Synthesis and biological evaluation of N-(aryl)-2-thiophen-2-ylacetamides series as a new class of antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2007.09.096

The present article describes a series of 21 N-(aryl)-2-thiophen-2-ylacetamides, which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concen

Full text of DOI:10.1016/j.bmcl.2007.09.096

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6895–6898
Synthesis and biological evaluation of N-(aryl)-2-thiophen-2-
ylacetamides series as a new class of antitubercular agents
Maria Cristina Silva Lourenc¸o,b Felipe Rodrigues Vicente,b
a
a
´
´
Maria das Grac¸as Muller de Oliveira Henriques, Andre Luis Peixoto Candea,
Raoni Schroeder Borges Gonc¸alves,a Thais Cristina M. Nogueira,a
a
a,
*
´
Marcelle de Lima Ferreira and Marcus Vinıcius Nora de Souza
aFioCruz-Fundac¸a˜o Oswaldo Cruz, Instituto de Tecnologia em Fa´rmacos-Far Manguinhos, Rua Sizenando Nabuco 100,
Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil
bInstituto de Pesquisas Clı´nica Evandro Chagas—IPEC, Av. Brasil, 4365 Manguinhos Rio de Janeiro, RJ, Brazil
Received 28 August 2007; revised 19 September 2007; accepted 28 September 2007
Available online 4 October 2007
Abstract—The present article describes a series of 21 N-(aryl)-2-thiophen-2-ylacetamides, which were synthesized and evaluated for
their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory con-
centration (MIC) in lg/mL. The compounds 2, 3, 7, 8, 11, 12, 15, 16, and 20 exhibited activity between 25 and 100 lg/mL and could
be a good start point to find new lead compounds in the fight against multidrug resistant tuberculosis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Nowadays, microorganisms resistant to multiple antimi-
crobial agents are a serious problem worldwide in the
fight against infectious diseases, increasing morbidity
and mortality with an overall increase in healthcare
costs. In this context, Tuberculosis (TB) has become
again an important public health problem worldwide
since the mid-1980s, due to two major factors, the AIDS
epidemic and the advent of multidrug resistant strains
(MDR). TB is responsible for 20% of all deaths in
adults, and each year there are about 8.9–9 millions of
new cases, of which 15% are children, and 1.7–2 millions
of deaths, of which 450,000 are children. Globally, the
number of TB cases is currently rising at 2% per year
with the estimative of 32% of the world population,
about 2 billion people, being infected by latent TB. In
the case of patients with AIDS, TB is the most common
opportunistic infection and cause of death killing 1 of
every 3 patients.1 Due to the increase of MDR-TB and
AIDS cases worldwide and the lack of new drugs now-
adays, there is an urgent need for new drugs to fight
against this disease. In this context, thiophene nucleus
represents a very important field in drug discovery,
which is present in many natural and synthetic products
with a wide range of pharmacological activities.2 Con-
sidering that, the aim of this article is to present a series
of 21 N-(aryl)-2-thiophen-2-ylacetamide derivatives,
which have been synthesized, see Scheme 1, and evalu-
ated for their in vitro antibacterial activity against
Mycobacterium tuberculosis.
The synthesis of N-(aryl)-2-thiophen-2-ylacetamide
derivatives (2–22) involved the reaction between appro-
priate anilines and thiopheneacetyl chloride, as de-
scribed in the general procedure, leading to the desired
compounds (2–22) in 68–100% yields (Scheme 1).3 All
the compounds were identified by spectral data. In
general, IR spectra showed the C@O peak at 1652–
1
1695 cmꢀ1. The H NMR spectrum showed the hydra-
zide (NH) proton as a large singlet at 9.25–10.78 ppm
and CH2CO proton as a singlet at 3.99–3.82 ppm. The
13C NMR spectrum showed the C@O signals at 175.2–
167.5, CH2CO signals at 40.4–36.1, and aromatic car-
bons at the region of 140–104 ppm3.
Keywords: Thiopheneacetamides; Tuberculosis; Antimycobacterial
activity.
