Synthesis, characterization, biological activity, and 3D-QSAR studies on some novel class of pyrrole derivatives as antitubercular agents

MEDICINAL

CHEMISTRY

RESEARCH

Med Chem Res (2014) 23:1123–1147

DOI 10.1007/s00044-013-0709-y

ORIGINAL RESEARCH

Synthesis, characterization, biological activity, and 3D-QSAR

studies on some novel class of pyrrole derivatives

as antitubercular agents

•

Shrinivas D. Joshi Uttam A. More

•

Sheshagiri R. Dixit Haresh H. Korat

•

Tejraj M. Aminabhavi Aravind M. Badiger

Received: 12 December 2012 / Accepted: 10 August 2013 / Published online: 25 August 2013

Ó Springer Science+Business Media New York 2013

Abstract A new series of pyrrole derivatives have been

designed, synthesized, and their structures have been elu-

cidated along with the evaluation of antitubercular activity

against Mycobacterium tuberculosis H₃₇Rv using the

microplate alamar blue assay method and antibacterial

activity against Staphylococcus aureus, Bacillus subtilis,

Klebsiella pneumoniae, and Escherichia coli by broth

micro-dilution assay method. Structural activity relation-

ships and 3D-QSAR analysis have been carried out by

Topomer Comparative Molecular Field Analysis (CoM-

FA). Training set of 42 and test set of 8 active compounds

were used to develop the method that showed cross-vali-

dated correlation coefﬁcient (q²) of 0.815, standard error of

prediction of 0.36, non-cross-validated correlation coefﬁ-

cient (r²) of 0.973, and standard error of estimate of 0.14

with six components.

Introduction

Tuberculosis (TB), a lung infection caused mainly by

Mycobacterium tuberculosis (MTB), is a leading infectious

disease claiming millions of death, mostly in developing

countries (Duncan and Barry, 2004; World Health Orga-

nization [WHO], 2008). According to the WHO reports

one-third of the world’s population is currently infected

with TB bacillus, each year 8 million people worldwide

develop active TB and about 1.7 million people die (Va-

ladas and Antunes, 2005). TB drugs available today in the

market have been discovered mainly during 1945–1965,

but since then innumerable new drugs have been developed

as well as drug-resistant strains of mycobacterium have

emerged in medical area. Multidrug-resistant TB and

extensive drug-resistant TB are the most dangerous forms

of TB that are resistant to isoniazid and rifampicin. This

has created greater challenges for the treatment of TB,

creating a need to develop new therapeutic agents. Among

the many organic moieties, pyrrole is the widely explored

heterocycle in plant and animal kingdom.

Keywords Pyrroles ꢀ Antibacterial activity ꢀ

Antitubercular activity ꢀ Broth dilution assay method ꢀ

Cytotoxicity ꢀ Topomer CoMFA

Pyrrole and its derivatives possess antitumor (Kamal

et al., 2012), analgesic (Ahmadi et al., 2011), antituber-

cular (Biava et al., 2010; Sbardella et al., 2004), and anti-

inﬂammatory activities (Mohamed et al., 2011). Several

macromolecular antibiotics having pyrrole structure have

been isolated from the biological sources and their activi-

ties have been identiﬁed (Jones and Bean, 1997; Jones,

1992). Recently, pyrrole derivatives have emerged as

chemotherapeutic agents potentially useful for inhibiting

the activities of MTB and other atypical mycobacteria,

including M. avium complex, an opportunistic pathogen

that greatly contributes to the death of AIDS patients.

Lipophilicity is a key property that inﬂuences the ability of

a drug to reach the target by transmembrane diffusion and to

S. D. Joshi (&) ꢀ U. A. More ꢀ S. R. Dixit ꢀ

H. H. Korat ꢀ T. M. Aminabhavi

Novel Drug Design and Discovery Laboratory, Department of

Pharmaceutical Chemistry, S.E.T.’s College of Pharmacy,

Sangolli Rayanna Nagar, Hubli-Dharwar 580 002, India

e-mail: shrinivasdj@rediffmail.com; shrinivasdj23@gmail.com

U. A. More

Centre for Research and Development, Prist University,

Thanjavur 613 403, Tamil Nadu, India

A. M. Badiger

BDR Pharmaceuticals International Pvt. Ltd.,

Baroda 390 021, India

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Med Chem Res (2014) 23:1123–1147

have a major effect on the biological activity. The azole an-

tituberculars are regarded as the emerging class of thiazoles

known as lipophilic analogs similar to imidazoles. Thiazoles

are utilized as pharmacophores due to their favorable meta-

bolic proﬁle and their ability to engage in hydrogen-bonding.

Biological activities of thiazole ring systems have been well

documented (Gorczynski et al., 2004; Vicini et al., 2003). On

the other hand, pyrrolylimido group has been widely used in

drug discovery due to its wide range of pharmacological and

biological activities such as anti-inﬂammatory, analgesic,

antispasmodic, antibacterial, antifungal, etc. (Abdel-Aziz,

2007; Borchhardt and Andricopulo, 2009).

Simulated annealing was performed for each ligand up to

200 cycles with default parameters and then conformations

were sorted out according to the least potential energy

value, which were minimized with quantum mechanical

semi-empirical AM1 (Austin Model 1) method using

MOPAC (Molecular Orbital PACkage). Atomic charges

were calculated using the MMFF94 (Merck Molecular

Force Field) method for Topomer structure and dataset was

then used for Topomer CoMFA analysis.

Topomer CoMFA

In drug design and discovery area, CoMFA (Compara-

tive Molecular Field Analysis), a 3D-QSAR technique, has

been the widely used computational tool (Cramer et al.,

1988), since it is capable of predicting the biological

activity of new chemical entities by establishing the rela-

tionship between steric/electrostatic properties and the

biological activities in the form of contour maps. The

present work is a continuation of our ongoing research on

the biologically active molecules such as pyrrole deriva-

tives (Joshi et al., 2008, 2010, 2013a,b). Herein, we report

the synthesis and characterization of some novel type of

pyrrolylimido as well as thiazole derivatives and estimate

their antibacterial and antitubercular activities.

Topomer CoMFA is a technique introduced by Cramer,

which has two main phases, the ﬁrst being generation of the

topomer 3D models for each of the ‘‘side chains’’ and the

second one is the CoMFA analysis itself (Cramer, 2003). It

delineates the need for alignment, which is mandatory for

typical CoMFA analysis. Topomer CoMFA has both

graphical and statistical results. Concerning the graphical

results, it was used to construct stdev/coeff contour maps to

show ﬁeld effects on the target features. The contour plots are

beneﬁcial to identify important regions where some changes

in steric or electrostatic ﬁelds can affect the biological

activity. The maps generated depict regions having scaled

coefﬁcients[80 % (favored) or\20 % (disfavored).

In Topomer CoMFA analysis, all molecules of the

dataset were separated into two fragments shown as R₁

(red) and R₂(blue) groups in Fig. 1. Two template mole-

cules were chosen for fragmentation, one from pyrrolyli-

mide 5h and another from pyrrolylthiazole 13h (Fig. 2),

which are the most active compounds of their respective

series and are having low-energy conformation. Each To-

pomer fragment was applied with topomer alignment to

make a 3D invariant representation (Cramer et al., 1996).

Steric and electrostatic interaction energies were calculated

using a carbon sp³probe.

3D-QSAR study

Computational details

The 3D-QSAR techniques of Topomer CoMFA have been

carried out with Tripos SYBYL-X 2.0 (Sybyl-X 2.0, 2012)

running on a Intel^ÒCore^TMi3-2130 CPU@ 3.40 GHz pro-

cessor using Windows 7 professional software. The activity

dataset consisted of 50 molecules (Tables 1 and 2). The

measurement of antitubercular activity used to develop the

Topomer CoMFA have been expressed as pMIC ¼

ꢁ logðMICÞ; where MIC is minimum inhibitory concentra-

tion values that were changed to minus logarithmic scale

value pMIC, as a dependent variable for Topomer CoMFA

analysis. Then the antitubercular activity data were con-

verted into logarithmic scale as the resulting model behaves

more reasonably that will offer better linear models.

Partial least square (PLS) analysis

The PLS method was used to set up a correlation between

the molecular ﬁelds and inhibitory activity of the molecules

(Cramer, 1993). Topomer CoMFA descriptors were used as

independent variable and the log activities as the dependent

variable in a PLS regression analysis. The optimum num-

ber of components was determined with SAMPLS (sam-

ples-distance PLS) (Bush and Nachbar Jr, 1993). The

cross-validation was carried out by the leave-one-out

(LOO) method, in which one molecule is removed from the

dataset and its activity is predicted using the model derived

from rest of the molecules in the dataset. The q²resulted in

an optimum number of components and the lowest stan-

dard error of prediction (StdErr). The equations for q²and

standard errors are given below.

The dataset was divided into a training set of 42 mole-

cules and test set of 8 molecules on the basis of biological

diversity, such that both the training and test sets consist of

high-, medium-, and low-activity molecules. All the dataset

molecules were sketched by the SKETCH module imple-

mented in the SYBYL program and ligand geometries were

optimized by energy minimization with Powel method

using the Tripos forceﬁeld. They were then subjected to

simulated annealing to get

a stable conformation.

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Med Chem Res (2014) 23:1123–1147

1125

Table 1 Antitubercular activity of a novel series of pyrrolylimides (5a–m) and (8a–m)

O

N

Compound

pMIC

5.20

6.10

5.51

6.40

Compound

pMIC

4.90

5.10

5.51

6.40

O

N

5a

5b

5c

5d

5e

8a

8b*

8c

O

N

O

N

O

N

8d

8e

O

N

O

r

B

O

r

B

6.10

6.40

6.70

6.40

6.70

N

5f

5g*

5h

8f

8g

8h

B

O

Cl

O

l

C

Cl

N

Cl

O

Cl

F

O

Cl

F

O

F

N

F

O

F

O

Cl

6.10

5.51

6.10

5.20

N

5i

5j

8i

8j

O

N

O

NO₂

O

NO₂

N

5.33

5.20

N

5k*

8k

O

NO₂

O

5.51

N

5l

8l*

8m

5.36

5.20

O

N

5m

O

Asterisk (*) indicates test set compounds.

rﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ

where n is number of compounds, c is number of compo-

P

2

_yðY_predꢁ Y_actual

_yðY_actualꢁ Y_mean

Þ

PRESS

q²¼ 1 ꢁ

;

SEE; SEP ¼

;

P

2

n ꢁ c ꢁ 1

Þ

P

where Y_predis predicted activity, Y_actualis experimental

activity, and Y_meanis the best estimate of the mean.

