetic pathway of compounds 2–29. Compounds: 30a: R’ = 4-F; 30b: R’ = 2-CF3; 30c: R’ = 4-CF3; 30d: R’ = 2-OCH3; 30e: R’ = 4-OCH3; 30f: R’ = 2-SCH3; 30g:
R’ = 4-SCH3; 30h: R’ = 4-CH3; 30i: R’ = 4-C2H5; 30j: R’ = 4-C3H7; 30k: R’ = 4-iC3H7; 32a: R’ = 4-F; 32b: R’ = 2-CF3; 32c: R’ = 4-CF3; 32d: R’ = 2-OCH3; 32e: R’ = 4-OCH3; 32f:
R’ = 2-SCH3; 32g: R’ = 4-SCH3; 32h: R’ = 4-CH3; 32i: R’ = 4-C2H5; 32j: R’ = 4-C3H7; 32k: R’ = 4-iC3H7; 33a: R = 4-F; R’ = 2-CF3; 33b: R = 2-CF3; R’ = 4-F; 33c: R = 4-F; R’ = 4-CF3;
33d: R = 4-CF3; R = 4-F; 33e: R = 4-F; R’ = 2-OCH3; 33f: R = 2-OCH3; R’ = 4-F; 33g: R = 4-F; R’ = 4-OCH3; 33h: R = 4-OCH3; R’ = 4-F; 33i: R = 4-F; R’ = 2-SCH3; 33j: R = 2-SCH3;
R=4-F; 33k: R = 4-F; R’ = 4-SCH3; 331: R = 4-SCH3; R = 4-F; 33m: R = 4-OCH3; R’ = 4-CH3; 33n: R = 4-CH3; R’ = 4-OCH3; 33o: R = 4-OCH3; R’ = 4-C2H5; 33p: R = 4-C2H5;
R’ = 4-OCH3; 33q: R = 4-OCH3; R’ = 4-C3H7; 33r: R = 4-C3H7; R’ = 4-OCH3; 33s: R = 4-OCH3; R’ = 4-iC3H7; 33t: R = 4-iC3H7; R’ = 4-OCH3; 33u: R = 4-SCH3; R’ = 4-CH3; 33v:
R = 4-CH3; R’ = 4-SCH3; 33w: R = 4-SCH3; R’ = 4-C2H5; 33x: R = 4-C2H5; R’ = 4-SCH3; 33y: R = 4-SCH3; R’ = 4-C3H7; 33z: R = 4-C3H7; R’ = 4-SCH3; 33a0: R = 4-SCH3; R’ = 4-iC3H7;
33b0: R = 4-iC3H7; R’ = 4-SCH3. Reagents and conditions: (a) 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, TEA, mw, 15 min; (b) H2NC6H4R, p-toluensulfonic acid,
EtOH, mw 30 min; (c) (1) thiomorpholine, CH3CN, HCHO, CH3COOH, rt, 3 h; (2) NaOH 20% w/v.

M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
8079
parent pyrrole analogues, the ability of 12 to inhibit M. tuberculosis
H37Rv was even better than that of all the reference compounds. In
addition, it was characterized by a very good protection index (PI),
which is significantly higher than that found for rifampin. This is
particularly important considering that antimycobacterial drugs
are very often administered to immune-compromised patients
for which drug toxicity is the effective cause of death. Compound
12 was also tested against resistant M. tuberculosis strains [namely,
isoniazid-resistant (INH-R) and rifampin-resistant (RMP-R)] and
showed a very good antimycobacterial activity against the RMP-R
CF3 (2–5), a methoxy (6–9) and a methylsulphanyl (10–13) substi-
tuent, was characterized by the same substitution pattern as com-
pound 1. In fact, compounds 4, 8, and 12 had a p-F phenyl ring at
N1 and a thiomorpholinomethyl moiety at C3. Moreover, these re-
sults further confirm that the p-F phenyl ring at N1 is one of the
most profitable moieties for antimycobacterial activity. The
hypothesis that the preferential substitution pattern on the pyrrole
ring is that found for compound 1 is also confirmed by the activity
found for compounds 14–29. In fact, compounds with the alkyl
substituent at the N1 phenyl ring are in general more active than
the corresponding analogues bearing the same group at C5. Some
of the new derivatives showed an in vitro activity against M. tuber-
culosis better than that found for previous parent pyrrole deriva-
tives, as well as better than that of the antitubercular drugs
streptomycin and rifampin. In addition, several of them proved
to be less cytotoxic than rifampin. Among the compounds reported
herein, compound 12 is arguably the most potent and our present
study makes it an interesting compound when compared to the
current therapies.
strain (0.25 lg/mL), while it was inactive (>16 lg/mL) against the
INH-R strain (Table 2). Current drugs are poorly active or inactive
against drug-resistant mycobacteria; therefore, a multi-drug ther-
apy is needed. In this context, it is suggested that 12 may be used
alone or in combination with other antitubercular compounds for
the treatment of tuberculosis. Furthermore, it is noteworthy that
12 exerted a bactericidal activity on intracellular M. tuberculosis,
determined at several concentrations using the J774.A1 murine
macrophage cell line infected with M. tuberculosis H37Rv.18 At
the concentration of 0.125 lg/mL, a 96.12% reduction of the tuber-
cular bacilli survival was observed with compound 12, comparable
5. Experimental details
to the reduction induced by rifampin (Table 3).
5.1. General procedure for the preparation of pentane-1,4-
diones 32a–k
Finally, to extend our SAR studies, we decided to combine the
best substituents responsible for the good activity of compounds
2–13 with longer alkyl chain, on the basis of the good results pre-
viously obtained with a further increase of lipophilicity of the com-
pounds.16 Therefore, compounds 14–29, in which a p-methoxyl (as
for 8 and 9), a p-methylsulfanyl (as for 12 and 13) or a p-alkyl
(ethyl, propyl, and isopropyl) group is placed on the phenyl ring
at N1 or C5, were designed and synthesized. In principle, com-
pounds 14–29 showed a very good biological profile (Table 1). In
fact, all of them showed MIC values ranging from 0.125 to
Following the Stetter reaction, a mixture of the appropriate
benzaldehyde 30a–k (0.09 mol), triethylamine (19.5 mL, 0.14
mol), methyl vinyl ketone 31 (0.09 mol), and 3-ethyl-5-(2-
hydroxyethyl)-4-methylthiazolium bromide (3.53 g, 0.014 mol)
(Scheme 1) was put into a round-bottom flask equipped with a stir
bar. The flask was inserted into the cavity of a Discovery Micro-
wave System apparatus and heated (150 W for 15 min, internal
temperature 70 °C, and internal pressure 60 psi). The residue was
treated with 10 ml of 2 N HCl. After extraction with ethyl acetate,
the organic layer was washed with aqueous sodium bicarbonate
and water. The organic fractions were dried over Na2SO4, filtered,
and concentrated to give a crude orange liquid. After chromatogra-
phy on aluminum oxide (activity II–III, according to Brockmann)
(cyclohexane/ethyl acetate, 3:1 v/v), the desired 32a–k were iso-
lated as a light-yellow solids which, after recrystallization from
cyclohexane, gave an analytical sample as needles.
