Synthesis and biological evaluation of pyrrole-2-carboxamide derivatives: Oroidin analogues

Article abstract of DOI:10.1007/s00044-013-0743-9

The reaction of pyrrole or dibromopyrrole-2-trichloroacetone with various amines results in the series of novel pyrrole-2-carboxamide bearing aromatic heterocycle or aryl or alkyl groups. Synthesized molecules were evaluated for their in vitro antibacterial activities. Most of the compounds exhibited potent activity against both Gram-positive and negative pathogens.

Full text of DOI:10.1007/s00044-013-0743-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0743-9
ORIGINAL RESEARCH
Synthesis and biological evaluation of pyrrole-2-carboxamide
derivatives: oroidin analogues
•
Balaram S. Takale Neha V. Desai
•
•
•
Afsar Ali Siddiki Hemchandra K. Chaudhari
Vikas N. Telvekar
Received: 23 April 2013 / Accepted: 17 August 2013
Ó Springer Science+Business Media New York 2013
Abstract The reaction of pyrrole or dibromopyrrole-2-
trichloroacetone with various amines results in the series of
novel pyrrole-2-carboxamide bearing aromatic heterocycle
or aryl or alkyl groups. Synthesized molecules were eval-
uated for their in vitro antibacterial activities. Most of the
compounds exhibited potent activity against both Gram-
positive and negative pathogens.
alone is ineffective to cure biofilm related infections, a
major cause of nosocomial infections (Rice, 2006). Bac-
terial biofilm formation is often described as colonization
of free floating bacteria on living or nonliving things
(Costerton et al., 1987; Hall-Stoodley et al., 2004). Biofilm
cause serious threat to individual who suffers from various
diseases. Hence, there is a growing need for new classes of
antibacterial agents able to address resistance and persis-
tent infections because of biofilms (Imamura et al., 2008;
Lewis, 2001; Parsek and Singh, 2003).
Keywords Antibacterial Á Bromination Á Carboxamides Á
Esters Á Pyrrole
The importance of Pyrrole unit especially in the biology
is recently increasing, because of its presence in the natural
products (Fresneda et al., 2001; CosimaSchroif-Gregoire
et al., 2006). Various naturally occurring pyrrole alkaloids
have been found to show antibiotic activity. Pyrrolomycin
A and B (Ezaki et al., 1981; Kaneda et al., 1981) and the
antibacterial Pyoluteorin (Bailey et al., 1973) belong to
class of pyrrole derivatives that since 1965, has been sub-
jected to extensive structural modifications. Pyrrole-am-
inoimidazole alkaloids (PAIs) from marine sponges,
including dibromosceptrin and oroidin 1c (Walker et al.,
1981) show a broad spectrum of biological activities. The
pyrrole moiety containing carboxamide is found to be an
essential in the most cases for the antimicrobial activity,
recently dihalo pyrrole carboxamides (Rane and Telvekar,
2010) were reported to be possess good antibacterial
activity and also found to be important for the antimicro-
bial activity on the basis of biofilm formation (Ballard
et al., 2009).
Introduction
The increased use of antibacterial and antifungal agents in
recent years has resulted in the development of resistance
to these drugs with significant implications for morbidity,
mortality and health care costs (Kumar et al., 2009). It is
reported that certain infections that are essentially un-
treatable have begun to occur as epidemics both in the
developing and other developed regions as a result of
antimicrobial resistance (Rahangdale et al., 2008. The
infectious diseases are becoming a global problem since
bacterial resistance has dramatically increased during the
last two decades. Furthermore, antibacterial chemotherapy
In recent years, trans-cinnamic acid derivatives have
attracted much attention due to their antimicrobial prop-
erties. Recently,the synergistic activity (Bezerra et al.,
2006) of trans-cinnamic acid in drug combinations with
INH, rifamycin, and other known antimicrobial agents
against M. tuberculosis has been exemplified. Importantly,
B. S. Takale Á N. V. Desai Á A. A. Siddiki Á
H. K. Chaudhari Á V. N. Telvekar (&)
Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Matunga, Mumbai 400 019,
India
e-mail: vikastelvekar@rediffmail.com
123

Med Chem Res
superior intracellular and in vivo activity of a cinnamyl-
rifamycin derivative in comparison with rifamycin (Rast-
ogi et al., 1998) was observed when tested against 20
susceptible and MDR M. tuberculosis strains. Significantly,
trans-cinnamic acid was used to treat TB even before
antimicrobial chemotherapy was used (Reddy et al., 1995).
Molecular hybridization is recent concept where two
pharmacophoric moieties of bioactive substance combine
to give hybrid molecule with improved efficacy than parent
compound (Viegas-Junior et al., 2007). A series of novel
molecules containing dibromopyrrole-2-carboxamides and
cinnamic acid moiety were designed. Two moieties were
combined with the help of ethane linkage. Other objective
studied was the presence or absence of bromine or cin-
namic acid in the compounds.
Experimental
General procedure for the bromination
of 2-trichloroacetyl pyrrole
2-Trichloroacetyl pyrrole (2.6 mmol) and Sodium nitrite
(5.2 mmol) were stirred in 10 ml of dichloromethane,
48 % aqueous HBr (5.2 mmol) was added dropwise
through dropping funnel for period of 15 min. The reaction
mixture was stirred for 4 h at room temperature and
completion of reaction was monitored on TLC. Finally
reaction mixture was diluted with 10 ml water and
extracted with water. The organic layer was passed through
dry Na2SO4 and evaporated using rotvac. The crude
product was purified using silica gel column chromatog-
raphy using hexane:ethylacetate (9/1) to give 85 % of pure
dibromo product.
Chemistry
As we are continuously working on development of effi-
cient routes for synthesis of organic molecules with inter-
esting properties, we herein explored our previous
methodology where we used insitu generated bromine for
Decarboxylative bromination (Telvekar and Takale, 2011).
Bromine generally used for the bromination is toxic and
difficult to handle. Hence bromination with cheap and
easily available reagent is need for this reaction; to support
this we used Sodium nitrite in combination of aqueous HBr
for bromination of pyrrole. In this case when we use liquid
Br2 product 2 obtained with 65 % yield.
Synthesis of dibromopyrrole-2-carboxamide from 4,
5-dibromopyrrol-2-yl trichloromethyl ketone (3a–3f)
4,5-dibromopyrrol-2-yl trichloromethyl ketone 2 (1 mmol)
and various aliphatic amines (1 mmol) were added to
10 ml of dichloromethane, the reaction mixture were stir-
red for 1–5 h after adding 4–5 drops of triethyl amine.
Progress of the reaction was monitored on thin layer
chromatography and after completion; the reaction mixture
was diluted with dichloromethane and extracted with
water. The organic layer was separated and evaporated to
give crude product, which was purified by silica gel column
chromatography with hexane:ethylacetate as eluent to get
60–85 % yield of pure product.