2

nents, and PRESS ¼ _yðY_predꢁ Y_actualÞ :

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Med Chem Res (2014) 23:1123–1147

Predictive correlation coefﬁcient (r_p²_red

)

Table 2 Antitubercular activity of a novel series of pyrrolylthiazoles

(12a–l) and (13a–l)

The predictive ability of 3D-QSAR model was determined

from test set of eight molecules not included in the model

generation. The predictive correlation coefﬁcient (r_p²_red),

based on the test set molecules is deﬁned as:

Compound R

pMIC Compound R

pMIC

12a

12b

12c

12d

12e

12f

12g^a

12h

12i

–4H

6.40 13a

6.40 13b

4.30 13c

6.10 13d

4.90 13e

6.40 13f

4.60 13g

6.70 13h

–4H

6.40

6.10

4.90

6.40

5.20

6.40

4.90

6.70

–4Cl

–4OH

–4Br

–4OH

–4Br

ðSD ꢁ PRESSÞ

;

r_p²_red

¼

SD

–4OCH₃

–4NO₂

–4NH₂

–4F

–4OCH₃

–4NO₂

–4NH₂

–4F

where SD is the sum of squared deviations between the

biological activity of the test set and the mean activity of

the training set molecules, PRESS is the sum of squared

deviations between the predicted and the actual activity

values for every molecule in the test set.

–2,4-dichloro 6.40 13i

–2,4-dichloro 6.40

12j

–3,4,5-

(OCH₃)₃

–3,4-

(OCH₃)₂

–3-NO₂

4.30 13j^a

4.30 13k

6.10 13l^a

–3,4,5-

(OCH₃)₃

–3,4-

(OCH₃)₂

–3-NO₂

4.90

4.30

6.40

12k^a

Materials and methods

12l

a

Chemistry

Test set compounds

Compounds 5a–m, 8a–m, 12a–l, and 13a–l were prepared

as per Schemes 1 and 2. The compounds N-(substituted)-4-

(1H-pyrrol-1-yl)benzamides (5a–m) were synthesized

from the commercially available 4-aminobenzoic acid (1)

(Scheme 1). 4-Aminobenzoic acid (1) was subjected to

esteriﬁcation reaction in ethanol and HCl gas to give ethyl

4-aminobenzoate (2). Ethyl 4-aminobenzoate (2) was

subjected to Paal–Knorr reaction with 2,5-dimethoxyte-

trahydrofuran in dried acetic acid to give ethyl 4-(1H-

pyrrol-1-yl)benzoate (3). Hydrazinolysis of ethyl 4-(1H-

O

N

HN N

N

S

O

Fig. 1 R₁fragment is represented by the red color and R₂fragment is

represented by blue color (Color ﬁgure online)

Fig. 2 Topological alignment

of R₁and R₂fragments

generated by Topomer CoMFA

analysis

A1

A2

R₁fragments

R₂fragments

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Med Chem Res (2014) 23:1123–1147

1127

O

HCl gas

C₂H₅OH

NH₂NH_2.H₂O

C₂H₅OH

O

H₂N

N

H₂N

CH₃COOH

OH

3

2

1

O

Different anhydrides

CH₃COOH, N₂gas

O

N

HN N

HN NH₂

O

5a-5m

4

O

NH₂NH_2.H₂O

C₂H₅OH

Different anhydrides

CH₃COOH, N₂gas

O

CH₃COOH

O

N

2

N

HN NH₂

HN N

8a-8m

O

7

6

O

g

Cl

a

c

d

e

h

F

b

f

Br

O

N

O

N

O

N

Cl

F

Br

N

O

N

Br

O

5/8

Cl

F

Br

m

j

k

l

i

NO₂

O

N

O

NO₂

Cl

N

O

N

O

Scheme 1 Synthetic route of a novel series of pyrrolylimides

R

O

R

O

H₂N

NH₂

O

Br₂/I₂

CH₃

N

S

CH₃COOH

N

S

NH₂

S

9a-9-l

10

11a-11l

12a-12l

O

CH₃COOH

R

O

N

S

13a-13l

j

c

e

k

d

g

l

a

f

b

h

i

2,4-(Cl)₂

12,13-

4-OCH₃4-NO₂4-NH₂

3,4,5-(OCH₃)₃

3-NO₂

R 4-H

4-F

4-Cl 4-OH 4-Br

3,4-(OCH₃)₂

Scheme 2 Synthetic route of a novel series of pyrrolylthiazoles

pyrrol-1-yl)benzoate (3) with hydrazine hydrate in ethanol

gave 4-(1H-pyrrol-1-yl)benzoic acid hydrazide (4). The

N-(substituted)-4-(1H-pyrrol-1-yl)benzamide compounds

(5a–m; Scheme 1) were prepared by cyclodehydration of 4-

(1H-pyrrol-1-yl)benzoic acid hydrazide (4) with different

anhydrides in dried acetic acid media under nitrogen

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Med Chem Res (2014) 23:1123–1147

Scheme 3 Routes for the

mechanism of formation of

pyrrolylimide derivatives 5a–m

and 8a–m

Route A

O

ArHN

OH

NH₂Ar

N Ar

O

H₂N Ar

O

Route B

O

ArH₃N

O

NH₃Ar

O

NHAr

OH

O

H₂N Ar

O

-H₂O

O

N

Ar =

OR

N Ar

O

NH

atmosphere. Paal–Knorr condensation reaction between ethyl

4-aminobenzoate (2) and 2,5-hexanedione in glacial acetic

acid furnished the ethyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)ben-

zoate (6). Nucleophilic reaction of hydrazine hydrate with the

ester 6 in ethanolic medium produced 4-(2,5-dimethyl-1H-

pyrrol-1-yl)benzoic acid hydrazide (7). The N-(substituted)-4-

(2,5-dimethyl-1H-pyrrol-1-yl)benzamides (8a–m) were syn-

thesized by cyclodehydration of 7 with different anhydrides in

dried acetic acid under nitrogen atmosphere.

Limited, and Spectrochem Pvt. Ltd. Solvents were of

reagent grade and when necessary these were puriﬁed

and dried by the standard methods. Melting points (mp)

of the synthesized compounds were determined by Shital

Scientiﬁc Industries mp apparatus and are uncorrected.

Infrared spectra were recorded on a Bruker spectropho-

tometer using the KBr pellets. The ¹H and ¹³C NMR

spectra were recorded on Bruker AVANCE II 400 MHz

and Bruker AVANCE III 500 MHz instruments using

dimethylsulfoxide (DMSO-d₆) solvent and TMS as an

internal standard. The chemical shifts are expressed as d

values (ppm).

In Scheme 2, 2-amino-4-(4-substituted phenyl)thiazoles

(11a–l) were synthesized as described previously in which 4-

substituted acetophenones (9a–l) were used as the starting

materials. Compounds (9a–l) were condensed with thiourea

(10) in the presence of iodine or bromine as a catalyst, to give

the key compounds; viz 2-amino-4-(4-substituted

phenyl)thiazoles (11a–l). 4-(4-Substituted phenyl)-2-(1H-

pyrrol-1-yl)thiazoles (12a–l; Scheme 2) and 4-(4-substi-

Mass spectra (MS) were taken in JEOL GCMATE II

GC-Mass spectrometer and Waters Micromass Q-Tof

Micro LC-Mass spectrometer. All the compounds exhib-

ited spectral data consistent with the proposed structures

and values of microanalysis were within 0.4 % of the

theoretical values. Analytical thin-layer chromatography

(TLC) was performed on the precoated TLC sheets of

silica gel 60 F₂₅₄(Merck, Darmstadt, Germany) visualized

by long- and short-wavelength ultraviolet lamps. Chro-

matographic puriﬁcations were performed on Merck alu-

minum oxide (70–230 mesh) and Merck silica gel (70–230

mesh).

tuted

phenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiazoles

(13a–l; Scheme 2) were synthesized by Paal–Knorr reaction

of thiazoles (11a–l) with 2,5-dimethoxytetrahydrofuran and

2,5-hexanedione, respectively, in dried glacial acetic acid.

The cyclic imide formation possibly takes place

according to one of the two mechanism routes shown in

Scheme 3. The possible mechanism for Paal–Knorr pyr-

role synthesis is depicted in Scheme 4.

Synthesis of 4-(1H-pyrrol-1-yl)benzoic acid hydrazide (4)

Experimental

Ethyl 4-(1H-pyrrol-1-yl)benzoate (3; 15 mmol) was

reﬂuxed with hydrazine hydrate (10 mL) in absolute eth-

anol (10 mL) for 3 h. The reaction mixture was cooled and

Chemicals used in the synthesis of the compounds

were purchased from Sigma-Aldrich, S. D. Fine-Chem

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Med Chem Res (2014) 23:1123–1147

1129

Scheme 4 Routes for the

mechanism of formation of

pyrrole derivatives 3, 6, 12a–l,

and 13a–l

Paal-Knorr Pyrrole Synthesis Mechanism

Route A

H

H₂N Ar

OH

H

NHAr

H

O

Ar

H

O

N

H

O

H

OH

H

-2H₂O

N Ar

Route B

H₂N Ar

CH₃

OH

H₃C

CH₃

O

NHAr

O

H₃C

H

Ar

-2H₂O

O

N Ar

CH₃

N

H

O

H

O

H

H₃C

OH

CH₃

R

O

N

Ar =

OR

S

the crystalline mass obtained was further recrystallized

from ethanol.

ppm: 6.32 (dd, 2H, pyrrole–C₃and C₄–H), 7.51 (dd, 2H,

pyrrole–C₂and C₅–H), 7.75 (d, 2H, J = 5 Hz, Ph–C₃and

C₅–H), 8.00 (d, 2H, J = 10 Hz, Ph–C₂and C₆–H), 10.64

(s, 2H, 2,5-dihydropyrrole–C₃and C₄–H), 13.05 (s, 1H,

amide–NH); ¹³C NMR (500 MHz, DMSO-d₆) d ppm:

167.41 (amide–C=O), 164.92 (2,5-dihydropyrrole–C₂),

163.76 (2,5-dihydropyrrole–C₅), 142.82 (Ph–C₄), 133.57

(2,5-dihydropyrrole–C₃and C₄), 129.68 (Ph–C₃and C₅),

128.87 (Ph–C₁), 119.47 (Ph–C₂and C₆), 118.92 (pyrrole–

C₂and C₅), 111.70 (pyrrole–C₃and C₄); MS (ESI): m/z =

found 281.08 [M^?], 216, 171; calcd. 281.27. Anal.