2 lg/mL, while only few compounds also had a low cytotoxicity,
thus leading to high values of the protection index. As examples,
18, 22, 26, 28, and 29 are characterized by CC50 values from
37.58 to 128
69.06 to >512.
lg/mL thus resulting in PI values ranging from
4. Conclusion
To summarize, the most active and safe compound of each of
the three subseries obtained by replacing the methyl group at
the para-position of the C5 phenyl ring of compound 1 with a
5.1.1. 1-[4-(Fluoro)phenyl]-pentane-1,4-dione (32a)
Yellowish needles (yield 75%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.18
Table 2
In vitro antimycobacterial activity (against INH-R and RMP-R M. tuberculosis strains)
of compound 12 and reference compounds
5.1.2. 1-[2-(Trifluoromethyl)phenyl]-pentane-1,4-dione (32b)
Yellowish needles (yield 80%), mp 75 °C. 1H NMR (400 MHz,
CDCl3) d 7.06–7.04 (m, 1H), 7.00–7.02 (m, 3H), 3.49 (t, J = 6.7 Hz,
2H), 2.71 (t, J = 6.7 Hz, 2H), 2.12 (s, 3H). Anal. (C12H11O2F3) C, H, F.
Compound
MIC (
lg/mL)
MIC (lg/mL)
M. tuberculosis INH-R
M. tuberculosis RMP-R
1 (BM521)
32
0.50
0.25
0.50
>64
12
>16
0.50
0.80
Sa
5.1.3. 1-[4-(Trifluoromethyl)phenyl]-pentane-1,4-dione (32c)
Yellowish needles (yield 75%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.19
Rb
a
S: Streptomycin.
R: Rifampin.
b
5.1.4. 1-[2-(Methoxy)phenyl]-pentane-1,4-dione (32d)
Yellowish needles (yield 66%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.20
Table 3
Intracellular antimycobacterial activity of compounds 12 and Rifampicin against
intracellular M. tuberculosis
5.1.5. 1-[4-(Methoxy)phenyl]-pentane-1,4-dione (32e)
Yellowish needles (yield 70%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.21
Compound
1
l
g/mL
0.5
l
g/mL
0.25
lg/mL
0.125 lg/mL
12
99.81
99.97
99.72
99.93
99.02
99.83
96.12
96.59
Ra
5.1.6. 1-[2-(Methylthio)phenyl]-pentane-1,4-dione (32f)
Yellowish needles (yield 65%), mp 60 °C. 1H NMR (400 MHz,
CDCl3) d 7.12–7.13 (m, 1H), 7.06–7.08 (m, 3H), 3.50 (t, J = 6.7 Hz,
Data are expressed as % of growth reduction respect to untreated controls after
6 days of treatment.
a
R: Rifampin.

8080
M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
2H), 2.75 (t, J = 6.7 Hz, 2H), 2.29 (s, 3H), 2.13 (s, 3H). Anal.
(C13H14O2S) C, H, S.
5.2.5. 2-Methyl-5-[2-(methoxy)phenyl]-1-[4-(fluoro)phenyl]-
1H-pyrrole (33e)
White needles (yield 50%), mp 186 °C. 1H NMR (400 MHz,
5.1.7. 1-[4-(Methylthio)phenyl]-pentane-1,4-dione (32g)
Yellowish needles (yield 80%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.22
CDCl3) d 7.26–7.22 (m, 7H), 6.68–6.63 (m, 1H), 6.30 (m,
J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 2.07 (s, 3H). Anal.
(C18H16FNO) C, H, N, F.
5.1.8. 1-[4-(Methyl)phenyl]-pentane-1,4-dione (32h)
White needles (yield 76%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.23
5.2.6. 2-Methyl-5-[4-(fluoro)phenyl]-1-[2-(methoxy)phenyl]-
1H-pyrrole (33f)
White needles (yield 52%), mp 195 °C. 1H NMR (400 MHz,
CDCl3) d 7.13–7.09 (m, 2H), 7.04–7.00 (m, 4H), 6.86–6.82 (m,
2H), 6.30 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 2.06 (s, 3H).
Anal. (C18H16FNO) C, H, N, F.
5.1.9. 1-[4-(Ethyl)phenyl]-pentane-1,4-dione (32i)
Yellow oil (yield 60%). Analytical data, mp, and 1H NMR spec-
trum were consistent with literature.16
5.2.7. 2-Methyl-5-[4-(methoxy)phenyl]-1-[4-(fluoro)phenyl]-
1H-pyrrole (33g)
5.1.10. 1-[4-(Propyl)phenyl]-pentane-1,4-dione (32j)
Yellow oil (yield 63%). Analytical data, mp, and 1H NMR spec-
trum were consistent with literature.16
Yellowish needles (yield 78%), mp 85 °C. 1H NMR (400 MHz,
CDCl3) d 7.14–7.09 (m, 4H), 7.08 (d, J = 7.27 Hz, 2H), 6.96 (d,
J = 7.27 Hz, 2H), 6.29 (d, J = 3.5 Hz, 1H), 6.14 (d, J = 3.5 Hz, 1H),
3.81 (s, 3H), 2.07 (s, 3H). Anal. (C18H16FNO) C, H, N, F.
5.1.11. 1-[4-(i-Propyl)phenyl]-pentane-1,4-dione (32k)
Yellow oil (yield 68%). Analytical data, mp, and 1H NMR spec-
trum were consistent with literature.16
5.2.8. 2-Methyl-5-[4-(fluoro)phenyl]-1-[4-(methoxy)phenyl]-
1H-pyrrole (33h)
5.2. General procedure for the preparation of 1,5-diarylpyrroles
33a–b0
White needles (yield 70%), mp 185 °C. 1H NMR (400 MHz,
CDCl3) d 7.08–7.00 (m,4H), 6.90–6.84 (m, 4H), 6.26 (d, J = 3.5 Hz,
1H), 6.10 (d, J = 3.5 Hz, 1H), 3.77 (s, 3H), 2.03 (s, 3H). Anal.
(C18H16FNO) C, H, N, F, O.
Following the Paal-Knorr reaction, the proper diketone 32
(2.28 mmol) was dissolved in ethanol (2 mL) into a round-bottom
flask equipped with a stir bar. The suitable amine (2.28 mmol) and
p-toluenesulfonic acid (30 mg, 0.17 mmol) were added. The flask
was inserted into the cavity of the Discovery Microwave System
apparatus and heated (150 W for 30 min, internal temperature
160 °C, and internal pressure 150 psi). The reaction mixture was
cooled and concentrated. The crude material was purified by
chromatography on aluminum oxide (activity II–III, according to
Brockmann) with cyclohexane as the eluant to give the expected
1,5-diarylpyrroles 33a–b0 as solids in satisfactory yield.