We tried to use Catalytic NaNO2 in the presence of air
but rate of reaction was found to be very low. The
respective product could be achieved in maximum yield
when 2 equivalent of NaNO2 was used (Table 1). When
pyrrole-2-trichloracetone treated with 2 equivalent of
NaNO2 and 2 equivalents of 48 % aqueous HBr, the
product 2 could be achieved in almost 85 % yield.
N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide 3a Brown
solid; m.p. 255–258 °C; IR (KBr, cm-1): 3335, 3195,
1
1610, 716; H NMR (CDCl3, 400 MHz): d 4.21 (s, 2H,
Table 1 Bromination of trichloroacetyl pyrrole
r
B
Reagent
l
COCC 3
l
COCC 3
Solvent
r
B
N
H
1
N
H
2
Entry
Reagent
Time (h)
Yield (%)
1
2
3
4
Br2 (2 eq.)/CHCl3/0 °C
Br2 (2 eq.)/CH2Cl2/0 °C
NaNO2 (2 eq.)/HBr (2 eq.)/CH2Cl2/RT
8
6
60
65
85
10
4
NaNO2 (0.05 eq.)/HBr (2 eq.)/air/CH2Cl2/RT
24
123

Med Chem Res
–NH–CH2–Ar), 6.12 (s, 1H, NH of pyrrole), 6.76 (s, 1H,
CH of pyrrole), 7.21–7.42 (m, 5H, ArH), 11.23 (s, 1H, NH–
C=O); 13CNMR (CDCl3, 400 MHz): d 42.9 (ArCH2–NH–),
d 127.5–101.0 (pyrrole), d 138.7–127.1 (Ar–C), d 161.2
(NH–C=O); MS m/z: 357.91(M?), 359.91(M?2); Anal.
calcd. for C12H10Br2N2O (358.03): C, 40.26; H, 2.82; N,
7.82; Found: C, 40.12; H, 2.98; N, 7.90.
(NH–C=O); MS m/z: 370.91(M?), 373.52(M?2); Anal.
calcd. for C13H12Br2N2O (372.06): C, 41.97; H, 3.25; N,
7.53; Found: C, 42.03; H, 3.17; N, 7.59.
4,5-Dibromo-N-cyclohexyl-1H-pyrrole-2-carboxamide 3f
Brown solid; m.p. 249–250 °C; IR (KBr, cm-1): 3418,
3115, 2927, 1647; 1H NMR (CDCl3, 400 MHz): d 1.27 (m,
4H, –CH2–CH2–CH2–CH2– CH2– of cyclohexane), 1.47
(m, 2H, –CH2–CH2–CH2– of cyclohexane), 1.50 (m, 4H,
(–CH2)2–CH–NH– of cyclohexane), 3.62 (m, 1H, –CH– of
cyclohexane), 6.11 (s, 1H, NH of pyrrole), 6.67 (s, 1H,
CH of pyrrole), 11.02 (s, 1H, NH–C=O); 13C NMR
(CDCl3, 400 MHz): d 24.6, 27.3, 35.1 (–CH2– of cyclo-
hexane), d 53.1 (–CH– of cyclohexane),d 126.7–101.7
(pyrrole), d 157.8 (NH–C=O); MS m/z: 349.91(M?),
351.71(M?2); Anal. calcd. for C11H14Br2N2O (350.05): C,
37.74; H, 4.03; N, 8.00; Found: C, 37.45; H, 4.23; N, 8.11.
Synthesis of 4,5-dibromo-N-(2-hydroxyethyl)-1H-pyr-
role-2-carboxamide (3g): 4,5-dibromopyrrol-2-yl trichlo-
romethyl ketone 2 (2.7 mmol), ethanolamine (2.97 mmol)
and 0.5 ml of triethyl amine were stirred in 15 ml of
Dichloromethane at room temperature for 2 h. After
completion of reaction, mixture was diluted with water and
extracted with dichloromethane. Organic layer was then
evaporated to get crude product. Pure product was obtained
by silica gel column chromatography using hexane:ethyl-
acetate (6:4) as white solid in 85 % yield.
4,5-Dibromo-N-butyl-1H-pyrrole-2-carboxamide 3b Brown
solid; m.p. 230–232 °C; IR (KBr, cm-1): 3341, 3161,
1
1609, 1568; H NMR (CDCl3, 400 MHz): d 0.81(t, 3H,
–CH2–CH3), 1.27 (m, 2H,–CH2–CH3), 1.29–1.52 (m, 4H,
–CH2–CH2–CH3), 3.15 (q, 2H, CH2–NH–), 6.12 (s, 1H,
NH of pyrrole), 6.62 (s, 1H, CH of pyrrole), 11.12 (s, 1H,
NH–C=O);13C NMR (CDCl3, 400 MHz): d 12.7 (–CH2–
CH3), d 31.6 (–CH2–)2, d 38.0 (CH2–NH–), d 128.1–99.7
(pyrrole), d 160.3 (NH–C=O); MS m/z: 323.93(M?),
325.93(M?2); Anal. calcd. forC13H20Br2N2O (324.01): C,
41.08; H, 5.30; N, 7.37; Found: C, 41.21; H, 5.15; N, 7.30.
4,5-Dibromo-N-hexyl-1H-pyrrole-2-carboxamide 3c Brown
solid; m.p. 245–246 °C; IR (KBr, cm-1): 3332, 3155, 1619,
1
1268; H NMR (CDCl3, 400 MHz): d 0.91 (t, 3H, CH2–
CH3), 1.28–1.35 (m, 6H,–CH2–CH2–CH2–CH3), 1.62
(m, 2H,–NH–CH2–CH2–CH2–), 3.35 (t, 2H, CH2–NH), 6.22
(s, 1H, NH fof pyrrole), 6.70 (s, 1H, CH of pyrrole), 11.01
(s, 1H, NH–C=O); 13C NMR (CDCl3, 400 MHz): d 13.3
(–CH2–CH3), d 30.6–21.7 (–CH2–)4, d 39.3 (CH2–NH–), d
128.1–99.7 (pyrrole), d 160.3 (NH–C=O); MS m/z:
351.96(M?), 353.96 (M?2); Anal. calcd. forC11H16Br2N2O
(352.07): C, 37.53; H, 4.58; N, 7.96; Found: C, 37.10; H,
4.70; N, 7.11.
4,5-Dibromo-N-(2-hydroxyethyl)-1H-pyrrole-2-carboxam-
ide 3g Brown solid; m.p. 261–263 °C; IR (KBr, cm-1):
3374, 3249, 2931, 1604, 1578; 1H NMR (CDCl3,
400 MHz): d 3.87 (q, 2H,–CH2–NH–), 4.48 (t, 2H, –CH2–
OH), 4.80 (s, 1H, –CH2–OH), 6.31 (s, 1H, NH of pyrrole),
6.69 (s, 1H, CH of pyrrole), 10.82 (s, 1H, NH–C=O); 13C
NMR (CDCl3, 400 MHz): d 38.0 (–CH2–NH–), d 46.3, d
69.2 (–CH2–OH), d 129.3–101.2 (pyrrole), d 161.8 (NH–
C=O);MS m/z: 311.89(M?), 313.23(M?2); Anal. calcd. for
C7H8Br2N2O2 (311.96): C, 26.95; H, 2.58; N, 8.98; Found:
C, 27.03; H, 2.61; N, 8.97.