C₁₅H₁₁N₃O₃.

Yield 74 %. mp 180–182 °C (Joshi et al., 2008).

General procedure for the preparation of N-(substituted)-

4-(1H-pyrrol-1-yl)benzamides (5a–m)

Mixture of 4-(1H-pyrrol-1-yl)benzohydrazide (25 mmol)

and anhydride (25 mmol) in 10 mL dried acetic acid was

stirred for 30 min at room temperature. The separated solid

was ﬁltered, washed with diethyl ether, and dried. The solid

was dissolved in 30 mL dried acetic acid and stirred

overnight under nitrogen atmosphere. The reaction mixture

was then poured into ice-cold water; the separated solid

was collected, washed with water, dried, and recrystallized

by aqueous DMF to get the desired product 5a–m.

N-(2,5-dioxopyrrolidin-1-yl)-4-(1H-pyrrol-1-yl)benzamide

(5b) Yield 41 %. mp 228–230 °C; FTIR (KBr): 3221

(NH), 3036, 2967 (Ar–H), 1694 (pyrrolidine C=O), 1646

;

(amide C=O) cm^-^{1 1}H NMR (500 MHz, DMSO-d₆) d

N-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-(1H-pyrrol-1-

yl)benzamide (5a) Yield 43 %. mp 198–200 °C; FTIR

(KBr): 3215 (NH), 3105, 2999 (Ar–H), 1717 (2,5-dihy-

dropyrrole C=O), 1655 (2,5-dihydropyrrole C=O), 1630

ppm: 2.46–2.51 (m, 4H, pyrrolidine–C₃and C₄–H), 6.32

(dd, 2H, pyrrole–C₃and C₄–H), 7.50 (dd, 2H, pyrrole–C₂

and C₅–H), 7.73 (d, 2H, J = 5 Hz, Ph–C₃and C₅–H), 7.98

(d, 2H, J = 10 Hz, Ph–C₂and C₆–H), 9.93 (s, 1H, amide–

NH); ¹³C NMR (500 MHz, DMSO-d₆) d ppm: 174.02

(amide C=O) cm^-^{1 1}H NMR (500 MHz, DMSO-d₆) d

;

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Med Chem Res (2014) 23:1123–1147

(pyrrolidine–C₂), 171.04 (pyrrolidine–C₅), 165.08 (amide–

C=O), 142.69 (Ph–C₄), 129.57 (Ph–C₃and C₅), 129.19

(Ph–C₁), 119.45 (Ph–C₂and C₆), 118.90 (pyrrole–C₂and

C₅), 111.65 (pyrrole–C₃and C₄), 29.29 (pyrrolidine–C₃),

28.64 (pyrrolidine–C₄); MS (ESI): m/z = found 283.10

[M^?], 186; calcd. 283.28. Anal. C₁₅H₁₃N₃O₃.

(isoindoline–C₁), 134.83 (isoindoline–C₅, C₆, C₈and C₉),

130.13 (Ph–C₄), 129.54 (Ph–C₃and C₅), 124.15 (Ph–C₁, C₂

and C₆), 119.65 (isoindoline–C₄and C₇), 119.01 (pyrrole–

C₂and C₅), 111.70 (pyrrole–C₃and C₄); MS (ESI): m/

z = found 331.10 [M^?], 266, 186, 119, 102, 78; calcd.

331.32. Anal. C₁₉H₁₃N₃O₃.

N-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-(1H-

pyrrol-1-yl)benzamide (5c) Yield 65 %. mp 178–180 °C;

FTIR (KBr): 3370 (NH), 3099, 2924 (Ar–H), 1733 (2,5-di-

N-(4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl)-4-(1H-

pyrrol-1-yl)benzamide (5f) Yield 47 %. mp 282–284 °C;

FTIR (KBr): 3258 (NH), 3041, 2981 (Ar–H), 1784 (iso-

indoline C=O), 1741 (isoindoline C=O), 1699 (amide C=O)

cm^-1; ¹H NMR (400 MHz, DMSO-d₆) d ppm: 6.15 (dd, 2H,

pyrrole–C₃and C₄–H), 7.24 (dd, 2H, pyrrole–C₂and C₅–H),

7.55 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 7.93 (d, 2H,

1

hydropyrrole C=O), 1608 (amide C=O) cm^-1; H NMR

(400 MHz, CDCl₃) d ppm: 2.13 (s, 3H, CH₃at 2,5-dihydro-

pyrrole–C₃), 6.32 (dd, 2H, pyrrole–C₃and C₄–H), 6.64 (s, 1H,

2,5-dihydropyrrole–C₃–H), 7.30 (dd, 2H, pyrrole–C₂and C₅–

H), 7.61 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.07 (d, 2H,

J = 12 Hz, Ph–C₂and C₆–H), 11.24 (s, 1H, amide–NH); ¹³

C

J = 8 Hz, Ph–C₂and C₆–H), 10.94 (s, 1H, amide–NH); ¹³

C

NMR (400 MHz, DMSO-d₆) d ppm: 171.90 (amide–C=O),

164.39 (isoindoline–C₃), 161.14 (isoindoline–C₁), 143.04

(Ph–C₄), 137.65 (isoindoline–C₈and C₉), 129.65 (isoindo-

line–C₅and C₆), 128.81 (Ph–C₃and C₅), 126.67 (isoindo-

line–C₄and C₇), 121.40 (Ph–C₁), 118.73 (Ph–C₂and C₆),

118.59 (pyrrole–C₂and C₅), 111.26 (pyrrole–C₃and C₄); MS

(ESI): m/z = found 646.73 [M^?], 644.74 [M^?-2], 648.73

[M^??2], 580/578, 568/566, 488/486, 406, 326, 248, 150,

120, 105, 84; calcd. 646.91. Anal. C₁₉H₉Br₄N₃O₃.

NMR (400 MHz, CDCl₃) d ppm: 168.77 (amide–C=O),

167.54 (2,5-dihydropyrrole–C₂), 164.54 (2,5-dihydropyr-

role–C₅), 144.53 (2,5-dihydropyrrole–C₃), 142.84 (Ph–C₄),

129.43 (Ph–C₂and C₆, 2,5-dihydropyrrole–C₄), 126.97 (Ph–

C₃and C₅), 126.52 (Ph–C₁), 118.49 (pyrrole–C₃and C₄),

111.11 (pyrrole–C₂and C₅), 10.99 (CH₃of 2,5-dihydropyr-

role–C₃); MS (ESI): m/z = found 296.10 [M^??1], 299, 281,

267, 216, 170; calcd. 295.29. Anal. C₁₆H₁₃N₃O₃.

N-(3-methylene-2,5-dioxopyrrolidin-1-yl)-4-(1H-pyrrol-1-

yl)benzamide (5d) Yield 80 %. mp 202–204 °C; FTIR

(KBr): 3202 (NH), 3026, 2917 (Ar–H), 1680 (pyrrolidine

4-(1H-pyrrol-1-yl)-N-(4,5,6,7-tetrachloro-1,3-dioxoisoin-

dolin-2-yl)benzamide (5g) Yield 49 %. mp 298–300 °C;

FTIR (KBr): 3233 (NH), 3017, 2981 (Ar–H), 1787 (iso-

indoline C=O), 1750 (isoindoline C=O), 1699 (amide C=O)

C=O), 1630 (amide C=O) cm^-^{1 1}H NMR (400 MHz,

;

1

DMSO-d₆) d ppm: 5.78 (d, 2H, CH₂at pyrrolidine–C₃),

6.21(d, 2H, CH₂at pyrrolidine–C₄), 6.26 (dd, 2H, pyrrole–

C₃and C₄–H), 7.23 (dd, 2H, pyrrole–C₂and C₅–H), 7.54

(d, 2H, J = 12 Hz, Ph–C₃and C₅–H), 7.98 (d, 2H,

cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 6.40 (dd,

2H, pyrrole–C₃and C₄–H), 7.34 (dd, 2H, pyrrole–C₂and

C₅–H), 7.83 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.11 (d,

2H, J = 10 Hz, Ph–C₂and C₆–H), 11.33 (s, 1H, amide–

NH); ¹³C NMR (400 MHz, DMSO-d₆) d ppm: 167.81

(amide–C=O), 165.33 (isoindoline–C₁and C₃), 145.39

(Ph–C₄), 137.05 (isoindoline–C₅and C₆), 135.60 (isoind-

oline–C₈and C₉), 130.21 (Ph–C₃and C₅), 129.11 (iso-

indoline–C₄and C₇), 128.57 (Ph–C₁), 127.22 (Ph–C₂and

C₆), 122.01 (pyrrole–C₂and C₅), 111.89 (pyrrole–C₃and

C₄); MS (ESI): m/z = found 468.94 [M^?], 466.94[M^?-2],

470.93[M^??2], 402/400, 300/298, 286/284, 186, 170, 142,

120, 67; calcd. 469.11. Anal. C₁₉H₉Cl₄N₃O₃.