5.2.9. 2-Methyl-5-[2-(methylthio)phenyl]-1-[4-(fluoro)phenyl]-
1H-pyrrole (33i)
White needles (yield 57%), mp 112 °C. 1H NMR (400 MHz,
CDCl3) d 7.15–7.08 (m, 1H), 7.07–7.03 (m, 3H), 6.97–6.90 (m,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.13 (d, J = 3.5 Hz, 1H), 2.55 (s, 3H),
2.08 (s, 3H). Anal. (C18H16FNS) C, H, N, F, S.
5.2.10. 2-Methyl-5-[4-(fluoro)phenyl]-1-[2-(methylthio)phenyl]-
1H-pyrrole (33j)
White needles (yield 91%), mp 96 °C. 1H NMR (400 MHz, CDCl3)
d 7.29–7.22 (m, 1H), 7.15–7.09 (m, 5H), 6.82–6.74 (m, 2H), 6.31 (d,
J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 2.53 (s, 3H), 1.99 (s, 3H).
Anal. (C18H16FNS) C, H, N, F, S.
5.2.1. 2-Methyl-5-[2-(trifluoromethyl)phenyl]-1-[4-(fluoro)
phenyl]-1H-pyrrole (33a)
White needles (yield 50%), mp 185 °C. 1H NMR (400 MHz,
CDCl3) d 7.62–7.60 (m, 1H), 7.32–7.29 (m, 2H), 7.11–7.09 (m,
5H), 6.34 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 2.07 (s, 3H).
Anal. (C18H13F4N) C, H, N, F.
5.2.11. 2-Methyl-5-[4-(methylthio)phenyl]-1-[4-(fluoro)phenyl]-
1H-pyrrole (33k)
White needles (yield 93%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.22
5.2.2. 2-Methyl–5-[4-(fluoro)phenyl]-1-[2-(trifluoromethyl)
phenyl]-1H-pyrrole (33b)
5.2.12. 2-Methyl-5-[4-(fluoro)phenyl]-1-[4-(methylthio)phenyl]-
1H-pyrrole (33l)
White needles (yield 70%), mp 197 °C. 1H NMR (400 MHz,
CDCl3) d 7.72–7.69 (m, 2H), 7.53–7.52 (m, 1H), 7.41–7.37 (m,
1H), 7.00–6.98 (m, 2H), 6.83–6.79 (m, 2H), 6.35 (d, J = 3.5 Hz,
1H), 6.13 (d, J = 3.5 Hz, 1H), 1.91 (s, 3H). Anal. (C18H13F4N) C, H,
N, F.
White needles (yield 92%), mp 114 °C. 1H NMR (400 MHz,
CDCl3) d 7.39–7.30 (m, 2H), 7.15–7.09 (m, 4H), 7.07–7.00 (m,
2H), 6.35 (d, J = 3.5 Hz, 1H), 6.08 (d, J = 3.5 Hz, 1H), 2.60 (s, 3H),
2.06 (s, 3H). Anal. (C18H16FNS) C, H, N, F, S.
5.2.3. 2-Methyl-5-[4-(trifluoromethyl)phenyl]-1-[4-(fluoro)
phenyl]-1H-pyrrole (33c)
5.2.13. 2-Methyl-5-[4-(methyl)phenyl]-1-[4-(methoxy)phenyl]-
1H-pyrrole (33m)
White needles (yield 65%), mp 101 °C. 1H NMR (400 MHz,
CDCl3) d 7.30 (d, J = 7.27 Hz, 2H), 7.24 (d, J = 7.27 Hz, 2H), 7.13–
7.10 (m, 4H), 6.37 (d, J = 3.5 Hz, 1H), 6.10 (d, J = 3.5 Hz, 1H), 2.10
(s, 3H). Anal. (C18H13F4N) C, H, N, F.
White needles (yield 66%), mp 137 °C. 1H NMR (400 MHz,
CDCl3)
d 7.07 (d, J = 7.27 Hz, 2 H), 6.94 (m, 4H), 6.88 (d,
J = 7.27 Hz, 2H), 6.28 (d, J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H),
3.81 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H). Anal. (C19H19NO) C, H, N.
5.2.14. 2-Methyl-5-[4-(methoxy)phenyl]-1-[4-(methyl)phenyl]-
1H-pyrrole (33n)
5.2.4. 2-Methyl-5-[4-(fluoro)phenyl]-1-[4-(trifluoromethyl)
phenyl]-1H-pyrrole (33d)
White needles (yield 66%), mp 85 °C. 1H NMR (400 MHz, CDCl3)
d 7.22(d, J = 7.27 Hz, 2H), 7.03 (d, J = 7.27 Hz, 2H), 6.98–6.90 (m,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 3.81 (s, 3H),
2.40 (s, 3H), 2.05 (s, 3H). Anal. (C19H19NO) C, H, N.
White needles (yield 63%), mp 198 °C. 1H NMR (400 MHz,
CDCl3) d 7.74 (d, J = 7.27 Hz, 2H), 7.38 (d, J = 7.27 Hz, 2H), 7.05 (d,
J = 7.27 Hz, 2H), 7.02 (d, J = 7.27 Hz, 2H), 6.33 (d, J = 3.5 Hz, 1H),
6.11 (d, J = 3.5 Hz, 1H), 2.09 (s, 3H). Anal. (C18H13F4N) C, H, N, F.

M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
8081
5.2.15. 2-Methyl-5-[4-(ethyl)phenyl]-1-[4-(methoxy)phenyl]-
1H-pyrrole (33o)
J = 7.1 Hz, 2H), 2.50 (s, 3H), 2.05 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).
Anal. (C20H21NS) C, H, N, S.
White needles (yield 80%), mp 71 °C. 1H NMR (400 MHz, CDCl3)
d 7.10 (d, J = 7.27 Hz, 2 H), 6.95 (s, 4H), 6.84 (d, J = 7.27 Hz, 2H),
6.31 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 3.78 (s, 3H), 2.77
(q, J = 7.1 Hz, 2H), 2.04 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). Anal.
(C20H21NO) C, H, N.
5.2.24. 2-Methyl-5-[4-(methylthio)phenyl]-1-[4-(ethyl)phenyl]-
1H-pyrrole (33x)
Yellowish needles (yield 41%), mp 78 °C. 1H NMR (400 MHz,
CDCl3) d 7.23 (d, J = 7.27 Hz, 2H), 7.08–7.00 (m, 6H), 6.28 (d,
J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 2.71 (q, J = 7.1 Hz, 2H),
2.42 (s, 3H), 2.05 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Anal. (C20H21NS)
C, H, N, S.
5.2.16. 2-Methyl-5-[4-(methoxy)phenyl]-1-[4-(ethyl)phenyl]-
1H-pyrrole (33p)
Yellowish needles (yield 53%), mp 80 °C. 1H NMR (400 MHz,
CDCl3) d 7.17 (d, J = 7.27 Hz, 2 H), 7.02 (d, J = 7.27 Hz, 2H), 6.97
(d, J = 7.27 Hz, 2H), 6.67 (d, J = 7.27 Hz, 2H), 6.24 (d, J = 3.5 Hz,
1H), 6.11 (d, J = 3.5 Hz, 1H), 3.73 (s, 3H), 2.72 (q, J = 7.1 Hz, 2H),
2.05 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). Anal. (C20H21NO) C, H, N.