The antimycobacterial activities of compounds (2–22)
were assessed against M. tuberculosis ATTC 27294,4
*
Corresponding author. Tel.: +55 2139772404; fax: +55
2125602518; e-mail: marcos_souza@far.fiocruz.br
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.096

6896
M. C. S. Lourenc¸o et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6895–6898
R1
R1
H
N
R2
R3
R2
S
S
Cl H2N
THF
+
O
O
R5
68-100%
R5
R3
1
R4
2-22
R4
Different anilines
Scheme 1.
using the microplate Alamar blue assay (MABA)5
(Table 1). This methodology is nontoxic, uses ther-
mally stable reagent, and shows good correlation with
proportional and BACTEC radiometric methods.6,7
Briefly, two hundred microliters of sterile deionized
water was added to all outer-perimeter wells of sterile
96-well plates (falcon, 3072: Becton Dickinson, Lin-
coln Park, NJ) to minimize evaporation of the med-
ium in the test wells during incubation. The 96-well
plates received 100 lL of the Middlebrook 7H9 broth
(Difco laboratories, Detroit, MI, USA) and a serial
dilution of the compounds 9–16 was made directly
on the plate. The final drug concentrations tested were
0.01–10.0 lL/mL. Plates were covered and sealed with
parafilm and incubated at 37 ꢁC for 5 days. After this
time, 25 mL of a freshly prepared 1:1 mixture of
Alamar blue (Accumed International, Westlake, Ohio)
reagent and 10% Tween 80 was added to the plate and
incubated for 24 h. A blue color in the well was inter-
preted as no bacterial growth, and a pink color was
scored as growth. The MIC (Minimal Inhibition Con-
centration) was defined as the lowest drug concentra-
tion, which prevented a color change from blue to
pink.
Cellular viability in the presence and absence of test
compounds was determined by Mosmans’s MTT (3-
(4,5-dimethylthiazol-2yl)-2,5-dimethyl tetrazolium bro-
mide; Merck) microcultured tetrazolium assay as de-
scribed.8,9 The cells (macrophage cell line, J774) were
plated in flat-bottomed 96-well plates (2.5 · 106 cells/
mL), cultured for 1 h in controlled atmosphere (CO2
5% at 37 ꢁC), and non-adherent cells were washed by
gentle flushing with RPMI 1640. Adherent cells were
cultured in the presence of medium alone, Tween 20
(3%) (live and dead controls, respectively) or different
concentrations of compounds (0.1, 1.0, 10.0, and
100 lg/mL) in a triplicate assay. After 18 h, stock
MTT solution (5 mg/mL of saline; 20 lL/well) was
added to the culture and 4 h later, supernatant was dis-
charged and DMSO (100 lL/well) was added for forma-
zan crystal solubilization and the absorbance was read
at 540 nm in a plate reader (Bio-Rad—450). The results
were represented as percentage cell viability (Table 2).
Table 1. Antimycobacterial activities, LogP measurements, and yields of N-(arryl)-2-thiophen-2-ylacetamides (2–22)
Compound
R1
R2
R3
R4
R5
MICa
LogPb
Yield
2
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
OCH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3
Cl
—
—
—
—
25
100
2.55
2.74
2.66
2.81
3.86
3.55
2.71
3.94
2.86
2.96
3.01
3.31
2.75
3.44
2.77
2.92
3.96
3.56
3.41
2.67
2.66
ꢀ0.58
ꢀ2.38
96
90
100
100
100
70
70
68
100
88
98
96
86
76
92
90
76
97
98
70
72
—
—
3
CH3
OCH3
NO2
CF3
—
4
—
—
—
—
Resistant
Resistant
Resistant
50
5
6
—
Cl
—
—
7
8
—
—
OCH3
CF3
NO2
—
—
—
50
9
Resistant
Resistant
100
10
11
12
13
14
15
16
17
18
19
20
21
22
INH
RIP
—
—
—
CH3
F
—
—
—
—
100
Br
OCH3
Cl
Resistant
Resistant
100
—
—
—
—
—
—
—
NO2
—
50
CH3
Cl
Resistant
Resistant
Resistant
100
—
—
—
Cl
F
F
Cl
—
—
OCH3
—
—
—
Resistant
Resistant
0.2
–OCH2O–
1.0
a Minimal inhibition concentration is expressed in lg/mL.
b Calculated by www.logp.com.