J = 8 Hz, Ph–C₂and C₆–H), 9.91 (s, 1H, amide–NH); ¹³

C

NMR (400 MHz, DMSO-d₆) d ppm: 168.87 (amide–C=O),

167.46 (pyrrolidine–C₂), 164.63 (pyrrolidine–C₅), 142.26

(Ph–C₄), 135.02 (pyrrolidine–C₃), 129.12 (CH₂at pyrroli-

dine–C₃), 128.76 (Ph–C₃and C₅), 127.12 (Ph–C₁), 118.52

(Ph–C₂and C₆), 118.44 (pyrrole–C₂and C₅), 110.95

(pyrrole–C₃and C₄), 36.53 (pyrrolidine–C₄); MS (ESI): m/

z = found 295.10 [M^?], 297, 171, 154; calcd. 295.29.

Anal. C₁₆H₁₃N₃O₃.

N-(1,3-dioxoisoindolin-2-yl)-4-(1H-pyrrol-1-yl)benzamide

(5e) Yield 75 %. mp 189–190 °C; FTIR (KBr): 3368

(NH), 3141, 2985 (Ar–H), 1728 (isoindoline C=O), 1672

4-(1H-pyrrol-1-yl)-N-(4,5,6,7-tetraﬂuoro-1,3-dioxoisoin-

dolin-2-yl)benzamide (5h) Yield 43 %. mp 260–262 °C;

FTIR (KBr): 3230 (NH), 3222, 2911 (Ar–H), 1785 (iso-

indoline C=O), 1749 (isoindoline C=O), 1691 (amide C=O)

(amide C=O) cm^-^{1 1}H NMR (400 MHz, DMSO-d₆) d

;

1

ppm: 6.35 (dd, 2H, pyrrole–C₃and C₄–H), 7.32 (dd, 2H,

pyrrole–C₂and C₅–H), 7.64 (d, 2H, J = 8 Hz, Ph–C₃and

C₅–H), 7.89–7.97 (m, 4H, isoindoline–C₄, C₅, C₆and

C₇–H). 8.13 (d, 2H, J = 8 Hz, Ph–C₂and C₆–H), 11.20

(s, 1H, amide–NH); ¹³C NMR (500 MHz, CDCl₃) d ppm:

167.18 (amide–C=O), 165.38 (isoindoline–C₃), 164.52

cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 6.43 (dd,

2H, pyrrole–C₃and C₄–H), 7.39 (dd, 2H, pyrrole–C₂and

C₅–H), 7.87 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.13 (d,

2H, J = 8 Hz, Ph–C₂and C₆–H), 13.01 (s, 1H, amide–

NH); ¹³C NMR (400 MHz, DMSO-d₆) d ppm: 167.93

(amide–C=O), 166.01 (isoindoline–C₁and C₃), 144.58

123

Med Chem Res (2014) 23:1123–1147

1131

(Ph–C₄), 143.60 (isoindoline–C₅and C₆), 142.81 (isoind-

oline–C₄and C₇), 130.61 (Ph–C₃and C₅), 128.80 (Ph–C₁),

128.56 (Ph–C₂and C₆), 122.19 (pyrrole–C₂and C₅),

120.09 (isoindoline–C₈and C₉), 111.30 (pyrrole–C₃and

C₄); MS (ESI): m/z = found 403.06 [M^?], 338, 218, 186,

142, 120, 105, 67; calcd. 403.29. Anal. C₁₉H₉F₄N₃O₃.

2H, J = 8.5 Hz, Ph–C₂and C₆–H), 8.15–8.70 (m, 3H,

isoindoline–C₄, C₆and C₇–H), 12.09 (s, 1H, amide–NH);

¹³C NMR (400 MHz, DMSO-d₆) d ppm: 170.09 (amide–

C=O), 167.13 (isoindoline–C₁and C₃), 155.03 (isoindo-

line–C₅), 145.21 (Ph–C₄), 140.11 (isoindoline–C₈), 133.90

(isoindoline–C₉), 131.09 (Ph–C₃and C₅), 130.11 (isoind-

oline–C₇), 129.03 (Ph–C₂and C₆), 128.88 (Ph–C₁), 128.05

(isoindoline–C₆), 122.29 (isoindoline–C₄), 118.05 (pyr-

role–C₂and C₅), 111.89 (pyrrole–C₃and C₄); MS (ESI): m/

z = found 376.08 [M^?], 266, 207, 191, 186, 170, 167, 146,

67; calcd. 376.32. Anal. C₁₉H₁₂N₄O₅.

N-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)-4-(1H-pyrrol-1-

yl)benzamide (5i) Yield 51 %. mp 254–256 °C; FTIR

(KBr): 3223 (NH), 2993, 2955 (Ar–H), 1777 (isoindoline

C=O), 1745 (isoindoline C=O), 1687 (amide C=O) cm^-1

;

¹H NMR (400 MHz, DMSO-d₆) d ppm: 6.33 (dd, 2H,

pyrrole–C₃and C₄–H), 7.47 (dd, 2H, pyrrole–C₂and C₅–

H), 7.68 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.03 (d, 2H,

J = 8.5 Hz, Ph–C₂and C₆–H), 8.15 (d, 2H, isoindoline–C₄

and C₇–H), 12.27 (s, 1H, amide–NH); ¹³C NMR

(400 MHz, DMSO-d₆) d ppm: 169.80 (amide–C=O),

165.89 (isoindoline–C₁and C₃), 141.89 (Ph–C₄), 135.29

(isoindoline–C₅and C₆), 133.21 (isoindoline–C₈and C₉),

130.30 (Ph–C₃and C₅), 129.57 (isoindoline–C₄and C₇),

128.30 (Ph–C₁), 128.01 (Ph–C₂and C₆), 119.70 (pyrrole–

C₂and C₅), 110.89 (pyrrole–C₃and C₄); MS (ESI): m/

z = found 400.02 [M^?], 401.01 [M^??1], 402.02 [M^??2],

334/332, 230/232, 215/213, 186, 142, 120, 67; calcd.

400.21. Anal. C₁₉H₁₁Cl₂N₃O₃.

4-(1H-pyrrol-1-yl)-N-(4-nitro-1,3-dioxoisoindolin-2-yl)

benzamide (5l) Yield 40 %. mp 252–254 °C; FTIR

(KBr): 3255 (NH), 3001, 2976 (Ar–H), 1750 (isoindoline

C=O), 1713 (isoindoline C=O), 1651 (amide C=O) cm^-1; ¹H

NMR (400 MHz, DMSO-d₆) d ppm: 6.20 (dd, 2H, pyrrole–

C₃and C₄–H), 7.35 (dd, 2H, pyrrole–C₂and C₅–H), 7.83 (d,

2H, J = 8 Hz, Ph–C₃and C₅–H), 8.29 (d, 2H, J = 8 Hz, Ph–

C₂and C₆–H), 8.35–8.76 (m, 3H, isoindoline–C₅, C₆and C₇–

H), 13.01 (s, 1H, amide–NH); ¹³C NMR (400 MHz, DMSO-

d₆) d ppm: 169.70 (amide–C=O), 167.80 (isoindoline–C₁

and C₃), 149.21 (isoindoline–C₄), 145.03 (Ph–C₄), 135.29

(isoindoline–C₆), 134.70 (isoindoline–C₈), 130.23 (isoind-

oline–C₇), 129.08 (Ph–C₃and C₅), 128.88 (Ph–C₁, C₂and

C₆), 128.03 (isoindoline–C₅and C₉), 121.05 (pyrrole–C₂and

C₅), 111.57 (pyrrole–C₃and C₄); MS (ESI): m/z = found

376.08 [M^?], 311, 207, 191, 186, 170, 167, 146, 67; calcd.

376.32. Anal. C₁₉H₁₂N₄O₅.

N-(5-methyl-1,3-dioxoisoindolin-2-yl)-4-(1H-pyrrol-1-yl)

benzamide (5j) Yield 60 %. mp 240–242 °C; FTIR

(KBr): 3230 (NH), 3011, 2988 (Ar–H), 1781 (isoindoline

C=O), 1749 (isoindoline C=O), 1680 (amide C=O) cm^-1

;

¹H NMR (400 MHz, DMSO-d₆) d ppm: 2.51 (s, 3H, iso-

indoline–5-CH₃), 6.40 (dd, 2H, pyrrole–C₃and C₄–H),

7.30 (dd, 2H, pyrrole–C₂and C₅–H), 7.56–7.77 (m, 3H,

Ph–C₃, C₅–H and isoindoline–C₆–H), 7.83–8.01 (m, 2H,

isoindoline–C₄and C₇–H), 8.20 (d, 2H, J = 10 Hz, Ph–C₂

and C₆–H), 11.29 (s, 1H, amide–NH); ¹³C NMR

(400 MHz, DMSO-d₆) d ppm: 168.01 (amide–C=O),

165.73 (isoindoline–C₁and C₃), 142.23 (Ph–C₄), 141.83

(isoindoline–C₅), 133.19 (isoindoline–C₆), 132.30 (isoind-

oline–C₉), 130.13 (Ph–C₃and C₅), 129.81 (isoindoline–

C₈), 125.88 (Ph–C₁), 125.33 (Ph–C₂and C₆), 124.55

(isoindoline–C₄and C₇), 120.66 (pyrrole–C₂and C₅),

111.37 (pyrrole–C₃and C₄), 22.13 (isoindoline–5-CH₃);

MS (ESI): m/z = found 345.11 [M^?], 280, 200, 186, 176,

170, 160, 146, 67; calcd. 345.35. Anal. C₂₀H₁₅N₃O₃.