5.2.25. 2-Methyl-5-[4-(propyl)phenyl]-1-[4-(methylthio)phenyl]-
1H-pyrrole (33y)
White needles (yield 54%), mp 77 °C. 1H NMR (400 MHz, CDCl3)
d 7.19 (d, J = 7.27 Hz, 2H), 7.03 (d, J = 7.27 Hz, 2H), 6.98–6.92 (m,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.07 (d, J = 3.5 Hz, 1H), 2.54–2.48 (m,
5H), 2.05 (s, 3H), 1.60–1.54 (m, 2H), 0.91 (t, J = 7.1 Hz, 3H). Anal.
(C21H23NS) C, H, N, S.
5.2.17. 2-Methyl-5-[4-(propyl)phenyl]-1-[4-(methoxy)phenyl]-
1H-pyrrole (33q)
White needles (yield 55%), mp 55 °C. 1H NMR (400 MHz, CDCl3)
d 7.07 (d, J = 7.27 Hz, 2 H), 6.95 (m, 6H), 6.29 (d, J = 3.5 Hz, 1H), 6.09
(s, J = 3.5 Hz, 1H), 3.81 (s, 3H), 2.43 (t, J = 7.1 Hz, 2H), 2.04 (s, 3H),
1.64–1.60 (m, 2H), 0.91 (t, J = 7.1 Hz, 3H). Anal. (C21H23NO) C, H, N.
5.2.26. 2-Methyl-5-[4-(methylthio)phenyl]-1-[4-(propyl)phenyl]-
1H-pyrrole (33z)
Yellowish needles (yield 75%), mp 87 °C. 1H NMR (400 MHz,
CDCl3) d 7.19 (d, J = 7.27 Hz, 2H), 7.08–7.00 (m, 6H), 6.30 (d,
J = 3.5 Hz, 1H), 6.10 (d, J = 3.5 Hz, 1H), 2.61 (t, J = 7.1 Hz, 2H), 2.40
(s, 3H), 2.05 (s, 3H), 1.65 (m, J = 7.1 Hz, 2H), 0.93 (s, 3H). Anal.
(C21H23NS) C, H, N, S.
5.2.18. 2-Methyl-5-[4-(methoxy)phenyl]-1-[4-(propyl)phenyl]-
1H-pyrrole (33r)
Yellowish needles (yield 79%), mp 85 °C. 1H NMR (400 MHz,
CDCl3) d 7.16 (d, J = 7.27 Hz, 2H), 7.05 (d, J = 7.27 Hz, 2H), 6.92 (s,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 3.81 (s, 3H),
2.60 (t, J = 7.1 Hz, 2H), 2.05 (s, 3H), 1.68–1.63 (m, 2H), 0.94 (t,
J = 7.1 Hz, 3H). Anal. (C21H23NO) C, H, N.
5.2.27. 2-Methyl-5-[4-(i-propyl)phenyl]-1-[4-(methylthio)phe-
nyl]-1H-pyrrole (33a0)
White needles (yield 51%), mp 91 °C. 1H NMR (400 MHz, CDCl3)
d 7.23 (d, J = 7.27 Hz, 2H), 7.03 (d, J = 7.27 Hz, 2H), 6.94–6.90 (m,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 2.94–2.90 (m,
1H), 2.38 (s, 3H), 2.06 (s, 3H), 1.27 (s, 3H), 1.20 (s, 3H). Anal.
(C21H23NS) C, H, N, S.
5.2.19. 2-Methyl-5-[4-(i-propyl)phenyl]-1-[4-(methoxy)phenyl]-
1H-pyrrole (33s)
White needles (yield 65%), mp 83 °C. 1H NMR (400 MHz, CDCl3)
d 7.07 (d, J = 7.27 Hz, 2H), 6.98 (s, 4H), 6.87 (d, J = 7.27 Hz, 2H), 6.29
(d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 3.83 (s, 3H), 2.88–2.84
(m, 1H), 2.03 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H). Anal. (C21H23NO)
C, H, N.
5.2.28. 2-Methyl-5-[4-(methylthio)phenyl]-1-[4-(i-propyl)
phenyl]-1H-pyrrole (33b0)
White needles (yield 68%), mp 82 °C. 1H NMR (400 MHz, CDCl3)
d 7.23 (d, J = 7.27 Hz, 2H), 7.08–7.03 (m, 6H), 6.30 (d, J = 3.5 Hz,
1H), 6.07 (d, J = 3.5 Hz, 1H), 2.83–2.80 (m,1H), 2.41 (s, 3H), 2.06
(s, 3H), 1.28 (s, 3H), 1.25 (s, 3H). Anal. (C21H23NS) C, H, N,S.
5.2.20. 2-Methyl-5-[4-(methoxy)phenyl]-1-[4-(i-propyl)phenyl]-
1H-pyrrole (33t)
White needles (yield 66%), mp 84 °C. 1H NMR (400 MHz, CDCl3)
d 7.21 (d, J = 7.27 Hz, 2H), 7.06 (d, J = 7.27 Hz, 2H), 6.98–6.93 (m,
4H), 6.30 (d, J = 3.5 Hz, 1H), 6.09 (d, J = 3.5 Hz, 1H), 3.85 (s, 3H),
2.92–2.88 (m, 1H), 2.06 (s, 3H), 1.27 (s, 3H), 1.20 (s, 3H). Anal.
(C21H23NO) C, H, N.
5.3. General procedure for the preparation of compounds 2–29
Following the Mannich reaction, to a stirred solution of an
appropriate pyrrole 33a–b0 (5.6 mmol) in acetonitrile (20 mL), a
mixture of thiomorpholine (0.57 g, 5.6 mmol), formaldehyde
(0.18 g, 5.6 mmol) (40% in water), and 5 mL of acetic acid was
added dropwise. After the addition was complete, the mixture
was stirred at room temperature for 1 h and then treated with a
solution of sodium hydroxide (20%, w/v) and extracted with ethyl
acetate. The organic extracts were combined, washed with water,
and dried. After removal of solvent, the residue was purified by col-
umn chromatography, using silica gel and petroleum ether/ethyl
acetate (3:1 v/v). The eluates were combined after TLC control
and the solvent was removed to give 2–29 as solids in satisfactory
yield. Recrystallization from diethyl ether gave compounds 2–29 as
solids in satisfactory yields.
5.2.21. 2-Methyl-5-[4-(methyl)phenyl]-1-[4-(methylthio)phe-
nyl]-1H-pyrrole (33u)
White needles (yield 73%), mp 91 °C. 1H NMR (400 MHz, CDCl3)
d 7.25 (d, J = 7.27 Hz, 2H), 7.13 (d, J = 7.27 Hz, 2H), 6.94 (s, 4H), 6.31
(d, J = 3.5 Hz, 1H), 6.07 (d, J = 3.5 Hz, 1H), 2.49 (s, 3H), 2.25 (s, 3H),
2.06 (s, 3H). Anal. (C19H19NS) C, H, N, S.