M. C. S. Lourenc¸o et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6895–6898
6897
NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d:
9.49 (1H; s; NH); 7.39–7.37 (m; 2H; H1,60); 7.19 (d; 2H;
J = 7.5 Hz; H30); 7.15 (t; 1H; J = 7.0 Hz; H40); 7.07; (t; 1H;
J = 7.5 Hz; H50); 7.0–6.97 (m; 2H; H2,3); 3.90 (s, 2H,
CH2CO); 2.18 (s; 3H; CH3) ppm. 13C NMR (125.0 MHz,
DMSO-d6) d: 168.0; 137.4; 136.0; 131.7; 130.3; 126.6; 126.2;
125.9; 125.3; 125.0; 36.9; 17.7 ppm; IVmmax(cmꢀ1; KBr
pellets): 1652 (CO); compound 4: N-(2-methoxyphenyl)-2-
thiophen-2-ylacetamide; yield: 100%;mp: 58–60 ꢁC; CG/
MS: m/z [M]+Æ: 247; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 9.27 (s; 1H; NH); 7.94
(d, 1H, H30; J = 8.0 Hz) 7.38 (dd; 1H; J = 5.0 and 1.5 Hz;
H1); 7.08–7.02 (m; 2H; H60,40); 6.99–6.95 (m; 2H; H2,3);
6.88 (t; 1H; J = 8.0 Hz); 3.98 (s; 2H; CH2CO); 3.82 (s; 3H;
OCH3) ppm. 13C NMR (125.0 MHz, DMSO- d6) d: ppm
175.2; 144.4; 136.8; 135.0; 132.6; 131.1; 128.1; 124.0; 122.8;
118.9; 113.5; 56.4; 40.4 ppm; IV mmax (cmꢀ1; KBr pellets):
1670 (CO); compound 5: N-(2-nitrophenyl)-2-thiophen-2-
ylacetamide; yield: 100%; mp: 40–42 ꢁC; CG/MS: m/z [M]+Æ:
Table 2. Cytotoxic effects of test compounds on murine macrophage
cells 18 h after the treatment
Compound
100 lg/mL
10 lg/mL
1 lg/mL
0.1 lg/mL
2
100%
100%
100%
85,35%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
100%
7
8
16
The percentage cell viability of compounds 2, 7, 8, and 16 in all con-
centrations tested.
In conclusion, the antimycobacterial activities of the
N-(aryl)-2-thiophen-2-ylacetamide derivatives described
here suggest that they may be selectively targeted to
M. tuberculosis growth. These compounds are not cyto-
toxic to host cells at the concentrations effective in inhib-
iting M. tuberculosis infection. The compounds 2, 3, 7, 8,
11, 12, 15, 16, and 20 exhibited activity between 25 and
100 lg/mL when compared with first line drugs such as
isoniazid (INH) and rifampin (RIP), which could be a
good start point to further studies, as well as find new
lead compounds.