N-(1,3-dioxohexahydro-1H-isoindol-2(3H)-yl)-4-(1H-pyr-

rol-1-yl)benzamide (5m) Yield 57 %. mp 228–230 °C;

FTIR (KBr): 3241 (NH), 2999, 2956 (Ar–H), 1729 (iso-

indoline C=O), 1699 (isoindoline C=O), 1629 (amide C=O)

1

cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 1.40–1.52

(m, 4H, isoindoline–C₅and C₆–H), 1.55–1.79 (m, 4H,

isoindoline–C₄and C₇–H), 2.57 (d, 2H, isoindoline–C₈and

C₉–H), 6.13 (dd, 2H, pyrrole–C₃and C₄–H), 7.31 (dd, 2H,

pyrrole–C₂and C₅–H), 7.51 (d, 2H, J = 8 Hz, Ph–C₃and

C₅–H), 8.01 (d, 2H, J = 8 Hz, Ph–C₂and C₆–H), 11.33 (s,

1H, amide–NH); ¹³C NMR (400 MHz, DMSO-d₆) d ppm:

176.01 (isoindoline–C₃), 167.09 (amide–C=O), 145.01

(Ph–C₄), 130.05 (Ph–C₃and C₅), 129.08 (Ph–C₁), 128.81

(Ph–C₂and C₆), 120.40 (pyrrole–C₂and C₅), 111.01

(pyrrole–C₃and C₄), 40.11 (isoindoline–C₈and C₉), 28.09

(isoindoline–C₄and C₇), 26.03 (isoindoline–C₅and C₆);

MS (ESI): m/z = found 337.14 [M^?], 271, 186, 170, 168,

152, 120, 67; calcd. 337.37. Anal. C₁₉H₁₉N₃O₃.

N-(5-nitro-1,3-dioxoisoindolin-2-yl)-4-(1H-pyrrol-1-yl)

benzamide (5k) Yield 40 %. mp 270–272 °C; FTIR

(KBr): 3241 (NH), 3217, 2971 (Ar–H), 1732 (isoindoline

C=O), 1701 (isoindoline C=O), 1636 (amide C=O) cm^-1

;

Synthesis of ethyl 4-(2,5-dimethylpyrrol-1-yl)benzoate (6)

¹H NMR (400 MHz, DMSO-d₆) d ppm: 6.17 (dd, 2H,

pyrrole–C₃and C₄–H), 7.20 (dd, 2H, pyrrole–C₂and C₅–

H), 7.59 (d, 2H, J = 8.5 Hz, Ph–C₃and C₅–H), 8.01 (d,

A mixture of acetonyl acetone (13.69 g, 120 mmol) and

ethyl 4-aminobenzoate (2; 16.5 g, 100 mmol) in glacial

123

1132

Med Chem Res (2014) 23:1123–1147

acetic acid (100 mL) was reﬂuxed for 1 h. The solvent was

removed under reduced pressure, residue thus obtained was

collected by ﬁltration, washed with water, dried, and re-

crystallized from ethanol (yield 65 %). mp 87–88 °C (Joshi

et al., 2013a).

(KBr): 3251 (NH), 3022, 2931 (Ar–H), 1745 (pyrrolidine

C=O), 1681 (amide C=O) cm^-^{1 1}H NMR (500 MHz,

;

DMSO-d₆) d ppm: 2.03 (s, 6H, 2CH₃), 2.49–2.58 (m, 4H,

pyrrolidine–C₃and C₄–H), 5.81 (dd, 2H, pyrrole–C₃and

C₄–H), 7.69 (d, 2H, J = 7.5 Hz, Ph–C₃and C₅–H), 7.99 (d,

2H, J = 8 Hz, Ph–C₂and C₆–H), 10.59 (s, 1H, amide–

NH); ¹³C NMR (500 MHz, DMSO-d₆) d ppm: 170.29

(pyrrolidine–C₂and C₅), 165.29 (amide–C=O), 142.23

(Ph–C₄), 130.33 (Ph–C₃and C₅), 128.81 (Ph–C₁), 128.55

(Ph–C₂and C₆), 127.49 (pyrrole–C₂and C₅), 105.87

(pyrrole–C₃and C₄), 29.71 (pyrrolidine–C₃and C₄), 12.70

(pyrrole–2CH₃); MS (ESI): m/z = found 311.13 [M^?],

283, 256, 218, 198, 141, 114, 98; calcd. 311.34. Anal.

C₁₇H₁₇N₃O₃.

Synthesis of 4-(2,5-dimethylpyrrol-1-yl)benzoic acid

hydrazide (7)

Compound 2 was synthesized by reﬂuxing a mixture of

ethyl 4-(2,5-dimethylpyrrol-1-yl)benzoate (1; 3.64 g,

15 mmol) with hydrazine hydrate (10 mL) in absolute

ethanol (10 mL) for 3 h (monitored by TLC). The cooled

mixture was poured gradually onto crushed ice cubes with

stirring. The mixture was allowed to stand and solid was

separated. It was ﬁltered, washed thoroughly with cold

water, dried, and recrystallized from ethanol (yield 80 %).

mp 170–172 °C (Joshi et al., 2013a).

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(3-methyl-2,5-dioxo-

2,5-dihydro-1H-pyrrol-1-yl)benzamide (8c) Yield 60 %.

mp 208–210 °C; FTIR (KBr): 3267 (NH), 3087, 2919 (Ar–

H), 1738 (pyrrole C=O), 1661 (amide C=O) cm^-^{1 1}H

;

General procedure for the preparation of N-(substituted)-

NMR (400 MHz, CDCl₃) d ppm: 1.96 (s, 6H, 2CH₃), 2.10

(s, 3H, CH₃at 2,5-dihydropyrrole–C₃), 5.79 (s, 2H, pyr-

role–C₃and C₄–H), 6.71 (s, 1H, 2,5-dihydropyrrole–C₃–

H), 7.36 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.05 (d, 2H,

J = 8 Hz, Ph–C₂and C₆–H), 11.05 (s, 1H, amide–NH);

¹³C NMR (400 MHz, CDCl₃) d ppm: 168.72 (amide–

C=O), 167.64 (2,5-dihydropyrrole–C₂), 164.49 (2,5-dihy-

dropyrrole–C₅), 144.62 (2,5-dihydropyrrole–C₃), 142.03

(Ph–C₄), 130.67 (Ph–C₃and C₅), 129.74 (Ph–C₂and C₆)

127.79 (2,5-dihydropyrrole–C₄), 127.52 (Ph–C₁), 126.62

(pyrrole–C₂and C₅), 106.35 (pyrrole–C₃and C₄), 12.74

(CH₃of 2,5-dihydropyrrole–C₃), 11.07 (pyrrole–2CH₃);

MS (ESI): m/z = found 323.13 [M^?], 230, 171, 153, 126,

112, 110, 96; calcd. 323.35. Anal. C₁₈H₁₇N₃O₃.

4-(2,5-dimethyl-1H-pyrrol-1-yl)benzamides (8a–m)

Mixture of 4-(2,5-dimethyl-1H-pyrrol-1-yl)benzohydrazide

(25 mmol) and anhydride (25 mmol) in 10 mL dried acetic

acid was stirred for 30 min at room temperature. The

separated solid was ﬁltered, washed with diethyl ether, and

dried. The solid was dissolved in 30 mL dried acetic acid

and stirred overnight under nitrogen atmosphere. The

reaction mixture was then poured into ice-cold water; the

separated solid was collected, washed with water, dried,

and recrystallized by aqueous methanol/DMF to get the

desired product 8a–m.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxo-2,5-dihy-

dro-1H-pyrrol-1-yl)benzamide (8a) Yield 40 %. mp

254–256 °C; FTIR (KBr): 3239 (NH), 3019, 2985 (Ar–H),

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(3-methylene-2,5-di-

oxopyrrolidin-1-yl)benzamide (8d) Yield 52 %. mp

184–186 °C; FTIR (KBr): 3221 (NH), 3022, 2923 (Ar–H),

1750 (2,5-dihydropyrrole C=O), 1673 (amide C=O) cm^-1

;

¹H NMR (500 MHz, DMSO-d₆) d ppm: 1.99 (s, 6H, 2CH₃),

5.85 (dd, 2H, pyrrole–C₃and C₄–H), 7.79 (d, 2H, J = 8 Hz,

Ph–C₃and C₅–H), 8.01 (d, 2H, J = 8 Hz, Ph–C₂and C₆–H),

9.29 (s, 2H, 2,5-dihydropyrrole–C₃and C₄–H), 11.29 (s, 1H,

amide–NH); ¹³C NMR (500 MHz, DMSO-d₆) d ppm:

165.21 (amide–C=O), 164.81 (2,5-dihydropyrrole–C₂),

164.33 (2,5-dihydropyrrole–C₅), 143.21 (Ph–C₄), 138.29

(2,5-dihydropyrrole–C₃and C₄), 131.20 (Ph–C₃and C₅),

129.21 (Ph–C₁), 128.91 (Ph–C₂and C₆), 127.35 (pyrrole–C₂

and C₅), 106.01 (pyrrole–C₃and C₄), 11.99 (pyrrole–2CH₃);

MS (ESI): m/z = found 309.11 [M^?], 283, 256, 216, 171,

139, 112, 96; calcd. 309.32. Anal. C₁₇H₁₅N₃O₃.

1693 (pyrrolidine C=O), 1636 (amide C=O) cm^-^{1 1}H

;

NMR (400 MHz, DMSO-d₆) d ppm: 2.01 (s, 6H, 2CH₃),

5.82 (s, 2H, CH₂at pyrrolidine–C₃), 6.21 (s, 2H, CH₂at

pyrrolidine–C₄), 6.26 (s, 2H, pyrrole–C₃and C₄–H), 7.30

(d, 2H, J = 8.4 Hz, Ph–C₃and C₅–H), 8.08 (d, 2H,

J = 8.4 Hz, Ph–C₂and C₆–H), 10.00 (s, 1H, amide–NH);

¹³C NMR (400 MHz, DMSO-d₆) d ppm: 168.86 (amide–

C=O), 167.58 (pyrrolidine–C₂), 164.76 (pyrrolidine–C₅),

141.26 (Ph–C₄), 134.78 (pyrrolidine–C₃), 131.29 (CH₂at

pyrrolidine–C₃), 128.35 (Ph–C₃and C₅), 127.65 (Ph–C₁),

127.45 (Ph–C₂and C₆), 127.26 (pyrrole–C₂and C₅),

106.00 (pyrrole–C₃and C₄), 36.60 (pyrrolidine–C₄), 12.68

(pyrrole–2CH₃); MS (ESI): m/z = found 323.13 [M^?],

283, 256, 230, 198, 126, 110, 98, 95; calcd. 323.35. Anal.