5.2.22. 2-Methyl-5-[4-(methylthio)phenyl]-1-[4-(methyl)
phenyl]-1H-pyrrole (33v)
White needles (yield 68%), mp 109 °C. 1H NMR (400 MHz,
CDCl3) d 7.27 (d, J = 7.27 Hz, 2H), 7.08–7.00 (m, 6H), 6.31 (d,
J = 3.5 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H),
2.04 (s, 3H). Anal. (C19H19NS) C, H, N, S.
5.3.1. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[2-(trifluo-
romethyl)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrole (2)
5.2.23. 2-Methyl-5-[4-(ethyl)phenyl]-1-[4-(methylthio)phenyl]-
1H-pyrrole (33w)
Yellow oil (yield 42%). 1H NMR (400 MHz, CDCl3) d 7.68–7.60
(m, 1H), 7.24 (d, J = 7.27 Hz, 2H), 7.08–7.03 (m, 5H), 6.26 (s, 1H),
3.49 (s, 2H), 2.82–2.77 (m, 4H), 2.73–2.70 (m, 4H), 2.06 (s, 3H).
13C NMR (400 MHz, CDCl3) d 10.61, 28.14, 50.01, 55.30, 110.66,
113.95, 115.00, 116.19, 124.14, 127.54, 127.59, 127.64, 127.69,
White needles (yield 58%), mp 96 °C. 1H NMR (400 MHz, CDCl3)
d 7.21 (d, J = 7.27 Hz, 2H), 7.05 (d, J = 7.27 Hz, 2H), 6.98–6.93 (m,
4H), 6.29 (d, J = 3.5 Hz, 1H), 6.07 (d, J = 3.5 Hz, 1H), 2.55 (q,

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M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
128.90, 128.97, 129.00, 129.32, 129.40, 129.45, 130.77, 132.35,
132.59, 133.25, 137.55, 159.10, 162.41. Anal. (C23H22F4N2S) C, H,
N, F, S.
128.10, 128.43, 129.20, 131.15, 131.61, 136.50, 138.51, 159.60,
162.92. Anal. (C23H25FNOS) C, H, N, F, S.
5.3.8. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[4-(methoxy)phenyl]-1H-pyrrole (9)
5.3.2. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole (3)
White needles (yield 52%), mp 130 °C. 1H NMR (400 MHz,
CDCl3) d 7.04–7.00 (m, 4H), 6.88–6.84 (m, 4H), 6.26 (s, 1H), 3.79
(s, 3H), 3.45 (s, 2H), 2.78–2.76 (m, 4H), 2.70–2.68 (m, 4H), 2.03
(s, 3H). 13C NMR (400 MHz, CDCl3) d 11.07, 29.01, 49.00, 53.68,
56.33, 113.80, 114.80, 120.33, 120.55, 128.10, 128.20, 129.60,
131.10, 131.77, 136.44, 138.62, 158.93, 162.88. Anal. (C23H25FNOS)
C, H, N, F, S.
White needles (yield 48%), mp 130 °C. 1H NMR (400 MHz,
CDCl3) d 7.69 (d, J = 7.27 Hz, 2H), 7.55–7.48 (m, 1H), 7.33–7.30
(m, 1H), 6.96 (d, J = 7.27 Hz, 2H), 6.73–6.68 (m, J = 7.27 Hz, 2H),
6.30 (s, 1H), 3.52 (s, 2H), 2.76–2.70 (m, 4H), 2.55–2.52 (m, 4H),
2.33 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.61, 28.14, 54.01,
55.30, 110.70, 114.00, 114.98, 116.15, 124.55, 127.54, 127.59,
127.64, 127.69, 128.90, 128.97, 129.00, 129.32, 129.40, 129.45,
130.77, 132.35, 132.59, 133.25, 137.55, 159.10, 162.41. Anal.
(C23H22F4N2S) C, H, N, F, S.
5.3.9. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[2-(methyl-
thio)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrole (10)
White needles (yield 75%), mp 156 °C. 1H NMR (400 MHz,
CDCl3) d 7.10–7.06 (m, 1H), 7.087.04 (m, 3H), 6.95–6.92 (m, 4H),
6.26 (s, 1H), 3.52 (s, 2H), 2.82–2.78 (m, 4H), 2.74–2.70 (m, 4H),
2.33 (s, 3H), 2.08 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.30,
22.30, 28.33, 49.30, 55.60, 113.22, 114.32, 119.12, 120.25, 124.46,
128.30, 128.22, 129.51, 131.23, 131.61, 135,13, 136.53, 138.58,
158.22, 161.90. Anal. (C23H25FN2S2) C, H, N, F, S.
5.3.3. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(trifluo-
romethyl)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrole (4)
White needles (yield 57%), mp 145 °C. 1H NMR (400 MHz,
CDCl3) d 7.36 (d, J = 7.27 Hz, 2H), 7.26 (d, J = 7.27 Hz, 2H), 7.15–
7.10 (m, 4H), 6.49 (s, 1H), 3.52 (s, 2H), 2.86–2.82 (m, 4H), 2.80–
2.76 (m, 4H), 2.10 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.59,
28.41, 54.56, 55.44, 110.99, 114.08, 114.90, 116.27, 125.44,
126.30, 126.35, 126.40, 126.45, 128.77, 129.00, 129.21, 130.11,
130.45, 130.80, 132.36, 132.60, 137.51, 158.50, 161.61. Anal.
(C23H22F4N2S) C, H, N, F, S.
5.3.10. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[2-(methylthio)phenyl]-1H-pyrrole (11)
White needles (yield 25%), mp 127 °C. 1H NMR (400 MHz,
CDCl3) d 7.28–7.25 (m, 1H), 7.12–7.08 (m, 5H), 6.79–6.75 (m,
2H), 6.33 (s, 1H), 3.48 (s, 2H), 2.79–2.75 (m, 4H), 2.72–2.68 (m,
4H), 2.35 (s, 3H), 1.99 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.19,
22.27, 28.33, 49.20, 55.37, 114.08, 114.32, 118.70, 119.85, 124.69,
127.90, 128.30, 129.61, 130.28, 131.33, 135.18, 136.40, 138.28,
159.22, 163.60. Anal. (C23H25FN2S2) C, H, N, F, S.
5.3.4. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrrole (5)
Yellow oil (yield 56%). 1H NMR (400 MHz, CDCl3) d 7.77 (d,
J = 7.27 Hz, 2H), 7.41 (d, J = 7.27 Hz, 2H), 7.05 (d, J = 7.27 Hz, 2H),
7.02 (d, J = 7.27 Hz, 2H), 6.30 (s, 1H), 3.38 (s, 2H), 2.68–2.64 (m,
4H), 2.60–2.56 (m, 4H), 2.09 (s, 3H). 13C NMR (400 MHz, CDCl3) d
10.45, 28.45, 49.89, 55.66, 111.09, 114.10, 114.98, 116.30, 125.31,
126.25, 126.40, 126.45, 126.50, 128.81, 129.10, 129.32, 130.12,
130.47, 130.56, 132.36, 133.00, 137.51, 158.45, 161.56. Anal.