1
262; H NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-
d6] d: 10.45 (1H; s; NH); 7.96 (t; 1H; J = 8.0 Hz; H30); 7.69–
7.75 (m, 2H, H40,60); 7.41 (dd; 1H; J = 4.5 Hz and 1.0 Hz;
H1); 7.37 (t, 1H, J = 8.0 Hz; H50); 7.10–6.99 (m; 2H; H2,3);
3.95 (s, 2H, CH2CO) ppm. 13C NMR (125.0 MHz, DMSO-
d6) d: 168.2; 147.2; 141.9; 135.6; 134.0; 131.1; 126.7; 125.3;
125.2; 119.1; 115.4; 36.9 ppm; IV mmax (cmꢀ1; KBr pellets):
1695 (CO); compound 6: N-(2-trifluorophenyl)-2-thiophen-
2-ylacetamide; yield: 100%; mp: 85–87 ꢁC; CG/MS: m/z
[M]+Æ: 285; 1H NMR [500.00 MHz (FIDRES 0.15 Hz),
DMSO-d6] d: 9.73 (1H; s; NH); 7.72 (d; 1H; J = 10.0 Hz;
H30); 7.67 (t; 1H; J = 10.0 Hz; H40); 7.50 (d; 1H;
J = 10.0 Hz; H60); 7.45 (t; 1H; J = 10.0 Hz; H50); 7.39 (t;
1H; J = 4.5 Hz; H1); 6.99–6.97 (m; 2H; H2,3); 3.93 (s, 2H,
CH2CO) ppm. 13C NMR (125.0 MHz, DMSO-d6) d: 168.9;
136.7; 135.1; 132.9; 129.7; 126.6–123.1 (m); 125.0; 124.3;
122.1; 36.4 ppm; IV mmax (cmꢀ1; KBr pellets): 1666 (CO);
compound 7: N-(3-chlorophenyl)-2-thiophen-2-ylacetamide;
yield: 70%; mp: 75–77 ꢁC; CG/MS: m/z [M]+Æ: 251; 1H
NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d:
10.38 (1H; s; NH); 7.80 (s; 1H; H20); 7.44 (dd;1H; J = 8.0
and 0.5 Hz; H40); 7.38 (dd; 1 H; J = 5.0 and 1.5 Hz; H1);
7.33 (t; 1H; J = 8.0 Hz; H50); 7.10 (d; 1H; J = 8.0 Hz; H60);
6.99–6.97 (m; 2H; H2,3); 3.88 (s, 2H, CH2CO) ppm. 13C
NMR (125.0 MHz, DMSO-d6) d: 168.3; 140.4; 136.6; 133.0;
130.4; 126.6; 126.4; 125.0; 123.0; 118.6; 117.5; 37.4 ppm;
IVmmax (cmꢀ1; KBr pellets): 1684 (CO); compound 8: N-(3-
methoxyphenyl)-2-thiophen-2-ylacetamide; yield: 70%; mp:
References and notes
1. http://www.who.int/tdr/diseases/tb/default.htm.
2. Kleemann, A.; Engel, J.; Kutscher; Reichert Pharmaceuti-
cal Substances; Syntheses, Patents, Applications; Thieme,
4th, ed.; 2001; vols. 1 and 2.
3. General procedures. Melting points were determined on a
Buchi apparatus and are uncorrected. Infrared spectra were
recorded on a Thermo Nicolet Nexus 670 spectrometer as
potassium bromide pellets and frequencies are expressed in
cmꢀ1. Mass spectra (CG/MS) were recorded on a Agilent
Technologies 6890/5972A mass spectrometer. NMR spectra
were recorded on a Bruker Avance 500 spectrometer
operating at 500.00 MHz (1H) and 125.0 MHz (13C), in
deuterated dimethylsulfoxide. Chemical shifts are reported
in ppm (d) relative to tetramethylsilane. Proton and carbon
spectra were typically obtained at room temperature. For
TLC plates coated with silica gel were run in ethyl acetate
and spots were developed in Ultraviolet.
General procedures for the synthesis of N-(aryl)-2-thiophen-
2-ylacetamide derivatives (2–22): The N-(aryl)-2-thiophen-
2-ylacetamides derivatives (2–22) were prepared by reaction
between the appropriate anilines and thiophenylacetylchlo-
ride in tetrahydrofuran, under nitrogen atmosphere
(Scheme 1). After stirring for 2–3 h at room temperature
the reaction mixture was quenched with 30 mL of water
and extracted with ethylacetate (20 mL · 2). The combined
organic layers were washed with saturated aqueous
NaHCO3 and brine, dried (MgSO4), filtered, and concen-
trated in vacuo to produce the desired amides without
further purification.