C₁₈H₁₇N₃O₃.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-

yl)benzamide (8b) Yield 39 %. mp 190–192 °C; FTIR

123

Med Chem Res (2014) 23:1123–1147

1133

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(1,3-dioxoisoindolin-2-

yl)benzamide (8e) Yield 79 %. mp 196–198 °C; FTIR

(KBr): 3246 (NH), 3017, 2913 (Ar–H), 1705 (isoindoline

284, 299, 284, 266, 214, 198, 171, 95; calcd. 497.16. Anal.

C₂₁H₁₃Cl₄N₃O₃.

C=O), 1667 (amide C=O) cm^-^{1 1}H NMR (400 MHz,

;

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(4,5,6,7-tetraﬂuoro-

1,3-dioxoisoindolin-2-yl)benzamide (8h) Yield 40 %.

mp 284–286 °C; FTIR (KBr): 3243 (NH), 2987, 2930 (Ar–

H), 1751 (isoindoline C=O), 1676 (isoindoline C=O), 1641

DMSO-d₆) d ppm: 2.02 (s, 6H, 2CH₃), 5.83 (s, 2H, pyr-

role–C₃and C₄–H), 7.29 (d, 2H, J = 8.24 Hz, Ph–C₃and

C₅–H), 7.50–7.94 (m, 4H, isoindoline–C₄, C₅, C₆and C₇–

H). 8.17 (d, 2H, J = 8 Hz, Ph–C₂and C₆–H), 10.70 (s, 1H,

amide–NH); ¹³C NMR (500 MHz, CDCl₃) d ppm: 168.11

(amide–C=O), 164.91 (isoindoline–C₃), 159.93 (isoindo-

line–C₁), 141.32 (Ph–C₄), 135.97 (isoindoline–C₅and C₆),

132.19 (isoindoline–C₉), 131.30 (isoindoline–C₈), 129.37

(Ph–C₃and C₅), 128.54 (Ph–C₁), 128.26 (Ph–C₂and C₆),

127.59 (pyrrole–C₂and C₅), 127.47 (isoindoline–C₄and

C₇), 106.11 (pyrrole–C₃and C₄), 12.71 (pyrrole–2CH₃);

MS (ESI): m/z = found 359.13 [M^?], 283, 266, 256, 214,

198, 171, 162, 146, 95; calcd. 359.38. Anal. C₂₁H₁₇N₃O₃.

(amide C=O) cm^-^{1 1}H NMR (400 MHz, DMSO-d₆) d

;

ppm: 2.10 (s, 6H, 2CH₃), 5.89 (dd, 2H, pyrrole–C₃and C₄–

H), 7.83 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.11 (d, 2H,

J = 10 Hz, Ph–C₂and C₆–H), 11.12 (s, 1H, amide–NH);

¹³C NMR (400 MHz, DMSO-d₆) d ppm: 167.11 (amide–

C=O), 165.71 (isoindoline–C₁and C₃), 145.71 (isoindo-

line–C₅and C₆), 145.01 (isoindoline–C₄and C₇), 143.71

(Ph–C₄), 131.22 (Ph–C₃and C₅), 129.11 (Ph–C₁, C₂and

C₆), 128.71 (pyrrole–C₂and C₅), 119.09 (isoindoline–C₈

and C₉), 107.11 (pyrrole–C₃and C₄), 12.70 (pyrrole–

2CH₃); MS (ESI): m/z = found 431.09 [M^?], 338, 234,

218, 214, 198, 176, 171, 95; calcd. 431.34. Anal.

C₂₁H₁₃F₄N₃O₃.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(4,5,6,7-tetrabromo-

1,3-dioxoisoindolin-2-yl)benzamide (8f) Yield 53 %.

mp[300 °C; FTIR (KBr): 3237 (NH), 2976, 2919 (Ar–H),

1744 (isoindoline C=O), 1699 (amide C=O), 1651 (iso-

N-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)-4-(2,5-dimethyl-

1H-pyrrol-1-yl)benzamide (8i) Yield 49 %. mp 274–

276 °C; FTIR (KBr): 3220 (NH), 2999, 2945 (Ar–H), 1759

(isoindoline C=O), 1681 (isoindoline C=O), 1637 (amide

1

indoline C=O) cm^-1; H NMR (400 MHz, DMSO-d₆) d

ppm: 2.05 (s, 6H, 2CH₃), 5.85 (s, 2H, pyrrole–C₃and C₄–

H), 7.40 (d, 2H, J = 8.48 Hz, Ph–C₃and C₅–H), 8.16 (d,

2H, J = 8.52 Hz, Ph–C₂and C₆–H), 11.47 (s, 1H, amide–

NH); ¹³C NMR (400 MHz, DMSO-d₆) d ppm: 160.85

(amide–C=O), 160.31 (isoindoline–C₁and C₃), 142.24

(Ph–C₄), 137.66 (isoindoline–C₈and C₉), 128.88 (isoind-

oline–C₅and C₆), 128.72 (Ph–C₃and C₅), 127.84 (Ph–C₁,

C₂and C₆), 127.55 (pyrrole–C₂and C₅), 121.37 (isoindo-

line–C₄and C₇), 106.39 (pyrrole–C₃and C₄), 12.76 (pyr-

role–2CH₃); MS (ESI): m/z = found 674.76 [M^?], 672.77

[M^?-2], 676.76 [M^??2], 582/580, 476/474, 462/460, 283,

256, 214, 198, 171, 95; calcd. 674.96. Anal.

C₂₁H₁₃Br₄N₃O₃.

1

C=O) cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 2.01

(s, 6H, 2CH₃), 5.81 (dd, 2H, pyrrole–C₃and C₄–H), 7.81

(d, 2H, J = 8.5 Hz, Ph–C₃and C₅–H), 8.09 (d, 2H,

J = 8.5 Hz, Ph–C₂and C₆–H), 8.09 (d, 2H, isoindoline–C₄

and C₇–H), 11.87 (s, 1H, amide–NH); ¹³C NMR

(400 MHz, DMSO-d₆) d ppm: 170.23 (amide–C=O),

167.31 (isoindoline–C₁and C₃), 144.22 (Ph–C₄), 140.21

(isoindoline–C₅and C₆), 135.21 (isoindoline–C₈and C₉),

130.51 (Ph–C₃and C₅), 129.85 (isoindoline–C₄and C₇),

129.23 (Ph–C₁), 128.83 (Ph–C₂and C₆), 127.15 (pyrrole–

C₂and C₅), 106.50 (pyrrole–C₃and C₄), 12.75 (pyrrole–

2CH₃); MS (ESI): m/z = found 428.05 [M^?], 430.05

[M^??2], 334/332, 258/256, 232/230, 215, 214, 198, 171,

95; calcd. 428.27. Anal. C₂₁H₁₅Cl₂N₃O₃.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(4,5,6,7-tetrachloro-

1,3-dioxoisoindolin-2-yl)benzamide (8g) Yield 57 %.

mp[300 °C; FTIR (KBr): 3255 (NH), 3018, 2928 (Ar–H),

1740 (isoindoline C=O), 1696 (isoindoline C=O), 1650

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(5-methyl-1,3-dioxois-

oindolin-2-yl)benzamide (8j) Yield 65 %. mp 192–

194 °C; FTIR (KBr): 3257 (NH), 3021, 2977 (Ar–H), 1746

(isoindoline C=O), 1693 (isoindoline C=O), 1650 (amide

(amide C=O) cm^-^{1 1}H NMR (400 MHz, DMSO-d₆) d

;

ppm: 2.03 (s, 6H, 2CH₃), 5.87 (dd, 2H, pyrrole–C₃and C₄–

H), 7.77 (d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.09 (d, 2H,

J = 8 Hz, Ph–C₂and C₆–H), 10.89 (s, 1H, amide–NH);

¹³C NMR (400 MHz, DMSO-d₆) d ppm: 165.27 (amide–

C=O), 164.59 (isoindoline–C₁and C₃), 143.55 (Ph–C₄),

140.11 (isoindoline–C₅and C₆), 135.29 (isoindoline–C₈

and C₉), 130.91 (isoindoline–C₄and C₇), 128.11 (Ph–C₃

and C₅), 128.01 (Ph–C₁), 127.81 (Ph–C₂and C₆), 127.35

(pyrrole–C₂and C₅), 106.17 (pyrrole–C₃and C₄), 12.31

(pyrrole–2CH₃); MS (ESI): m/z = found 496.97 [M^?],

494.97 [M^?-2], 498.97 [M^??2], 404/402, 300/298, 286/

1

C=O) cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 1.96

(s, 6H, 2CH₃), 2.30 (s, 3H, isoindoline–5-CH₃), 5.81 (dd,

2H, pyrrole–C₃and C₄–H), 7.66–7.79 (m, 3H, Ph–C₃, C₅–

H and isoindoline–C₆–H), 7.89–7.98 (m, 2H, isoindoline–

C₄and C₇–H), 8.01 (d, 2H, J = 8.5 Hz, Ph–C₂and C₆–H),

12.01 (s, 1H, amide–NH); ¹³C NMR (400 MHz, DMSO-

d₆) d ppm: 170.20 (amide–C=O), 167.33 (isoindoline–C₁

and C₃), 142.11 (Ph–C₄), 141.81 (isoindoline–C₅), 133.45

(isoindoline–C₆), 132.21 (isoindoline–C₉), 130.27 (Ph–C₃

123

1134

Med Chem Res (2014) 23:1123–1147

and C₅), 129.73 (isoindoline–C₈), 128.39 (Ph–C₁), 128.11

(Ph–C₂and C₆), 127.81 (pyrrole–C₂and C₅), 126.58 (iso-

indoline–C₄and C₇), 106.28 (pyrrole–C₃and C₄), 22.01

(isoindoline–5-CH₃), 12.71 (pyrrole–2CH₃); MS (ESI): m/

z = found 373.14 [M^?], 280, 214, 198, 176, 171, 162, 160,

146, 95; calcd. 373.40. Anal. C₂₂H₁₉N₃O₃.