4,5-Dibromo-N-(tert-butyl)-1H-pyrrole-2-carboxamide 3d
Brown solid; m.p. 240–241 °C; IR (KBr, cm-1): 3351,
1
3175, 1611, 1233; H NMR (CDCl3, 400 MHz): d 1.39 (s,
9H,((–CH3)3), 6.32 (s, 1H, NH of pyrrole), 6.75 (s, 1H,
CH of pyrrole), 11.05 (s, 1H, NH–C=O); 13C NMR
(CDCl3, 400 MHz): d 13.3 (–CH2–CH3), d 28.7 (–CH3)3, d
61.2 (–C–NH–), d 129.3–100.2 (pyrrole), d 160.0 (NH–
C=O); MS m/z: 323.93(M?), 325.92 (M?2); Anal. calcd.
for C9H12Br2N2O (324.01): C, 33.36; H, 3.73; N, 8.65;
Found: C, 33.15; H, 3.97; N, 8.74.
Synthesis of N-(2-hydroxyethyl)-1H-pyrrole-2-
carboxamide (4)
2-Trichloroacetyl pyrrole
1 (2 mmol), ethanolamine
4,5-Dibromo-N-(1-phenylethyl)-1H-pyrrole-2-carboxamide
3e Brown solid; m.p. 250–252 °C; IR (KBr, cm-1): 3417,
3151, 1645, 1509;1 H NMR (CDCl3, 400 MHz): d 1.62 (d,
3H, –CH–CH3), 5.40 (m, 1H, CH3(CH)Ph), 6.07 (d, 1H,
NH of pyrrole), 6.60 (s, 1H, CH of pyrrole), 7.28–7.39(m,
5H, ArH), 11.27(s, 1H, NH–C=O);13C NMR (CDCl3,
400 MHz): d 21.73 (ArCH–CH3), d 48.9(ArCH–NH–), d
128.8–99.52(pyrrole), d 142.62–126.03 (ArC), d 158.82
(2.1 mmol) and 0.5 ml of triethyl amine were stirred in
15 ml of dichloromethane at room temperature for 2 h.
After completion of reaction, mixture was diluted with
water and extracted with dichloromethane. Organic layer
was then evaporated to get crude product. Pure product was
obtained by silica gel column chromatography using hex-
ane:ethylacetate (6:4) as colorless liquid in 85 % yield.
123

Med Chem Res
General procedure for synthesis of simple ester derivatives
400 MHz): d 3.85 (q, 2H, –CH2–CH2–NH–), 4.55 (t, 2H,
–CH2–CH2–O–), 6.39 (s, 1H, NH of pyrrole), 6.60 (s, 1H,
CH of pyrrole), 7.46–7.61 (m, 3H, ArH), 8.05 (m, 2H,
ArH), 10.28 (s, 1H, NH–C=O); 13C NMR (CDCl3,
400 MHz): d 39.2 (–CH2–NH–), d 65.5(–CH2–O–), d
128.2–100.1 (pyrrole),d 132 (ArCH–C=O), d 134.7–128.2
(Ar C), d 160.3 (NH–C=O), d 167.4 (O=C–O–); MS
m/z:415.91(M?), 417.92(M?2); Anal. calcd. for
C14H12Br2N2O3 (416.06): C, 40.41; H, 2.91; N, 6.73;
Found: C, 40.13; H, 3.01; N, 6.79.
(5a–5j)
Acid chlorides (2 mmol) were added to 25 ml two necked
round bottom flask containing 3 g or 4 (1 equiv) in 15 ml
dichloromethane. Triethyl amine 0.5 ml was added dropwise
to neutralize the acid liberated during the reaction, finally the
reaction mixture was stirred for 1–3 h to get respective
product (observed on TLC). This crude product is then sub-
jected to silica gel column chromatography with required
percentage of eluent to get pure product in 70–80 % yield.
2-(1H-pyrrole-2-carboxamido)ethyl 3,4-dimethoxybenzo-
ate 5e Brown solid; m.p. 240–242 °C; IR (KBr, cm-1):
3430, 2931, 1710, 1018; H NMR (CDCl3, 400 MHz): d
2-(1H-pyrrole-2-carboxamido)ethyl acetate 5a Brown
solid; m.p. 235–237 °C; IR (KBr, cm-1): 3225, 2975,
1745, 1316;1H NMR (CDCl3, 400 MHz): d 2.22 (s, 3H,
CH3–C=O), 3.78 (t, 2H, –CH2–CH2–NH–), 4.52 (t, 2H,
–CH2–CH2–O–), 6.20 (s, 1H, NH of pyrrole), 6.36 (t, 1H),
6.68 (d, 1H, CH of pyrrole) 7.21 (d, 1H, CH of pyrrole),
10.23 (s, 1H, NH–C=O);13C NMR (CDCl3, 400 MHz): d
19.6(CH3–C=O), d 36.9 (–CH2–NH–), d 68.6(–CH2–O–), d
129.8–109.2 (pyrrole), d 160.1 (NH–C=O), d 175.3 (O=C–
O–);MS m/z: 196.07(M?); Anal. calcd. for C9H12N2O3
(196.20): C, 55.09; H, 6.16; N, 14.28; Found: C, 55.14; H,
6.31; N, 14.08.
1
3.83 (s, 6H,(–OCH3)2), 3.85 (q, 2H, –CH2–CH2–NH–),
4.53 (t, 2H, –CH2–CH2–O–), 6.31 (s, 1H, NH of pyrrole),
7.15 (m, 1H,ArH), 7.12–7.32 (m,2H, ArH), 7.11–7.69 (m,
3H, CH of pyrrole), 10.36 (s, 1H, NH–C=O); 13C NMR
(CDCl3, 400 MHz): d 39.8 (–CH2–NH–), d 56.7 (CH3O–
),d 65.2(–CH2–O–), d 122.2 (ArCH–C=O), d 128.9–110.2
(pyrrole), d 156.4–110.7 (Ar C), d 160.2 (NH–C=O), d
168.9 (O=C–O–); MS m/z: 318.12(M?); Anal. calcd. for
C16H18N2O5 (318.32): C, 60.37; H, 5.70; N, 8.80; Found:
C, 60.53; H, 5.78; N, 8.91.
2-(4, 5-Dibromo-1H-pyrrole-2-carboxamido)ethyl acetate
5b Brown solid; m.p. 211–213 °C; IR (KBr, cm-1): 3235,
2960, 1741, 1370;1H NMR (CDCl3, 400 MHz): d 2.29 (s, 3H,
CH3–C=O), 3.58 (q, 2H,–CH2–CH2–NH–), 4.35 (t, 2H,
–CH2–CH2–O–), 6.30 (s, 1H, NH of pyrrole) 6.70 (s, 1H,
CH of pyrrole), 10.78 (s, 1H, NH–C=O); 13C NMR (CDCl3,
400 MHz): d 24.8 (CH3–C=O), d 37.6 (–CH2–NH–), d 69.2
(–CH2–O–), d 128.0–97.9 (pyrrole), d 160.1 (NH–C=O), d
173.4 (O=C–O–); MS m/z: 353.91(M?), 355.90(M?2); Anal.
calcd. for C9H10Br2N2O3 (354.00): C, 30.54; H, 2.85; N, 7.91;
Found: C, 30.37; H, 2.67; N, 7.87.