(C23H22F4N2S) C, H, N, F, S.
5.3.11. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
ylthio)phenyl]-1-[4-(fluoro)phenyl]1H-pyrrole (12)
White needles (yield 68%). Analytical data, mp, and 1H NMR
spectrum were consistent with literature.22
5.3.5. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[2-(meth-
oxy)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrole (6)
5.3.12. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[4-(methylthio)phenyl]-1H-pyrrole (13)
White needles (yield 39%), mp 123 °C. 1H NMR (400 MHz,
CDCl3) d 7.28–7.23 (m, 7H), 6.68–6.63 (m, 1H), 6.22 (s, 1H), 3.53
(s, 2H), 3.38 (s, 3H), 2.80–2.76 (m, 4H), 2.66–2.60 (m, 4H), 2.07
(s, 3H). 13C NMR (400 MHz, CDCl3) d 10.56, 29.00, 49.90, 55.70,
56.20, 113.91, 114.10, 119.00, 119.60, 127.50, 128.11, 128.40,
129.40, 131.11, 131.62, 136.50, 137.67, 138.50, 159.05, 162.00.
Anal. (C23H25FNOS) C, H, N, F, S.
White needles (yield 44%), mp 153 °C. 1H NMR (400 MHz,
CDCl3) d 7.33 (d, J = 7.27 Hz, 2H), 7.12–7.08 (m, 4H), 7.03–7.00
(m, J = 7.27 Hz, 2H), 6.35 (s, 1H), 3.54 (s, 2H), 2.82–2.78 (m, 4H),
2.75–2.73 (m, 4H), 2.38 (s, 3H), 2.06 (s, 3H). 13C NMR (400 MHz,
CDCl3) d 10.29, 22.29, 28.55, 49.22, 55.50, 114.10, 114.27, 119.33,
120.31, 124.11, 128.55, 129.23, 131.41, 134.20, 136.70, 138.62,
158.11, 161.02. Anal. (C23H25FN2S2) C, H, N, F, S.
5.3.6. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(fluoro)
phenyl]-1-[2-(methoxy)phenyl]-1H-pyrrole (7)
5.3.13. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
yl)phenyl]-1-[4-(methoxy)phenyl]-1H-pyrrole (14)
White needles (yield 40%), mp 123 °C. 1H NMR (400 MHz,
CDCl3) d 7.14–7.08 (m, 2H), 7.04–7.00 (m, 4H), 6.82–6.79 (m,
2H), 6.29 (s, 1H), 3.67 (s, 3H), 3.48 (s, 2H), 2.80–2.76 (m, 4H),
2.72–2.68 (m, 4H), 1.98 (s, 3H). 13C NMR (400 MHz, CDCl3) d
10.66, 28.10, 49.60, 55.65, 56.33, 114.01, 114.12, 119.03, 119.40,
127.10, 128.11, 128.43, 129.22, 131.01, 131.70, 136.20, 137.67,
138.50, 159.49, 162.50. Anal. (C23H25FNOS) C, H, N, F, S.
White needles (yield 15%), mp 128 °C. 1H NMR (400 MHz,
CDCl3) d 7.07 (d, J = 7.27 Hz, 2H), 6.96–6.92 (m, 4H), 6.88 (d,
J = 7.27 Hz, 2H), 6.28 (s, 1H), 3.82 (s, 3H), 3.47 (s, 2H), 2.80–2.77
(m, 4H), 2.69–2.66 (m, 4H), 2.25 (s, 3H), 2.04 (s, 3H). 13C NMR
(400 MHz, CDCl3) d 10.29, 24.29, 28.55, 49.22, 55.50, 55.90,
114.00, 114.17, 119.35, 122.34, 124.11, 128.55, 129.23, 131.41,
134.20, 135.44, 136.70, 138.62. Anal. (C24H28N2OS) C, H, N, S.
5.3.7. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
oxy)phenyl]-1-[4-(fluoro)phenyl]-1H-pyrrole (8)
5.3.14. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
oxy)phenyl]-1-[4-(methyl)phenyl]-1H-pyrrole (15)
White needles (yield 20%), mp 120 °C. 1H NMR (400 MHz,
CDCl3) d 7.14–7.10 (m, 4H), 7.08 (d, J = 7.27 Hz, 2H), 6.96 (d,
J = 7.27 Hz, 2H), 6.26 (s, 1H), 3.76 (s, 3H), 3.50 (s, 2H), 2.82–2.78
(m, 4H), 2.78–2.74 (m, 4H), 2.07 (s, 3H). 13C NMR (400 MHz, CDCl3)
d 10.37, 29.01, 49.00, 55.68, 56.27, 113.92, 114.03, 119.12, 119.50,
White needles (yield 45%), mp 127 °C. 1H NMR (400 MHz,
CDCl3) d 7.21 (d, J = 7.27 Hz, 2H), 7.03 (d, J = 7.27 Hz, 2H), 6.98–
6.94 (m, 4H), 6.29 (s, 1H), 3.80 (s, 3H), 3.47 (s, 2H), 2.82–2.78 (m,
4H), 2.72–2.70 (m, 4H), 2.25–2.23 (m, 3H), 2.05 (s, 3H). 13C NMR
(400 MHz, CDCl3) d 10.34, 24.30, 28.57, 49.25, 55.56, 55.99,

M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
8083
114.09, 114.23, 119.33, 120.21, 124.51, 127.33, 128.15, 129.23,
131.46, 134.10, 135.70, 136.22. Anal. (C24H28N2OS) C, H, N, S.
28.43, 36.40, 49.39, 55.60, 59.41, 114.08, 114.09, 120.00, 122.34,
125.40, 128.90, 129.73, 131.22, 134.26, 135.11, 136.78, 148.69.
Anal. (C26H32N2OS) C, H, N, S.
5.3.15. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(ethyl)
phenyl]-1-[4-(methoxy)phenyl]-1H-pyrrole (16)
5.3.21. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
yl)phenyl]-1-[4-(methylthio)phenyl]-1H-pyrrole (22)
White needles (yield 25%), mp 92 °C. 1H NMR (400 MHz, CDCl3)
d 7.07 (d, J = 7.27 Hz, 2H), 6.97 (s, 4H), 6.86 (d, J = 7.27 Hz, 2H), 6.29
(s, 1H), 3.83 (s, 3H), 3.49 (s, 2H), 2.58–2.56 (m, 4H), 2.54–2.53 (m,
White needles (yield 60%), mp 153 °C. 1H NMR (400 MHz,
CDCl3) d 7.25 (d, J = 7.27 Hz, 2H), 7.13 (d, J = 7.27 Hz, 2H), 6.94 (s,
4H), 6.30 (s, 1H), 3.45 (s, 2H), 2.85–2.80 (m, 4H), 2.78–2.74 (m,
4H), 2.49 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H). 13C NMR (400 MHz,
CDCl3) d 10.30, 15.00, 24.43, 28.35, 49.39, 55.60, 114.05, 114.17,
120.33, 121.99, 125.40, 128.90, 129.73, 131.23, 134.27, 135.20,
136.78, 137.69. Anal. (C24H28N2S2) C, H, N, S.