2H, pyrrole–C₃and C₄–H), 7.73 (d, 2H, J = 8.5 Hz, Ph–C₃

and C₅–H), 8.09 (d, 2H, J = 8.5 Hz, Ph–C₂and C₆–H),

10.95 (s, 1H, amide–NH); ¹³C NMR (400 MHz, DMSO-

d₆) d ppm: 176.10 (isoindoline–C₃), 167.21 (amide–C=O),

145.27 (Ph–C₄), 130.21 (Ph–C₃and C₅), 129.31 (Ph–C₁, C₂

and C₆), 129.01 (pyrrole–C₂and C₅), 105.90 (pyrrole–C₃

and C₄), 40.22 (isoindoline–C₈and C₉), 29.01 (isoindo-

line–C₄and C₇), 26.33 (isoindoline–C₅and C₆), 12.29

(pyrrole–2CH₃); MS (ESI): m/z = found 365.17 [M^?],

271, 256, 214, 198, 171, 168, 152, 110, 95; calcd. 365.43.

Anal. C₂₁H₂₃N₃O₃.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(5-nitro-1,3-dioxoiso-

indolin-2-yl)benzamide (8k) Yield 39 %. mp 188–

190 °C; FTIR (KBr): 3249 (NH), 3003, 2954 (Ar–H), 1723

(isoindoline C=O), 1654 (isoindoline C=O), 1605 (amide

1

C=O) cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 2.03

(s, 6H, 2CH₃), 5.89 (dd, 2H, pyrrole–C₃and C₄–H), 7.57

(d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 8.11 (d, 2H,

J = 8 Hz, Ph–C₂and C₆–H), 8.15–8.70 (m, 3H, isoindo-

line–C₄, C₆and C₇–H), 12.63 (s, 1H, amide–NH); ¹³C

NMR (400 MHz, DMSO-d₆) d ppm: 168.35 (amide–C=O),

165.29 (isoindoline–C₁and C₃), 155.27 (isoindoline–C₅),

143.33 (Ph–C₄), 140.29 (isoindoline–C₈), 139.87 (isoind-

oline–C₉), 133.21 (Ph–C₃and C₅), 128.85 (isoindoline–C₇

and Ph–C₁), 128.55 (Ph–C₂and C₆), 128.20 (pyrrole–C₂

and C₅), 127.31 (isoindoline–C₆), 123.29 (isoindoline–C₄),

105.91 (pyrrole–C₃and C₄), 12.30 (pyrrole–2CH₃); MS

(ESI): m/z = found 404.11 [M^?], 311, 214, 198, 191, 171,

162, 146, 95; calcd. 404.38. Anal. C₂₁H₁₆N₄O₅.

General procedure for the preparation of 2-amino-4-(4-

substituted phenyl)thiazoles (11a–l)

Mixture of substituted acetophenone (100 mmol), thiourea

(200 mmol), and iodine or bromine (100 mmol) was

reﬂuxed for 24 h on a water bath. The reaction mixture was

cooled, washed with ether, added to boiling water, and

ﬁltered while hot. The ﬁltrate was cooled and basiﬁed with

ammonium hydroxide solution. The crude product obtained

was ﬁltered, dried, and recrystallized from aqueous ethanol

to get the desired product (11a–l; Pattan et al., 2006;

Dickey et al., 1959; Singh et al., 2010).

General procedure for the preparation of 4-(4-substituted

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(4-nitro-1,3-dioxoiso-

indolin-2-yl)benzamide (8l) Yield 39 %. mp 158–

160 °C; FTIR (KBr): 3271 (NH), 2989, 2933 (Ar–H), 1742

(isoindoline C=O), 1644 (isoindoline C=O), 1615 (amide

phenyl)-2-(1H-pyrrol-1-yl)thiazoles (12a–l)

To a solution of 2-amino-4-(4-substituted phenyl)thiazoles

(10 mmol) in 20 mL glacial acetic acid, 2,5-dimethoxyte-

trahydrofuran (15 mmol) was added slowly at room tem-

perature and was reﬂuxed for 1 h (monitored by TLC). The

reaction mixture was poured into ice-cold water and basi-

ﬁed with ammonium carbonate solution. The separated

solid was collected, washed with water, and dried. The

compounds were puriﬁed by column chromatography using

chromatotron (hexane/ethyl acetate 70:30).

1

C=O) cm^-1; H NMR (400 MHz, DMSO-d₆) d ppm: 2.07

(s, 6H, 2CH₃), 5.77 (dd, 2H, pyrrole–C₃and C₄–H), 7.69

(d, 2H, J = 8 Hz, Ph–C₃and C₅–H), 7.99 (d, 2H,

J = 10 Hz, Ph–C₂and C₆–H), 8.15–8.65 (m, 3H, isoind-

oline–C₅, C₆and C₇–H), 10.90 (s, 1H, amide–NH); ¹³C

NMR (400 MHz, DMSO-d₆) d ppm: 169.23 (amide–C=O),

167.30 (isoindoline–C₁and C₃), 147.23 (isoindoline–C₄),

144.81 (Ph–C₄), 135.23 (isoindoline–C₆), 134.29 (isoind-

oline–C₈), 130.25 (isoindoline–C₇), 129.35 (Ph–C₃and

C₅), 128.76 (Ph–C₁, C₂and C₆), 128.55 (isoindoline–C₅

and C₉), 128.31 (pyrrole–C₂and C₅), 106.21 (pyrrole–C₃

and C₄), 12.35 (pyrrole–2CH₃); MS (ESI): m/z = found

404.11 [M^?], 311, 266, 214, 198, 191, 171, 162, 149, 146,

95; calcd. 404.38. Anal. C₂₁H₁₆N₄O₅.

4-Phenyl-2-(1H-pyrrol-1-yl)thiazole (12a) Yield 71 %.

mp 59–61 °C; FTIR (KBr): 2921 and 2851 (Ar–H), 1599

(C=N) cm^-1; ¹H NMR (500 MHz, CDCl₃) d ppm: 6.39 (s,

2H, pyrrole–C₃and C₄–H), 7.15 (s, 1H, thiazole–C₅–H),

7.36–7.50 (m, 5H, Ph–C₃, C₄and C₅–H, pyrrole–C₂and

C₅–H), 7.95 (d, 2H, J = 7.5 Hz, Ph–C₂and C₆–H); ¹³C

NMR (500 MHz, CDCl₃) d ppm: 159.76 (thiazole–C₂),

152.44 (thiazole–C₄), 127.54 (Ph–C₂and C₆), 127.08 (Ph–

C₃and C₅), 119.67 (Ph–C₁and C₄), 114.09 (pyrrole–C₂

and C₅), 111.84 (pyrrole–C₃and C₄), 105.00 (thiazole–C₅);

MS (ESI): m/z = found 226.06 [M^?], 150, 119, 85; calcd.

226.30. Anal. C₁₃H₁₀N₂S.

4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(1,3-dioxohexahydro-

1H-isoindol-2(3H)-yl)benzamide (8m) Yield 59 %. mp

206–208 °C; FTIR (KBr): 3231 (NH), 3020, 2954 (Ar–H),

1709 (isoindoline C=O), 1651 (isoindoline C=O), 1610

(amide C=O) cm^-^{1 1}H NMR (400 MHz, DMSO-d₆) d

;

ppm: 1.45–1.52 (m, 4H, isoindoline–C₅and C₆–H), 1.56–

1.80 (m, 4H, isoindoline–C₄and C₇–H), 2.04 (s, 6H,

2CH₃), 2.53 (d, 2H, isoindoline–C₈and C₉–H), 5.80 (dd,

4-(4-Chlorophenyl)-2-(1H-pyrrol-1-yl)thiazole (12b) Yield

89 %. mp 64–66 °C; FTIR (KBr): 2971 and 2937 (Ar–H),

123

Med Chem Res (2014) 23:1123–1147

1135

1

1595 (C=N) cm^-1; H NMR (400 MHz, CDCl₃) d ppm:

4-(4-Nitrophenyl)-2-(1H-pyrrol-1-yl)thiazole (12f) Yield

68 %. mp 68–70 °C; FTIR (KBr): 2918 and 2851 (Ar–H),

6.32 (dd, 2H, pyrrole–C₃and C₄–H), 6.80–6.98 (m, 2H,

Ph–C₃and C₅–H), 7.12 (s, 1H, thiazole–C₅–H), 7.48 (dd,

2H, pyrrole–C₂and C₅–H), 7.81–7.92 (m, 2H, Ph–C₂and

C₆–H); ¹³C NMR (400 MHz, CDCl₃) d ppm: 159.69 (thi-

azole–C₂), 158.56 (Ph–C₄), 153.24 (thiazole–C₄), 127.26

(Ph–C₂and C₆), 125.85 (Ph–C₁), 119.98 (pyrrole–C₂and

C₅), 118.86 (Ph–C₃and C₅), 111.88 (pyrrole–C₃and C₄),

105.22 (thiazole–C₅); MS (ESI): m/z = found 260.02

[M^?], 262.02 [M^??2], 235, 217, 196/194, 150, 118; calcd.

260.74. Anal. C₁₃H₉ClN₂S.

1608 (C=N), 1502, and 1337 (NO₂) cm^-^{1 1}H NMR

;

(500 MHz, CDCl₃) d ppm: 6.32 (dd, 2H, pyrrole–C₃and

C₄–H), 7.10 (s, 1H, thiazole–C₅–H), 7.35–8.12 (m, 6H, Ph–

C₂, C₃, C₅and C₆–H, pyrrole–C₂and C₅–H); ¹³C NMR

(300 MHz, DMSO) d = ¹³C NMR (400 MHz, CDCl₃) d

ppm: 161.45 (Ph–C₄), 158.45 (thiazole–C₂), 151.88 (thia-

zole–C₄), 130.25 (Ph–C₃and C₅), 129.66 (Ph–C₂and C₆),

128.54 (Ph–C₁), 119.20 (pyrrole–C₂and C₅), 111.52

(pyrrole–C₃and C₄), 108.12 (thiazole–C₅); MS (ESI): m/

z = found 271.04 [M^?], 150, 119, 85; calcd. 271.29. Anal.