Compound 2: N-(Phenyl)-2-thiophen-2-ylacetamide; yield:
96%; mp: 101–106 ꢁC; CG/MS: m/z [M]+Æ 217; 1H NMR
[500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d: 10.15
(1H; s; NH); 7.58 (d; 2H; J = 8.0 Hz; H2060); 7.37 (dd;
1H; J = 5.0 and 2.0 Hz; H1); 7.30 (t; 2H; J = 8.0 Hz; H30,5);
7.05 (t; 1H; J = 8.0 Hz; H40); 6.98–6.96 (m; 2H; H2,3); 3.87
(s, 2H, CH2CO) ppm. 13C NMR (125.0 MHz, DMSO-d6) d:
168.0; 139.0; 137.1; 128.8; 126.7; 126.3; 125.1; 123.4; 119.1;
37.6 ppm; IV mmax (cmꢀ1; KBr pellets): 1657 (CO); com-
pound 3: N-(2-methylphenyl)-2-thiophen-2-ylacetamide;
yield: 90%; mp: 126–127 ꢁC; CG/MS: m/z [M]+Æ: 231; 1H
1
68–70 ꢁC; CG/MS: m/z [M]+Æ: 247; H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.15 (s; 1H; NH); 7.38
(dd; J = 4.0 and 2.0 Hz; H1); 7.29 (s; 1H; H20); 7.20 (t; 1H;
J = 8.0 Hz; H50); 7.11 (d; 1H; J = 8.0 Hz; H40); 6.98–6.96
(m; 2H; H2,3); 6.62 (dd; 1H; J = 8.0 and 2.0 Hz; H60); 3.86
(s; 2H; CH2CO); 3.70 (s; 3H; OCH3) ppm. 13C NMR
(125.0 MHz, DMSO-d6) d: 167.9; 159.5; 140.1; 137.0; 129.5;
126.6; 126.3; 125.0; 111.4; 108.8; 104.9; 54.9; 37.5 ppm; IV
mmax (cmꢀ1; KBr pellets): 1682 (CO); compound 9: N-(3-
trifluoromethylphenyl)-2-thiophen-2-ylacetamide;
yield:
68%; mp: 66–68 ꢁC; CG/MS: m/z [M]+Æ: 285; 1H NMR
[500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d: 10.53
(1H; s; NH); 8.07 (s; 1H; H20); 7.76 (d; 1H; J = 10.0 Hz;
H40); 7.53 (t; 1H; J = 10 Hz; H50); 7.41–7.38 (m; 2H;
H60,1); 6.99–6.97 (m; 2H; H2,3); 3.90 (s, 2H, CH2CO) ppm.
13C NMR (125.0 MHz, DMSO-d6) d: 168.6; 139.7; 136.6;
130.0; 129.7; 126.7; 126.5; 125.4; 125.2; 122.7; 119.7 (m);
115.2 (m); 37.5 ppm; IV mmax (cmꢀ1; KBr pellets): 1669
(CO); compound 10: N-(3-nitrophenyl)-2-thiophen-2-ylace-
tamide; yield: 100%; mp: 96–97 ꢁC; CG/MS: m/z [M]+Æ: 262;
1H NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d:
10.67 (1H; s; NH); 8.62 (s; 1H; H20); 7.91 (dd; 2H; J = 8.5

6898
M. C. S. Lourenc¸o et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6895–6898
and 2.5 Hz; H4060); 7.61 (t; 1H; J = 8.0 Hz; H50); 7.40 (dd;
135.1; 134.8; 127.6; 126.6; 126.4; 126.2; 124.8; 36.5;
17.9 ppm; IV mmax (cmꢀ1; KBr pellets): 1644 (CO); com-
pound 18: N-(2,5-dichlorophenyl)-2-thiophen-2-ylaceta-
mide; yield: 76%; mp: 138–140 ꢁC; CG/MS: m/z [M]+Æ:
1H; J = 5.0 and 1.5 Hz; H1); 7.01–6.98 (m; 2H; H2,3); 3.93
(s, 2H, CH2CO) ppm. 13C NMR (125.0 MHz, CDCl3) d:
168.1; 148.6; 138.5; 134.8; 129.9; 128.1; 127.9; 126.5; 125.5;
119.2; 114.6; 38.5; IVmmax (cmꢀ1; KBr pellets): 1673 (CO);
compound 11: N-(4-methylphenyl)-2-thiophen-2-ylaceta-
mide; yield: 88%; mp: 121–123 ꢁC; CG/MS: m/z [M]+Æ:
1
285; H NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-
d6] d: 10.07 (1H; s; NH); 7.53 (d; 2H; J = 8.0 Hz; H30,5);
7.38 (dd; 1H; J = 5.0 and 0.5 Hz; H1); 7.34 (t; 1H; J = 8.0;
H40); 7.02–6.97 (m; 2H; H2,3); 3.92 (s; 2H; CH2CO) ppm.