2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl
3,4-dim-
ethoxybenzoate 5f Brown solid; m.p. 246–248 °C; IR
(KBr, cm-1): 3460, 3388, 1694, 1651, 1230; 1H NMR
(CDCl3, 400 MHz): d 3.84 (s, 6H, (–OCH3)2),3.98 (q, 2H,
–CH2–CH2–NH–), 4.53 (t, 2H, –CH2–CH2–O–), 6.47 (s,
1H, NH of pyrrole), 6.84 (s, 1H, CH of pyrrole) 7.46 (s, 1H,
ArH), 7.55–7.81 (m, 2H, ArH), 10.49 (s, 1H, NH–C=O);
13C NMR (CDCl3, 400 MHz): d 39.3 (–CH2–NH–), d 56.3
(CH3O–), d 65.3(–CH2–O–), d 124.4 (ArCH–C=O), d
128.9–99.75 (pyrrole), d 156.7–110.2 (Ar C), d 161.7 (NH–
C=O), d 171.9 (O=C–O–); MS m/z:475.92(M?), 477.94
(M?2); Anal. calcd. for C16H16Br2N2O5 (476.12): C,
40.36; H, 3.39; N, 5.88; Found: C, 40.36; H, 3.39; Br,
33.56; N, 5.88.
2-(1H-pyrrole-2-carboxamido)ethyl benzoate 5c Brown
solid; m.p. 253–256 °C; IR (KBr, cm-1): 3336, 3240,
2959, 1710, 1370;1H NMR (CDCl3, 400 MHz): d 3.82 (q,
2H,–CH2–CH2–NH–), 4.45 (t, 2H,–CH2–CH2–O–), 6.65
(d, 1H, NH of pyrrole), 6.34–6.95 (m, 3H, CH of pyrrole),
7.41–8.32 (m, 5H,ArH), 10.28 (s, 1H, NH–C=O); 13C
NMR (CDCl3, 400 MHz): d 41.3 (–CH2–NH–), d 68.2
(–CH2–O–), d 129.8–107.3 (pyrrole),d 132.4 (ArCH–
C=O), d 137.2–128.6 (Ar–C), d 160.4 (NH–C=O), d 174.4
(O=C–O–);MS m/z: 258.10(M?); Anal. calcd. for
C14H14N2O3 (258.27): C, 65.11; H, 5.46; N, 10.85; Found:
C, 65.17; H, 5.78; N, 10.43.
2-(1H-pyrrole-2-carboxamido)ethyl 4-chlorobenzoate 5g
Brown solid; m.p. 222–224 °C; IR (KBr, cm-1): 3410,
2935, 1711, 1118; 1H NMR (CDCl3, 400 MHz): d 3.82 (q,
2H, –CH2–CH2–NH–), 4.65 (t, 2H, –CH2–CH2–O–), 6.23
(s, 1H, NH of pyrrole),6.72 (s, 1H, CH of pyrrole),
6.72–6.99 (m,2H, CH of pyrrole), 7.23–7.99 (m, 4H,ArH),
10.24 (s, 1H, NH–C=O); 13C NMR (CDCl3, 400 MHz): d
39.7 (–CH2–NH–), d 65.1(–CH2–O–), d 127.3–110.1
(pyrrole),134.2 (ArCH–C=O), d 135.9 (ArCH–Cl), d
140.5–128.8 (ArC), d 160.2 (NH–C=O), d 167.3 (O=C–O–);
MS m/z: 292.08(M?); Anal. calcd. for C14H13ClN2O3
(292.72): C, 57.44; H, 4.48; N, 9.57; Found: C, 57.56; H, 4.67;
N, 9.23.
2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl benzoate
5d Brown solid; m.p. 245–247 °C; IR (KBr, cm-1):
3336, 3240, 2959, 1710, 1370; 1H NMR (CDCl3,
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Med Chem Res
2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl 4-chlo-
robenzoate 5h Brown solid; m.p. 254–256 °C; IR (KBr,
cm-1): 3396, 3152, 1706, 1440; 1H NMR (CDCl3,
400 MHz): d 3.79 (q, 2H, –CH2–CH2–NH–), 4.54 (t, 2H,
–CH2–CH2–O–), 6.37 (s, 1H, NH of pyrrole) 6.81 (s, 1H,
CH of pyrrole), 7.35–7.69 (m, 4H,ArH), 10.41 (s, 1H, NH–
C=O); 13C NMR (CDCl3, 400 MHz): d 38.3 (–CH2–NH–), d
68.5 (–CH2–O–), d 125.8–101.6 (pyrrole), d 135.7 (ArCH–
Cl), d 142.4 (ArCH–C=O), d 142.9–118.2 (Ar C), d 160.1
(NH–C=O), d 167.6 (O=C–O–); MS m/z: 449.78(M?),
451.88(M?2); Anal. calcd. for C14H11Br2ClN2O3 (450.51):
C, 37.32; H, 2.46; N, 6.22; Found: C, 37.46; H, 2.57; N, 6.11.
2-(1H-pyrrole-2-carboxamido)ethylcinnamate 6a Yellow
solid; m.p. 234–236 °C; IR (KBr, cm-1): 3286, 2949,
1706, 1320; H NMR (CDCl3, 400 MHz): d 3.52 (q, 2H,
1
–CH2–CH2–NH–), 4.55 (t, 2H, –CH2–CH2–O–), 6.44 (s,
1H, NH of pyrrole), 6.55 (d, 1H, Ar–CH=CH–), 6.61 (t,
1H, CH of pyrrole), 6.71 –6. 98 (m, 2H, CH of pyrrole),
7.19 (d, 1H, Ar–CH=CH–), 7.31–7.91 (m, 5H,ArH), 10.28
(s, 1H, NH–C=O); 13C NMR (CDCl3, 400 MHz) d 39.2
(–CH2NH–), d 67.0 (–CH2–O–),d 126.8–108.0 (pyrrole), d
135.1–128.5(Ar–C), d 145.0 (Ar–CH2=CH2–), d 159.7(Ar–
CH2=CH2–),160.5 d (NH–C=O), 166.2 d (O=C–O–); MS
m/z: 284.14(M?); Anal. calcd. for C16H16N2O3 (284.31):
C, 67.59; H, 5.67; N, 9.85; Found: C, 67.67; H, 5.69; N,
9.72.