4H), 2.40 (q, J = 7.1 Hz, 2H), 2.04 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13
C
NMR (400 MHz, CDCl3) d 10.34, 14.30, 28.57, 32.19, 49.25, 55.56,
55.99, 114.06, 114.13, 119.43, 120.31, 124.51, 127.30, 128.25,
129.33, 131.40, 134.20, 135.70, 137.02. Anal. (C25H30N2OS) C, H,
N, S.
5.3.16. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
oxy)phenyl]-1-[4-(ethyl)phenyl]-1H-pyrrole (17)
5.3.22. 2-Methyl–3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
ylthio)phenyl]-1-[4-(methyl)phenyl]1H-pyrrole (23)
White needles (yield 35%), mp 105 °C. 1H NMR (400 MHz,
CDCl3) d 7.17 (d, J = 7.27 Hz, 2H), 7.03 (d, J = 7.27 Hz, 2H), 6.97 (d,
J = 7.27 Hz, 2H), 6.67 (d, J = 7.27 Hz, 2H), 6.24 (s, 1H), 3.73 (s, 3H),
3.47 (s, 2H), 2.82–2.78 (m, 4H), 2.74–2.70 (m, 6H), 2.05 (s, 3H),
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 10.30, 14.29,
28.60, 32.21, 49.28, 55.60, 60.09, 114.00, 114.11, 119.23, 120.21,
124.41, 127.40, 128.44, 129.33, 131.10, 134.38, 135.22, 137.19.
Anal. (C25H30N2OS) C, H, N, S.
White needles (yield 30%) mp 162 °C. 1H NMR (400 MHz, CDCl3)
d 7.25 (d, J = 7.27 Hz, 2H), 7.06–7.00 (m, 6H), 6.30 (s, 1H), 3.46 (s,
2H), 2.79–2.76 (m, 4H), 2.72–2.69 (m, 4H), 2.41 (s, 3H), 2.38 (s,
3H), 2.04 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.33, 14.40,
24.39, 28.40, 49.41, 55.57, 114.02, 114.25, 120.33, 122.18, 125.34,
128.97, 129.78, 131.11, 134.29, 136.10, 136.81, 137.69. Anal.
(C24H28N2S2) C, H, N, S.
5.3.23. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(ethyl)
phenyl]-1-[4-(methylthio)phenyl]-1H-pyrrole (24)
5.3.17. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(propyl)
phenyl]-1-[4-(methoxy)phenyl]-1H-pyrrole (18)
White needles (yield 35%), mp 112 °C. 1H NMR (400 MHz,
CDCl3) d 7.21 (d, J = 7.27 Hz, 2H), 7.06 (d, J = 7.27 Hz, 2H), 6.99–
6.96 (m, 4H), 6.27 (s, 1H), 3.47 (s, 2H), 2.84–2.80 (m, 4H), 2.78–
2.76 (m, 4H), 2.55 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 2.05 (s, 3H),
1.17 (t, J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 10.33, 14.40,
22.44, 32.39, 28.40, 49.41, 55.57, 114.02, 114.25, 120.33, 122.37,
125.34, 127.99, 128.78, 131.11, 134.29, 135.10, 136.21, 136.56.
Anal. (C25H30N2S2) C, H, N, S.
White needles (yield 35%), mp 127 °C. 1H NMR (400 MHz,
CDCl3) d 7.07 (d, J = 7.27 Hz, 2H), 6.98–6.93 (m, 6H), 6.29 (s, 1H),
3.83 (s, 3H), 3.46 (s, 2H), 2.80–2.76 (m, 4H), 2.73–2.70 (m, 4H),
2.43 (t, J = 7.1 Hz, 2H), 2.04 (s, 3H), 1.64–1.62 (m, 2H), 0.91 (t,
J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 10.30, 13.29, 24.56,
28.60, 38.21, 49.28, 55.60, 60.09, 113.98, 114.08, 119.03, 121.34,
125.41, 127.40, 128.24, 129.53, 131.15, 134.38, 135.00, 137.33.
Anal. (C26H32N2OS) C, H, N, S.
5.3.24. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
ylthio)phenyl]-1-[4-(ethyl)phenyl]-1H-pyrrole (25)
5.3.18. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
oxy)phenyl]-1-[4-(propyl)phenyl]-1H-pyrrole (19)
White needles (yield 35%), mp 168 °C. 1H NMR (400 MHz,
CDCl3) d 7.21 (d, J = 7.27 Hz, 2H), 7.04–7.00 (m, 6H), 6.31 (s, 1H),
3.47 (s, 2H), 2.84–2.80 (m, 4H), 2.75–2.70 (m, 6H), 2.42 (s, 3H),
2.05 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d
10.39, 14.42, 22.43, 32.40, 28.30, 49.43, 55.51, 114.09, 114.33,
121.30, 122.55, 124.74, 128.99, 130.07, 131.10, 134.29, 135.10,
136.11, 136.33. Anal. (C25H30N2S2) C, H, N, S.
White needles (yield 25%), mp 105 °C. 1H NMR (400 MHz,
CDCl3) d 7.16 (d, J = 7.27 Hz, 2H), 7.05 (d, J = 7.27 Hz, 2H), 6.92 (s,
4H), 6.29 (s, 1H), 3.81 (s, 3H), 3.48 (s, 2H), 2.80–2.78 (m, 4H),
2.74–2.71 (m, 4H), 2.60 (t, J = 7.1 Hz, 2H), 2.05 (s, 3H), 1.67–1.64
(m, 2H), 0.94 (t, J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d
10.30, 13.33, 24.40, 28.40, 38.33, 49.50, 55.55, 60.00, 113.98,
114.08, 120.03, 122.34, 125.40, 126.80, 128.94, 129.73, 130.05,
134.28, 135.01, 136.77. Anal. (C26H32N2OS) C, H, N, S.
5.3.25. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(propyl)
phenyl]-1-[4-(methylthio)phenyl]-1H-pyrrole (26)
5.3.19. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(i-pro-
pyl)phenyl]-1-[4-(methoxy)phenyl]-1H-pyrrole (20)
White needles (yield 40%), mp 122 °C. 1H NMR (400 MHz,
CDCl3) d 7.07 (d, J = 7.27 Hz, 2H), 6.98 (s, 4H), 6.87 (d, J = 7.27 Hz,
2H), 6.29 (s, 1H), 3.83 (s, 3H), 3.46 (s, 2H), 2.89–2.86 (m, 5H),
2.76–2.73 (m, 4H), 2.03 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H)). 13C
NMR (400 MHz, CDCl3) d 10.30, 23.44, 28.40, 36.33, 49.50, 55.55,
59.40, 113.98, 114.09, 120.00, 122.34, 125.40, 128.94, 129.73,
130.08, 134.26, 135.11, 136.78, 148.66. Anal. (C26H32N2OS) C, H,
N, S.