13C NMR (125.0 MHz, DMSO-d6) d: 168.0; 142.0; 136.7;
1
231; H NMR [500.00 MHz (FIDRES 0.15 Hz), CDCl3]
d: 9.37 (1H; s; NH); 7.24 (d; 2H; J = 9.0 Hz; H30,50); 7.27;
(t; 1H; J = 3.5 Hz; H1); 7.01–6.98 (m; 2H; H2,3); 7.26 (d;
2H; J = 9.0 Hz; H20,60); 3.77 (s, 2H, CH2CO); 2.26 (s, 3H,
CH3) ppm. 13C NMR (125.0 MHz, CDCl3) d: 176.8; 139.6;
136.8; 135.0; 132.6; 129.5; 128.7; 118.0; 40.3; 20.4.; IV mmax
(cmꢀ1; KBr pellets): 1670 (CO); compound 12: N-(4-
fluorophenyl)-2-thiophen-2-ylacetamide; yield: 98%; mp:
104–106 ꢁC; CG/MS: m/z [M]+Æ: 235; 1H NMR
[500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d: 10.12
(1H; s; NH); 7.61 (dd; 2H; J = 8.5 and 3.5 Hz; H30,50);
7.37 (dd; 1H; J = 4.5 and 2.0 Hz; H1); 7.13; (t; 2H;
J = 8.5 Hz; H20,60); 6.98–6.96 (m; 2H; H2,3); 3.86 (s, 2H,
CH2CO) ppm. 13C NMR (125.0 MHz, DMSO-d6) d: 167.8;
158.0 (238 Hz); 136.9; 135.3; 126.6; 126.3; 124.9; 120.8
(J = 8 Hz); 115.2 (J = 22 Hz); 37.3 ppm; IVmmax (cmꢀ1; KBr
pellets): 1665 (CO); compound 13: N-(4-bromophenyl)-2-
thiophen-2-ylacetamide; yield: 96%; mp: 138–139 ꢁC; CG/
MS: m/z [M]+Æ: 297; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.30 (1H; s; NH);
7.56 (d; 2H; J = 9.0 Hz; H30,50); 7.48 (d; 2H; J = 9.0 Hz;
H20,60); 7.38; (dd; 1H; J = 4.5 and 2.0 Hz; H1); 6.98–6.96
(m; 2H; H2,3); 3.87 (s, 2H, CH2CO) ppm. 13C NMR
(125.0 MHz, DMSO-d6) d: 168.1; 138.3; 136.8; 131.5; 126.6;
126.3; 125.0; 121.3; 114.8; 37.4 ppm; IV mmax (cmꢀ1; KBr
pellets): 1660 (CO); compound 14: N-(4-methoxyphenyl)-2-
thiophen-2-ylacetamide; yield: 86%; mp: 138–139 ꢁC; CG/
MS: m/z [M]+Æ: 247; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.00 (1H; s; NH);
7.48 (d; 2H; J = 9.0 Hz; H30,50); 7.37; (t; 1H; J = 3.5 Hz;
H1); 6.97–6.96 (m;2H; H2,3); 6.87 (d; 2H; J = 9.0 Hz;
H20,60); 3.82 (s, 2H, CH2CO); 3.71 (s, 3H, OCH3) ppm. 13C
NMR (125.0 MHz, DMSO-d6) d: 167.5; 155.2; 150.6; 142.3;
132.8; 128.5; 126.6; 125.2; 116.9; 36.1 ppm; IV mmax (cmꢀ1
;
KBr pellets): 1671 (CO); compound 19: N-(2,4-chlorofluor-
ophenyl)-2-thiophen-2-ylacetamide; yield: 97%; mp: 113–
114 ꢁC; CG/MS: m/z [M]+Æ: 269; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 9.76 (1H; s; NH); 7.67