2-(1H-pyrrole-2-carboxamido)ethyl 2-hydroxybenzoate 5i
Brown solid; m.p. 248–250 °C; IR (KBr, cm-1): 3410,
3232, 1708, 1270; 1H NMR (CDCl3, 400 MHz): d 3.58 (q,
2H, –CH2–CH2–NH–), 4.61 (t, 2H, –CH2–CH2–O–), 5.15
(s, 1H, NH of pyrrole), 5.43 (s, 1H, ArOH), 6.99–7.11 (m,
3H, CH of pyrrole), 7.27–7.91 (m, 4H, ArH), 10.56 (s, 1H,
NH–C=O); 13C NMR (CDCl3, 400 MHz): d 39.5 (–CH2–
NH–), d 65.8(–CH2–O–), d 112.3 (ArCH–C=O), d
127.3–109.6 (pyrrole), d 134.1–116.7 (ArC), d 159.2
(ArCH–OH), d 160.2 (NH–C=O), d164.4 (O=C–O–); MS
m/z: 274.12(M?), 276.25(M?2); Anal. calcd. for
C14H14N2O4 (274.27): C, 61.31; H, 5.14; N, 10.21; Found:
C, 61.35; H, 5.11; N, 10.42.
2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl cinnamate
6b Brown solid; m.p. 256–258 °C; IR (KBr, cm-1): 3442,
2935, 1705, 1643, 1219; 1H NMR (CDCl3, 400 MHz): d 3.41
(q, 2H, –CH2–CH2–NH–), 4.87 (t, 2H, –CH2–CH2–O–), 6.32
(s, 1H, NH of pyrrole), 6.43 (d, 1H, CH of pyrrole) 6.81 (d,
1H, Ar–CH=CH–), 7.11 (d, 1H, Ar–CH=CH–) 7.24–7.89
(m, 5H, ArH), 10.67 (s, 1H, NH–C=O); 13C NMR (CDCl3,
400 MHz)
d 39.4(–CH2NH–), d 67.1 (–CH2–O–),d
128.5–100.3(pyrrole),d 135.1–127.3 (Ar–C), d 145.4 (Ar–
CH2=CH2–), d 156.2(Ar–CH2=CH2–),d 162.5 (NH–C=O), d
168.6 (O=C–O–); MS m/z: 441.94(M?), 443.93(M?2);
Anal. calcd. for C16H14Br2N2O3 (442.10): C, 43.47; H, 3.19;
N, 6.34; Found: C, 43.58; H, 3.33; N, 6.23.
2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl 2-hydroxy-
benzoate 5j Brown solid; m.p. 251–253 °C; IR (KBr,
cm-1): 3336, 3235, 1705, 1241; 1H NMR (CDCl3,
400 MHz): d 3.67 (q, 2H, –CH2–CH2–NH–), 4.65 (t, 2H,
–CH2–CH2–O–), 5.35 (s, 1H, ArOH), 6.15 (s, 1H, NH of
pyrrole), 6.93 (d, 1H, CH of pyrrole), 7.31–7.77 (m, 4H,
ArH), 10.41 (s, 1H, NH–C=O); 13C NMR (CDCl3,
400 MHz): d 39.3 (–CH2–NH–), d 64.3(–CH2–O–), d 112.9
(ArCH–C=O), d 128.2–100.1 (pyrrole), d 134.5–116.8 (Ar
C),d 158.7 (ArCH–OH), d 160.2 (NH–C=O), d 164.2 (O=C–
O–); MS m/z:431.81(M?), 433.91(M?2); Anal. calcd. for
C14H12Br2N2O4 (432.06): C, 72.89; H, 4.33; N, 10.63;
Found: C, 72.63; H, 4.16; N, 10.37.
(E)-2-(1H-pyrrole-2-carboxamido)ethyl 3-(3,4-dimethoxy-
phenyl)acrylate 6c Yellow solid; m.p. 245–247 °C; IR
(KBr, cm-1): 3419, 2922, 1715, 1635;1H NMR (CDCl3,
400 MHz): d 3.46 (q, 2H, –CH2–CH2–NH–), 3.89 (s, 6H,
–(OCH3)2), 4.67 (t, 2H, –CH2–CH2–O–), 6.15 (s, 1H,
NH of pyrrole), 6.37 (d, 1H, Ar–CH=CH–), 6.71 (t, 1H,
CH of pyrrole), 6.73 –6. 92 (m, 2H, CH of pyrrole), 7.14
(d, 1H, Ar–CH=CH–) 7.42–7.86 (m, 3H, ArH), 10.87 (s,
1H, NH–C=O);13C NMR (CDCl3, 400 MHz)) d 39.2
(–CH2NH–), d 57.1 (–(OCH3)2), d 67.2 (–CH2–O–), d
106.8–100.5 (pyrrole), d 135.5–113.7 (Ar–C),d 145.3 (Ar–
CH2=CH2–), d 166.5 (Ar–CH2=CH2–),d 158.2 (NH–
C=O),d 167.4 (O=C–O–); MS m/z:344.10(M?); Anal.
calcd. for C18H20N2O5 (344.36): C, 62.78; H, 5.85; N,
8.13; Found: C, 62.87; H, 5.61; N, 8.25.
General procedure for synthesis of cinnamic ester
derivatives (6a–6n)
Acid chlorides (2 mmol) were added to 25 ml two necked
round bottom flask containing pyrrole-2-carboxamide 3 g
or 4 (2 mmol) in 15 ml dichloromethane. Triethyl amine
0.5 ml was added dropwise to neutralize the acid liberated
during the reaction, finally the reaction mixture was stirred
for 1–3 h to get respective product observed on TLC. This
crude product is then subjected to silica gel column chro-
matography with required percentage of hexane/ethyl
acetate eluent to get pure product in 75–85 % yield.
(E)-2-(4,5-dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(3,
4-dimethoxyphenyl)acrylate 6d Brown solid; m.p.
252–254 °C; IR (KBr, cm-1): 3246, 2941, 1701, 1638,
1
1229; H NMR (CDCl3, 400 MHz): d 3.56 (q, 2H, –CH2–
CH2–NH–), 4.29 (s, 6H, –(OCH3)2),4.67 (t, 2H, –CH2–
CH2–O–), 6.41 (s, 1H, NH of pyrrole), 6.51 (d, 1H,
Ar–CH=CH–), 6.73 (d, 1H, CH of pyrrole), 7.24 (d, 1H,
Ar–CH=CH–), 7.32–7.87 (m, 3H, ArH), 10.91 (s, 1H,
123

Med Chem Res
NH–C=O); 13C NMR (CDCl3, 400 MHz)
d
39.6
126.8–107.9 (pyrrole), d 135.5–125.4 (naphthalene), d
144.9 (naphthalene –CH2=CH2–), d 160.5(NH–C=O), d
166.5 (O=C–O–); MS m/z: 334.15(M?); Anal. calcd. for
C20H18N2O3 (334.37): C, 71.84; H, 5.43; N, 8.38; Found:
C, 71.67; H, 5.65; N, 8.16.
(–CH2NH–), d 56.8 (–(OCH3)2), d 67.6 (–CH2–O–), d
128.5–110.2 (pyrrole), d 135.1–127.3 (Ar–C), d 145.4 (Ar–
CH2=CH2–),
d 166.7(Ar–CH2=CH2–),d 160.1 (NH–
C=O),d 168.2 (O=C–O–); MS m/z: 501.91(M?),
503.95(M?2); Anal. calcd. for C18H18Br2N2O5 (502.15):
C, 43.05; H, 3.61; N, 5.58; Found: C, 43.13; H, 3.12; N,
5.34.