White needles (yield 45%), mp 125 °C. 1H NMR (400 MHz,
CDCl3) d 7.20 (d, J = 7.27 Hz, 2H), 7.06 (d, J = 7.27 Hz, 2H), 6.98–
6.93 (m, 4H), 6.29 (s, 1H), 3.46 (s, 2H), 2.79–2.76 (m, 4H), 2.72–
2.69 (m, 4H), 2.54–2.50 (m, 5H), 2.05 (s, 3H), 1.59–1.56 (m, 2H),
0.91 (t, J = 7.1 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 10.39, 13.78,
22.39, 24.34, 38.31, 28.33, 49.41, 55.49, 114.12, 114.55, 121.31,
122.01, 125.41, 128.92, 131.02, 131.10, 134.32, 135.22, 136.15,
137.93. Anal. (C26H32N2S2) C, H, N, S.
5.3.26. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
ylthio)phenyl]-1-[4-(propyl)phenyl]-1H-pyrrole (27)
5.3.20. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
oxy)phenyl]-1-[4-(i-propyl)phenyl]-1H-pyrrole (21)
Yellow oil (yield 45%). 1H NMR (400 MHz, CDCl3) d 7.17 (d,
J = 7.27 Hz, 2H), 7.04–7.00 (m, 6H), 6.31 (s, 1H), 3.47 (s, 2H),
2.80–2.76 (m, 4H), 2.74–2.70 (m, 4H), 2.61 (t, J = 7.1 Hz, 2H), 2.40
(s, 3H), 2.05 (s, 3H), 1.68–1.63 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). 13C
NMR (400 MHz, CDCl3) d 10.33, 13.81, 22.37, 24.32, 38.30, 28.39,
49.50, 55.50, 114.11, 114.18, 121.30, 122.21, 126.21, 127.72,
White needles (yield 20%), mp 118 °C. 1H NMR (400 MHz,
CDCl3) d 7.20 (d, J = 7.27 Hz, 2H), 7.05 (d, J = 7.27 Hz, 2H), 6.95–
6.90 (m, 4H), 6.28 (s, 1H), 3.85 (s, 3H), 3.48 (s, 2H), 2.94–2.90 (m,
1H), 2.82–2.78 (m, 4H), 2.74–2.70 (m, 4H), 2.06 (s, 3H), 1.27 (s,
3H), 1.20 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.30, 23.66,

8084
M. Biava et al. / Bioorg. Med. Chem. 18 (2010) 8076–8084
130.32, 131.70, 134.52, 135.00, 136.21, 138.00. Anal. (C26H32N2S2)
C, H, N, S.
References and notes
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2009. World Health Organization (WHO/HTM/TB/2009.411).
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8. Dorman, S. E.; Chaisson, R. E. Nat. Med. 2007, 13, 295.
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5.3.27. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(i-pro-
pyl)phenyl]-1-[4-(methylthio)phenyl]-1H-pyrrole (28)
White needles (yield 60%), mp 131 °C. 1H NMR (400 MHz,
CDCl3) d 7.21 (d, J = 7.27 Hz, 2H), 7.07 (d, J = 7.27 Hz, 2H), 6.92–
6.90 (m, 4H), 6.28 (s, 1H), 3.49 (s, 2H), 2.92–2.89 (m, 1H), 2.87–
2.81 (m, 4H), 2.74–2.72 (m, 4H), 2.38 (s, 3H), 2.06 (s, 3H), 1.27 (s,
3H), 1.20 (s, 3H). 13C NMR (400 MHz, CDCl3) d 10.33, 22.43,
23.41, 36.30, 28.39, 49.50, 55.50, 114.09, 114.11, 122.01, 125.03,
126.55, 127.72, 131.69, 135.02, 135.40, 136.22, 138.03, 147.77.
Anal. (C26H32N2S2) C, H, N, S.
10. O’Brien, R. J.; Nunn, P. P. Am. J. Respir. Crit. Care Med. 2001, 1635, 1055.
11. Deidda, D.; Lampis, G.; Fioravanti, R.; Biava, M.; Porretta, G. C.; Zanetti, S.;
Pompei, R. Antimicrob. Agents Chemother. 1998, 42, 3035.
12. Biava, M. Curr. Med. Chem. 2002, 9, 1859.
5.3.28. 2-Methyl-3-[(thiomorpholin-4-yl)-methyl]-5-[4-(meth-
ylthio)phenyl]-1-[4-(i-propyl)phenyl]-1H-pyrrole (29)
13. Biava, M.; Porretta, G. C.; Poce, G.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F.
Bioorg. Med. Chem. 2005, 13, 1221.
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P.; Manetti, F.; Botta, M. J. Med. Chem. 2006, 49, 4946.
15. Biava, M.; Porretta, G. C.; Manetti, F. Mini-Rev. Med. Chem. 2007, 7, 65.
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F.; De Rossi, E.; Botta, M. J. Med. Chem. 2008, 51, 3644.
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Rossi, E.; Botta, M. Eur. J. Med. Chem. 2009, 44, 4734.
18. Biava, M.; Porretta, G. C.; Deidda, D.; Pompei, R.; Tafi, A.; Manetti, F. Bioorg.
Med. Chem. 2003, 11, 515.
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20. Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R.; Wilson,
M. W.; Newton, R. S. J. Med. Chem. 1990, 33, 21.
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22. Biava, M.; Porretta, G. C.; Pompei, R.; Botta, M.; Manetti, F.; De Logu, A. PCT Int.
Appl. 2009, p 31, WO 2009040755 A2 20090402 AN 2009:386048.
23. Shridhar, D. R.; Jogibhukta, M.; Rao, P.; Shanthan, H.; Vijay, K. Synthesis 1982,
12, 1061.
Yellow oil (yield 52%). 1H NMR (400 MHz, CDCl3) d 7.22 (d,
J = 7.27 Hz, 2H), 7.04–7.00 (m, 6H), 6.31 (s, 1H), 3.49 (s, 2H),
2.78–2.80 (m,1H), 2.76–2.72 (m, 4H), 2.70–2.68 (m, 4H), 2.41 (s,
3H), 2.06 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H). 13C NMR (400 MHz,
CDCl3) d 10.30, 22.32, 23.39, 36.22, 28.41, 49.67, 55.61, 114.01,
114.33, 122.05, 123.63, 127.05, 127.70, 131.29, 135.12, 135.37,
136.10, 138.00, 148.01. Anal. (C26H32N2S2) C, H, N, S.
Acknowledgment
We are grateful for financial support from CARIPLO Foundation
(Rif. 2006.0880/10.8485 Bando 2006) and from Istituto Pasteur-
Fondazione Cenci Bolognetti.