(dd; 1H; J = 8.5 and 5.5 Hz; H30); 7.48 (dd; 1H; J = 8.5 and
3.0 Hz; H50); 7.38 (dd; 1H; J = 5.0 and 0.5 Hz; H1); 7.21
(ddd; 1H; J = 8.5; 5.0 and 3.0 Hz; H60); 7.02–6.97 (m; 2H;
H2,3); 3.92 (s; 2H; CH2CO) ppm. 13C NMR (125.0 MHz,
DMSO-d6) d: 168.4; 158.7 (J = 244 Hz); 136.8; 131.4; 131.3;
127.8-127.7 (m); 126.6; 126.4; 125.0; 116.5 (J = 25.6 Hz);
114.4 (J = 22.0 Hz); 36.6 ppm; IV mmax (cmꢀ1; KBr pellets):
1662 (CO); compound 20: N-(2,4-fluorochlorophenyl)-2-
thiophen-2-ylacetamide; yield: 98%; mp: 111–113 ꢁC; CG/
MS: m/z [M]+Æ: 269; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.05 (1H; s; NH);
7.93 (t; 1H; J = 9.0 Hz; H30); 7.47 (dd; 1H; J = 10 and
2.5 Hz; H50); 7.38 (dd; 1H; J = 4.5 and 1.5 Hz; H1); 7.24 (d;
1H; J = 10 Hz; H60); 6.98–6.96 (m; 2H; H2,3); 3.95 (s; 2H;
CH2CO) ppm. 13C NMR (125.0 MHz, DMSO-d6) d: 168.5;
153.0 (J = 247 Hz) 136.7; 128.1 (J = 23 Hz); 126.6; 126.4;
126.2; 125.0; 124.8; 124.5; 124.4; 116.0 (J = 95 Hz);
36.8 ppm; IV mmax (cmꢀ1; KBr pellets): 1668 (CO); com-
pound 21: N-(2,5-dimethoxyphenyl)-2-thiophen-2-ylaceta-
mide; yield: 70%; mp: 97–99 ꢁC; CG/MS: m/z [M]+Æ: 277; 1H
NMR [500.00 MHz (FIDRES 0.15 Hz), DMSO-d6] d:
9.25 (1H; s; NH); 7.71 (d; 1H; J = 5.0 Hz; H5); 7.38 (dd;
1H; J = 5.0 and 1.5 Hz; H4); 6.98–6.93 (m; 3H; H30,40,60);
6.61 (dd; 1H; J = 5.0 and 1.5 Hz; H3); 3.99 (s; 2H; CH2CO);
3.68 (s; 3H; OCH3); 3.67 (s; 3H; OCH3) ppm. 13C NMR
(125.0 MHz, DMSO-d6) d: 168.3; 152.8; 143.3; 137.1; 127.9;
126.6; 126.4; 125.0; 111.7; 108.0; 107.8; 56.1; 55.2;
37.1 ppm; IV mmax (cmꢀ1; KBr pellets): 1685 (CO); com-
pound 22: N-(1,3-benzodioxol-5-yl-)-2-thiophen-2-ylaceta-
mide; yield: 72%; mp: 105–108 ꢁC; CG/MS: m/z [M]+Æ: 261;
1H NMR [500.00 MHz (FIDRES 0.15 Hz), CDCl3] d:
10.6 (1H; s; NH); 7.30 (d; 1H; J = 4.0 Hz; H5); 7.28–7.16
(m; 4H; H4; Harom.) 7.04 (ls; 1H; H3); 5.90 (s; 2H; O–
CH2–O); 3.88 (s; 2H; CH2CO) ppm. 13C NMR
(125.0 MHz, CDCl3) d: 167.8; 147.8; 144.5; 135.6; 131.6;
127.9; 127.6; 126.7; 126.1; 113.2; 108.0; 102.9; 101.3;
38.4 ppm; IV mmax (cmꢀ1; KBr pellets): 1665 (CO).