(E)-2-(4,5-dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(naph-
thalen-2-yl)acrylate 6h Yellow solid; m.p. 264–266 °C;
1
IR (KBr, cm-1): 3284, 2922, 1718, 1630, 1043; H NMR
(E)-2-(1H-pyrrole-2-carboxamido)ethyl 3-(benzo[d][1,3]
dioxol-5-yl)acrylate 6e Yellow solid; m.p. 256–258 °C;
IR (KBr, cm-1): 3394, 2928, 1708, 1637;1H NMR (CDCl3,
400 MHz): d 3.52 (q, 2H, –CH2–CH2–NH–), 4.71 (t, 2H,
–CH2–CH2–O–), 6.11(s, 2H, –O–CH2–O–), 6.23 (s, 1H,
NH of pyrrole), 6.41 (d, 1H, Ar–CH=CH–), 6.58 (t, 1H,
CH of pyrrole), 6.63 –6.89 (m, 2H, CH of pyrrole), 7.25 (d,
1H, Ar–CH=CH–) 7.38–7.95 (m, 3H,ArH), 10.07 (s, 1H,
(CDCl3, 400 MHz): d 3.87 (q, 2H, –CH2–CH2–NH–), 4.58
(t, 2H, –CH2–CH2–O–), 5.58 (s, 1H, NH of pyrrole), 6.62
(d, 1H, naphtalene –CH=CH–) 6.81 (s, 1H, NH of pyrrole),
7.52–7.91(m, 8H, naphthalene –CH=CH–, naphthalene),
9.60 (s, 1H, NH–C=O); 13C NMR (CDCl3, 400 MHz) d
39.2(–CH2NH–), d 67.3 (–CH2–O–),d 122.8(naphthalene –
CH2=CH2–), d 128.5–100.7 (pyrrole), d 135.5–124.9
(naphthalene), d 145.1 (naphthalene–CH2=CH2–), d 159.8
(NH–C=O), d 163.5 (O=C–O–); MS m/z: 491.91(M?),
494.10(M?2); Anal. calcd. for C20H16Br2N2O3 (492.16):
C, 48.81; H, 3.28; N, 5.69; Found: C, 48.75; H, 3.16; N,
5.54.
NH–C=O); 13C NMR (CDCl3, 400 MHz)
d 39.1
(–CH2NH–), d 67.3 (–CH2–O–),d 99.2(–O–CH2–O–), d
116.4(Ar–CH2=CH2–),
145.3–101.3(dioxo–Ar),
d
d
126.8–108.0 (pyrrole),
145.0 (Ar–CH2=CH2–),
d
d
160.59 (NH–C=O),d 166.2 (O=C–O–); MS m/z:
328.11(M?); Anal. calcd. for C17H16N2O5 (328.32): C,
62.19; H, 4.91; N, 8.53; Found: C, 62.34; H, 4.75; N, 8.42.
(E)-2-(1H-pyrrole-2-carboxamido)ethyl
3-(furan-2-yl)
acrylate 6i Brown solid; m.p. 230–232 °C; IR (KBr,
cm-1): 3337, 3153, 1701, 1637, 1561; H NMR (CDCl3,
1
(E)-2-(4,5-dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(benzo
400 MHz): d 3.86 (q, 2H, –CH2–CH2–NH–), 4.56 (t, 2H,
–CH2–CH2–O–), 6.48 (s, 1H, NH of pyrrole), 6.69 (d, 1H,
furan–CH=CH–),6.71 (t, 1H, CH of pyrrole), 6.72 –6.91
(m, 2H, CH of pyrrole), 7.19 (d, 1H, furan–CH=CH–),
7.25–8.09 (m, 3H,furan), 10.36 (s, 1H, NH–C=O); 13C NMR
(CDCl3, 400 MHz) d 39.7 (–CH2NH–), d 66.9 (–CH2–O–),
d 126.8–108.4 (pyrrole), d 145.2 (furan–CH2=CH2–), d
151.5–112.8 (furan), d 159.4(furan–CH2=CH2–), d 160.3
(NH–C=O),d 166.1(O=C–O–); MS m/z:274.12(M?); Anal.
calcd. for C14H14N2O4 (274.27): C, 61.31; H, 5.14; N,
10.21; Found: C, 61.45; H, 5.11; N, 10.19.
[d][1,3]dioxol-5-yl)acrylate 6f Yellow
solid;
m.p.
258–260 °C; IR (KBr, cm-1): 3280, 2927, 1703, 1625,
1
1053; H NMR (CDCl3, 400 MHz): d 3.46 (q, 2H, –CH2–
CH2–NH–), 4.56 (t, 2H, –CH2–CH2–O–), 6.01 (s, 2H, –O–
CH2–O–),6.12 (s, 1H, NH of pyrrole), 6.35 (d, 1H,
Ar–CH=CH–), 6.81 (s, 1H, CH of pyrrole), 7.21 (d, 1H,
Ar–CH=CH–), 7.29–7.93 (m, 3H, ArH), 10.22 (s, 1H, NH–
C=O); 13C NMR (CDCl3, 400 MHz) d 39.4(–CH2NH–), d
67.1 (–CH2–O–),d 97.8(–O–CH2–O–),d 114.7(Ar–CH2=
CH2–), d 128.5–100.4 (pyrrole), d 145.3–101.8(dioxo–Ar),
d 145.4 (Ar–CH2=CH2–), d 162.5(NH–C=O), d 168.9
(O=C–O–); MS m/z: 485.91(M?), 487.91(M?2); Anal.
calcd. for C17H14Br2N2O5 (486.11): C, 42.00; H, 2.90; N,
5.76; Found: C, 42.12; H, 2.79; N, 5.79.
(E)-2-(4,5-dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(furan-
2-yl)acrylate 6j Brown solid; m.p. 235–237 °C; IR (KBr,
cm-1): 3393, 1704, 1636, 1563, 1261;1H NMR (CDCl3,
400 MHz): d 3.88 (t, 2H, –CH2–CH2–NH–), 4.61 (t, 2H,
–CH2–CH2–O–), 6.49 (s, 1H, NH of pyrrole), 6.54 (d, 1H,
furan–CH=CH–) 7.15 (d, 1H, furan–CH=CH–), 7.21 (s,
1H, CH of pyrrole),7.65–8.11(m, 3H,furan), 10.23 (s, 1H,
(E)-2-(1H-pyrrole-2-carboxamido)ethyl 3-(naphthalen-2-
yl)acrylate 6g Yellow solid; m.p. 267–269 °C; IR (KBr,
1
cm-1): 3410, 3235, 1705, 1642, 1239; H NMR (CDCl3,
400 MHz): d 3.72 (q, 2H, –CH2–CH2–NH–), 4.61 (t, 2H,
–CH2–CH2–O–), 6.19 (s, 1H, NH of pyrrole), 6.36 (d, 1H,
naphthalene –CH=CH–), 6.78 (t, 1H, CH of pyrrole),
6.89–7.19 (m, 2H, CH of pyrrole), 7.35–7.99 (m, 8H,
naphthalene –CH=CH–, naphthalene), 10.09 (s, 1H, NH–
C=O); 13C NMR (CDCl3, 400 MHz) d 38.9 (–CH2NH–), d
67.5 (–CH2–O–),d 124.2(naphthalene –CH2=CH2–),d
NH–C=O); 13C NMR (CDCl3, 400 MHz)
(–CH2NH–), d 67.4 (–CH2–O–), d 128.5–100.8 (pyrrole), d
151.5–112.2 (furan),d 145.5 (furan–CH2=CH2–),
154.7–116.8 (furan–CH2=CH2–),d 161.7 (NH–C=O),d
166.3(O=C–O–);MS m/z: 431.91(M?), 433.92(M?2);
Anal. calcd. for C14H12Br2N2O4 (432.06): C, 38.92; H,
2.80; N, 6.48; Found: C, 38.85; H, 2.89; N, 6.31.
d 39.2
d
123

Med Chem Res
(t, 2H,–CH2–CH2–O–), 5.99 (s, 1H, NH of pyrrole), 6.43
(d, 1H, Ar–CH=CH–), 6.70 (s, 1H, CH of pyrrole),
8.05–8.35 (m, 5H, Ar–CH=CH–,ArH), 10.46 (s, 1H, NH–
C=O);13C NMR (CDCl3, 400 MHz) d 39.1(–CH2NH–), d
67.4 (–CH2–O–),d 112.4 (Ar–CH2=CH2–),d 128.5–100.2
(pyrrole), d 147.2–123.8 (p-Nitro–Ar–C),d 145.6(Ar–
CH2=CH2–),d 161.9 (NH–C=O), d 168.9 (O=C–O–); MS
m/z: 486.92(M?), 488.91(M?2); Anal. calcd. for
C16H13Br2N3O5 (487.10): C, 39.45; H, 2.69; N, 8.63;
Found: C, 39.29; H, 2.75; N, 8.71.
X
NH
H
NH2
Y
N
N
N
H
O
1a X=Y=H Clathrodin
1b X=Br; Y=H Hymenidin
1c X=Y=Br Oroidin
Fig. 1 Pyrrole-aminoimidazole alkaloids
(E)-2-(1H-pyrrole-2-carboxamido)ethyl 3-(4-(2,4-dichlo-
rophenoxy)phenyl)acrylate 6m Yellow solid; m.p.
275–277 °C; IR (KBr, cm-1): 3396, 3292, 1708, 1623,
1115;1H NMR (CDCl3, 400 MHz): d 3.56 (q, 2H, –CH2–
CH2–NH–), 4.43(t, 2H, –CH2–CH2–O–), 5.68 (s, 1H,
NH of pyrrole), 6.79 (d, 1H, Ar–CH=CH–) 6.82 (t, 1H,
CH of pyrrole), 7.02 –8. 01 (m, 9H, Ar–CH=CH–, CH of
pyrrole, ArH), 10.05 (s, 1H, NH–C=O);13C NMR (CDCl3,
400 MHz) d 39.2 (–CH2NH–), d 67.7 (–CH2–O–), d 117.3
(Ar–CH2=CH2–),d 126.8–107.9 (pyrrole),d 135.5–128.4
(Ar–C), d 144.8 (Ar–CH2=CH2–),d 150.4–120.6 (Dichloro-
Ar–C), d 160.2 (NH–C=O),d 166.7 (O=C–O–); MS m/z:
444.10(M?); Anal. calcd. for C22H18Cl2N2O4 (445.30): C,
59.34; H, 4.07; N, 6.29; Found: C, 59.59; H, 4.01; N, 6.19.
(E)-2-(1H-pyrrole-2-carboxamido)ethyl 3-(4-nitrophenyl)
acrylate 6k Yellow solid; m.p. 256–258 °C; IR (KBr,
cm-1): 3396, 3251, 1718, 1643, 1515, 1341; 1H NMR
(CDCl3, 400 MHz): d 3.76 (t, 2H, –CH2–CH2–NH–), 4.62
(t, 2H, –CH2–CH2–O–), 6.82 (s, 1H, NH of pyrrole), 6.89
(d, 1H, Ar–CH=CH–) 6.92 (t, 1H, CH of pyrrole), 7.12 –8.
41 (m, 7H, Ar–CH=CH–, CH of pyrrole, ArH), 10.15 (s,
1H, NH–C=O); 13C NMR (CDCl3, 400 MHz) d 39.1
(–CH2NH–), d 67.0 (–CH2–O–),d 115.2 (Ar–CH2=CH2–),d
126.8–108.2 (pyrrole), d 147.2–123.6 (p-Nitro–Ar–C),d
145.2 (Ar–CH2=CH2–), d 160.9 (NH–C=O), d 166.1 (O=
C–O–); MS m/z: 329.15(M?); Anal. calcd. for C16H15N3O5
(329.31): C, 58.36; H, 4.59; N, 12.76; Found: C, 58.25; H,
4.36; N, 12.91.