4. Canetti, J.; Rist, E.; Grosset, R. Pneumology 1963, 27,
217.
137.3; 132.2; 114.5; 113.8; 55.2; 37.4 ppm; IV mmax (cmꢀ1
;
KBr pellets): 1679 (CO); compound 15: N-(4-chlorophenyl)-
2-thiophen-2-ylacetamide; yield: 76%; mp: 114–116 ꢁC; CG/
MS: m/z [M]+Æ: 251; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.30 (1H; s; NH);
7.62 (d; 2H; J = 9.0 Hz; H30,50); 7.38; (dd; 1H; J = 5.0 and
2.0 Hz; H1); 7.34 (d; 2H; J = 9.0 Hz; H20,60); 6.98–6.96 (m;
2H; H2,3); 3.87 (s, 2H, CH2CO) ppm. 13C NMR
(125.0 MHz, DMSO-d6) d: 168.1; 137.9; 136.8; 128.6;
126.8; 126.6; 126.3; 125.0; 120.6; 37.4 ppm; IV mmax (cmꢀ1
;
KBr pellets): 1658 (CO); compound 16: N-(4-nitrophenyl)-2-
thiophen-2-ylacetamide; yield: 92%; mp: 125–127 ꢁC; CG/
MS: m/z [M]+Æ: 262; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 10.78 (1H; s; NH);
8.22 (d; 2H; J = 7.5 Hz; H30,50); 7.84 (d; 2H; J = 7.5 Hz;
H20,60); 7.39; (dd; 1H; J = 5.0 and 0.5 Hz; H1); 7.0–6.97 (m;
2H; H2,3); 3.96 (s, 2H, CH2CO) ppm. 13C NMR
(125.0 MHz, DMSO-d6) d: 169.0; 145.2; 142.3; 136.3;
126.8; 126.7; 125.4; 118.9; 37.6 ppm; IV mmax (cmꢀ1; KBr
pellets): 1683 (CO); compound 17: N-(2,5-dimethylphenyl)-
2-thiophen-2-ylacetamide; yield: 90%; mp: 132–133 ꢁC; CG/
MS: m/z [M]+Æ: 245; 1H NMR [500.00 MHz
(FIDRES 0.15 Hz), DMSO-d6] d: 9.46 (1H; s; NH); 7.38
(dd; 1H; J = 6.5 and 2.0 Hz; H1); 7.05–6.97 (m; 5H;
H3,2,20-50); 3.82 (s; 2H; CH2CO); 2.09 (s; 6H; 2CH3)
ppm. 13C NMR (125.0 MHz, DMSO-d6) d: 167.7; 137.6;
5. Franzblau, S. G.; Witzig, R. S.; McLaughlin, J. C.; Torres,
P.; Madico, G.; Hernandez, A.; Degnan, M. T.; Cook, M.
B.; Quenzer, V. K.; Ferguson, R. M.; Gilman, R. H. J. Clin.
Microbiol. 1998, 36, 362.
6. Vanitha, J. D.; Paramasivan, C. N. Mycobacteriology 2004,
49, 179.
7. Reis, R. S.; Neves, I., Jr.; Lourenc¸o, S. L. S.; Fonseca, L. S.;
Lourenc¸o, M. C. S. J. Clin. Microbiol. 2004, 42, 2247.
8. Souza, M. C.; Siani, A. C.; Ramos, M. F. S.; Limas, O. M.,
Jr.; Henrique, M. G. M. O. Pharmazie 2003, 58, 582.
9. Carvalho, M. V.; Penido, C.; Siani, A. C.; Valente, L. M.
M.; Henriques, M. G. M. O. Gmelin Inflammopharmacol.
2006, 14, 48.