(E)-2-(4,5-dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(4-
(2,4-dichlorophenoxy)phenyl)acrylate 6n Brown solid;
m.p. 278–280 °C; IR (KBr, cm-1): 3367, 1711, 1638,
1313, 1211;1H NMR (CDCl3, 400 MHz): d 3.79 (q, 2H,
–CH2–CH2–NH–), 4.42 (t, 2H, –CH2–CH2–O–), 5.12 (s,
(E)-2-(4,5-Dibromo-1H-pyrrole-2-carboxamido)ethyl 3-(4-
nitrophenyl)acrylate 6l Brown solid; m.p. 261–263 °C;
IR (KBr, cm-1): 3393, 1704, 1636, 1563, 1261;1H NMR
(CDCl3, 400 MHz): d 3.53 (t, 2H, –CH2–CH2–NH–), 4.18
Scheme 1 Synthesis of
dibromopyrrole-2-carboxamides
(scaffold 1)
b
a
H
N
H
O
COCCl3
N
N
H
N
H
H
O
4
1
c
r
B
r
B
H
d
N
r
B
r
B
R
COCCl3
N
N
H
2
H
O
3a-3g
Scaffold1
3a: R= CH2Ph
3b: R= n-Butyl
3c: R= n-Hexyl
3d: R= t-Butyl
3e: R= CH3(CH)Ph
3f: R= Cyclohexyl
3g: R= CH2CH2OH
Reagents and Conditions: (a) CCl COCl, Ether, R for 2hr and then K CO ;
T
3
2
3
(b) ethanolamine, TEA, CH Cl RT for 2 hr; (c) NaNO /48% HBr 2-4h (d) RNH , TEA,
,
2
2
2
2
CH2Cl2, RT for 1-5 hr
123

Med Chem Res
Scheme 2 Simple ester and
cinnamic ester derivatives of
pyrrole-2-carboxamide (scaffold
2 and scaffold 3)
X
H
N
X
OH
N
H
O
r
3g o 4
Et3N, CH2Cl2, 1-2 h
RT
RCOCl
ClOC
R
X
X
O
H
N
COR
H
X
N
O
X
N
H
N
H
O
R
O
O
6a-6n
5a-5j
Scaffold 3
Scaffold 2
6a: X=H, R=Ph
6b; X=Br, R=Ph
6c: X=H, R=3,4-diOMePh
6d: X=Br, R=3,4-diOMePh
6e: X=H, R=3,4-phenylenedioxy
5a: X=H, R=CH3
5b; X=Br, R=CH3
5c: X=H, R=Ph
5d: X=Br, R=Ph
5e: X=H, R=3,4-diOMePh
5f: X=Br, R=3,4-diOMePh
5g: X=H, R=4-ClPh
5h: X=Br, R=4-ClPh
5i: X=H, R=2-OHPh
5j: X=Br, R=2-OHPh
:
= r
=
β
-
,
p
en ene ox
di
y
6f X B R 3 4
h
l
,
y
6g: X=H, R= -napthyl
6h: X=Br, R= -napthyl
6i: X=H, R=Furyl
β
6j: X=Br, R=Furyl
6k: X=H, R=4-nitroPh
6l: X=Br, R=4-nitroPh
6m: X=H, R=4-(2,4-dichlorophenoxy)Ph
6n: X=Br, R=4-(2,4-dichlorophenoxy)Ph
Table 2 Antimicrobial testing
results: (MIC lg/ml)
Compounds
X
R
S. aureus
E. coli
3a
3b
3c
3d
3e
3f
Br
Br
Br
Br
Br
Br
Br
H
CH2Ph
62.5
15.62
[125
[125
62.5
n-Octyl
n-Hexyl
t-Butyl
[125
[125
[125
1.56
CH3(CH)Ph
Cyclohexyl
CH2CH2OH
CH3
1.56
62.5
[125
[125
[125
[125
31.25
[125
[125
[125
62.5
3g
5a
5b
5c
5d
5e
5f
[125
[125
[125
7.81
Br
H
CH3
Ph
Br
H
Ph
[125
[125
[125
31.25
62.5
3,4-DiOMePh
3,4-DiOMePh
4-ClPh
Br
H
5g
5h
5i
Br
H
4-ClPh
[125
[125
[125
62.5
2-OHPh
2-OHPh
Ph
15.62
31.25
[125
62.5
5j
Br
H
6a
6b
6c
6d
Br
H
Ph
[125
31.25
31.25
3,4-DiOMePh
3,4-DiOMePh
15.62
[125
Br
123

Med Chem Res
Table 2 continued
Compounds
X
R
S. aureus
E. coli
6e
H
3,4-Phenylenedioxy
3,4-Phenylenedioxy
b-Napthyl
[125
[125
[125
31.25
[125
[125
3.12
[125
[125
62.5
6f
Br
H
6g
6h
Br
H
b-Napthyl
[125
[125
[125
[125
[125
[125
[125
0.5
6i
Furyl
6j
Br
H
Furyl
6k
4-NitroPh
6l
Br
H
4-NitroPh
[125
[125
[125
0.5
6m
4-(2,4-Dichlorophenoxy)Ph
4-(2,4-Dichlorophenoxy)Ph
–
6n
Ciprofloxacina
Br
–
a
Ciprofloxacin was used as the
reference drug
1H, NH of pyrrole), 6.69 (d, 1H, Ar–CH=CH–), 6.87–7.53
(m, 9H, Ar–CH=CH–, CH of pyrrole, ArH), 10.69 (s, 1H,
NH–C=O); 13C NMR (CDCl3, 400 MHz) d 39.1(–CH2NH–
scaffold, compound with secondary carbon in alkyl group
3e, 3f were found to be more potent than simple alkyl chain
carboxamides.
),
d
67.6 (–CH2–O–),
d
116.8 (Ar–CH2=CH2–),d
The attempt to increase activity by increasing hydro-
philicity through compound 3g was failed. To remove free
hydroxyl group and to check effect of molecular hybrid-
ization we combined two active moieties through ester
linkage. To check effect of halogen, simple pyrrole deriv-
atives were also synthesized and from biological activity
results of scaffold 2. From the compound 4a–4j, simple
pyrrole carboxamide 4c (X = H) was found to be the most
active in the series. In the most cases dibromo derivatives
showed good activity against S. aureus than E. coli.
Compounds 5a–5n (scaffold 3) was synthesized to find
importance of cinnamic acids derivatives in biological
activity. All of the compounds showed poor activity against
E. coli but some compound show promising activity
against S. aureus. Nitrocinnamate derivative 5k, showed
best biological activity from the series. Further develop-
ment in this field with special emphasis on cinnamic acid
derivatives as antibacterial and antimycobacterial would
expect to be more promising.
128.2–100.3 (pyrrole), d 135.1–128.2 (Ar–C),d 145.2 (Ar–
CH2=CH2–),d 151.4–123.2 (Dichloro-Ar–C), d 157.2 (NH–
C=O),d 171.7 (O=C–O–); MS m/z: 601.78(M?),
603.68(M?2); Anal. calcd. for C22H16Br2Cl2N2O4 (603.09):
C, 43.81; H, 2.67; N, 4.64; Found: C, 43.73; H, 2.77; N, 4.58.
Current work represents synthesis and antibacterial
evaluation of series of Pyrrole-2-carboxamides, scaffold 1
(Fig. 1, Scheme 1), 23 scaffold 2 24 and scaffold 3 25
(Scheme 2). Pyrrole on Trichloroacetylation gave 1 in
good yield. Trichloroacetyl pyrrole was then brominated in
the presence of our developed reaction conditions which
involve Stirring of 1 with 48 % aq HBr in Dichlorometh-
ane, NaNO2 was then added portion wise for a minute.
Antimicrobial activity
The series of synthesized molecules were tested against S.
aureus and E. Coli to determine minimum inhibitory
concentration (MIC) by Resazurin Microtitre Assay
(REMA) plate method with serial dilution. The test com-
pounds were serially diluted on plates with DMSO as a
solvent. Homogeneous bacterial culture with 105 cell per
well were suspended in microtitre plates. MIC was the
lowest inhibition concentration and was observed by colour
change of resazurin dye from blue to pink (Tables 1, 2).
Ciprofloxacin was used as the reference drug.
Conclusions
In conclusion, to the continuation of our previous work on
synthesis of pyrrole analogues, especially halopyrrole
derivatives, we herein described synthesis and antibacterial
evaluation of 31 new compounds with the focus on Oroidin
and cinnamic acid framework. Two compounds 3e and 6k
showed promising activity against both Gram positive and
Gram negative bacteria. These may provide potential lead
for further development in antimicrobial molecules.
Results and discussion
Compound 3a–3g were synthesized with changing R with
different alkyl substituents and according to results of
Acknowledgments Balaram S. Takale is thankful to CSIR India for
providing SRF award of research fellowship.
123

Med Chem Res
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