C₁₃H₉N₃O₂S.

4-(4-Hydroxyphenyl)-2-(1H-pyrrol-1-yl)thiazole (12c) Yield

70 %. mp 103–105 °C; FTIR (KBr): 3351 (OH), 2919 and

2852 (Ar–H), 1606 (C=N) cm^-^{1 1}H NMR (400 MHz,

;

4-(4-Aminophenyl)-2-(1H-pyrrol-1-yl)thiazole (12g) Yield

89 %. mp 127–129 °C; FTIR (KBr): 3220 (NH₂), 2920,

CDCl₃) d ppm: 6.37 (dd, 2H, pyrrole–C₃and C₄–H), 6.89–

6.92 (m, 2H, Ph–C₃and C₅–H), 6.99 (s, 1H, thiazole–C₅–

H), 7.42 (dd, 2H, pyrrole–C₂and C₅–H), 7.78–7.82 (m, 2H,

Ph–C₂and C₆–H), 8.50 (s, 1H, OH); ¹³C NMR (400 MHz,

CDCl₃) d ppm: 159.61 (thiazole–C₂), 157.49 (Ph–C₄),

151.86 (thiazole–C₄), 127.11 (Ph–C₂and C₆), 124.97 (Ph–

C₁), 119.11 (pyrrole–C₂and C₅), 115.27 (Ph–C₃and C₅),

111.57 (pyrrole–C₃and C₄), 104.74 (thiazole–C₅); MS

(ESI): m/z = found 242.05 [M^?], 192, 177, 176, 161;

calcd. 242.30. Anal. C₁₃H₁₀N₂OS.

2852 (Ar–H), 1609 (C=N) cm^-^{1 1}H NMR (400 MHz,

;

CDCl₃) d ppm: 5.34 (s, 2H, NH₂), 6.28 (dd, 2H, pyrrole–C₃

and C₄–H), 7.31 (dd, 2H, pyrrole–C₂and C₅–H), 7.35–7.51

(m, 4H, Ph–C₂, C₃, C₅and C₆–H), 8.06 (s, 1H, thiazole–

C₅–H); ¹³C NMR (400 MHz, CDCl₃) d ppm: 159.74 (thi-

azole–C₂), 158.22 (Ph–C₄), 150.56 (thiazole–C₄), 129.32

(Ph–C₂and C₆), 125.78 (Ph–C₁), 120.90 (pyrrole–C₂and

C₅), 116.58 (Ph–C₃and C₅), 111.23 (pyrrole–C₃and C₄),

105.22 (thiazole–C₅); MS (ESI): m/z = found 241.07

[M^?], 150, 119, 85; calcd. 241.31. Anal. C₁₃H₁₁N₃S.

4-(4-Bromophenyl)-2-(1H-pyrrol-1-yl)thiazole (12d) Yield

63 %. mp 115–117 °C; FTIR (KBr): 2922 and 2855 (Ar–

4-(4-Fluorophenyl)-2-(1H-pyrrol-1-yl)thiazole (12h) Yield

60 %. mp 106–108 °C; FTIR (KBr): 2989, 2941 (Ar–H),

1599 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d ppm: 6.41

(dd, 2H, pyrrole–C₃and C₄–H), 7.13 (d, 2H, J = 8 Hz, Ph–

C₃and C₅–H), 7.26 (dd, 2H, pyrrole–C₂and C₅–H), 7.31 (s,

1H, thiazole–C₅–H), 7.79–7.91 (m, 2H, Ph–C₂and C₆–H);

¹³C NMR (400 MHz, CDCl₃) d ppm: 161.53 (Ph–C₄),

159.71 (thiazole–C₂), 152.13 (thiazole–C₄), 135.21 (Ph–C₂

and C₆), 130.57 (Ph–C₁), 129.13 (pyrrole–C₂and C₅),

123.01 (Ph–C₃and C₅), 110.41 (pyrrole–C₃and C₄), 108.45

(thiazole–C₅); MS (ESI): m/z = found 244.05 [M^?], 150,

119, 95, 85; calcd. 244.29. Anal. C₁₃H₉FN₂S.

H), 1641 (C=N) cm^-^{1 1}H NMR (400 MHz, CDCl₃) d

;

ppm: 6.28 (dd, 2H, pyrrole–C₃and C₄–H), 7.04 (s, 1H,

thiazole–C₅–H), 7.31 (dd, 2H, pyrrole–C₂and C₅–H),

7.45–7.48 (m, 2H, Ph–C₃and C₅–H), 7.67–7.70 (m, 2H,

Ph–C₂and C₆–H); ¹³C NMR (400 MHz, CDCl₃) d ppm:

160.73 (thiazole–C₂), 151.43 (thiazole–C₄), 132.96 (Ph–

C₁), 131.86 (Ph–C₃and C₅), 127.78 (Ph–C₂and C₆),

122.34 (Ph–C₄), 119.69 (pyrrole–C₂and C₅), 112.15

(pyrrole–C₃and C₄), 107.29 (thiazole–C₅); MS (ESI): m/

z = found 305.96 [M^?], 303.97 [M^?-2], 291, 293, 238/

240, 175; calcd. 305.19. Anal. C₁₃H₉BrN₂S.

4-(3,4-Dichlorophenyl)-2-(1H-pyrrol-1-yl)thiazole (12i)

Yield 77 %. mp 126–128 °C; FTIR (KBr): 2969, 2921

(Ar–H), 1593 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d

ppm: 6.39 (dd, 2H, pyrrole–C₃and C₄–H), 7.19 (s, 1H,

thiazole–C₅–H), 7.31 (dd, 2H, pyrrole–C₂and C₅–H),

7.53–7.91 (m, 3H, Ph–C₃, C₄and C₆–H), 7.79–7.91 (m,

2H, Ph–C₂and C₆–H); ¹³C NMR (400 MHz, CDCl₃) d

ppm: 159.03 (thiazole–C₂), 150.81 (thiazole–C₄), 135.29

(Ph–C₄), 133.23 (Ph–C₃), 132.13 (Ph–C₁), 131.11 (Ph–C₅),

128.73 (Ph–C₂), 127.27 (Ph–C₆), 113.29 (pyrrole–C₂and

C₅), 109.10 (pyrrole–C₃and C₄), 108.43 (thiazole–C₅); MS

(ESI): m/z = found 295.98 [M^?], 293.98 [M^?-2], 150,

144/146,119, 67; calcd. 295.19. Anal. C₁₃H₈Cl₂N₂S.

4-(4-Methoxyphenyl)-2-(1H-pyrrol-1-yl)thiazole (12e) Yield

77 %. mp 105–107 °C; FTIR (KBr): 2918 and 2848 (Ar–

H), 1609 (C=N) cm^-^{1 1}H NMR (500 MHz, CDCl₃) d

;

ppm: 3.81 (s, 3H, OCH₃), 6.39 (dd, 2H, pyrrole–C₃and

C₄–H), 7.16 (s, 1H, thiazole–C₅–H), 7.28–7.95 (m, 6H, Ph–

C₂, C₃, C₅and C₆–H, pyrrole–C₂and C₅–H); ¹³C NMR

(400 MHz, CDCl₃) d ppm: 160.45 (Ph–C₄), 159.76 (thia-

zole–C₂), 152.41 (thiazole–C₄), 127.55 (Ph–C₂and C₆),

127.07 (Ph–C₁), 119.68 (pyrrole–C₂and C₅), 114.09 (Ph–

C₃and C₅), 111.87 (pyrrole–C₃and C₄), 105.03 (thiazole–

C₅), 55.36 (OCH₃); MS (ESI): m/z = found 256.07 [M^?],

191, 150,161, 119, 85, 78; calcd. 256.32. Anal.

C₁₄H₁₂N₂OS.

123

1136

Med Chem Res (2014) 23:1123–1147

2-(1H-pyrrol-1-yl)-4-(3,4,5-trimethoxyphenyl)thiazole (12j)

Yield 62 %. mp 144–146 °C; FTIR (KBr): 2921, 2883

(Ar–H), 1601 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d

ppm: 3.86 (s, 9H, 3OCH₃), 6.37 (dd, 2H, pyrrole–C₃and

C₄–H), 6.89 (d, 2H, J = 7.5 Hz, Ph–C₂and C₆–H), 7.21 (s,

1H, thiazole–C₅–H), 7.49 (dd, 2H, pyrrole–C₂and C₅–H);

¹³C NMR (400 MHz, CDCl₃) d ppm: 160.01 (thiazole–C₂),

154.29 (Ph–C₃and C₅), 151.39 (thiazole–C₄), 142.22 (Ph–

C₄), 129.53 (Ph–C₁), 115.29 (pyrrole–C₂and C₅), 110.09

(pyrrole–C₃and C₄), 109.87 (thiazole–C₅) 102.29 (Ph–C₂

and C₆), 61.73 (4-OCH₃), 56.89 (3,5-(OCH₃)₂); MS (ESI):

m/z = found 316.09 [M^?], 271, 250, 167, 150, 67; calcd.

316.37. Anal. C₁₆H₁₆N₂O₃S.

4-Phenyl-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole

(13a)

Yield 67 %. mp 60–62 °C; FTIR (KBr): 2920 and 2853

(Ar–H), 1598 (C=N) cm^-1; (400 MHz, CDCl₃) d ppm:

2.18 (s, 6H, 2CH₃), 5.75 (s, 2H, pyrrole–C₃and C₄–H),

7.28–7.36 (m, 3H, Ph–C₃, C₄and C₅–H), 7.50 (s, 1H,

thiazole–C₅–H), 7.88–8.10 (m, 2H, Ph–C₂and C₆–H); MS

(ESI): m/z = found 254.09 [M^?], 210, 178, 160, 95, 85;

calcd. 254.35. Anal. C₁₅H₁₄N₂S.

4-(4-Chlorophenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thia-

zole (13b) Yield 82 %. mp 58–60 °C; FTIR (KBr): 2956

and 2919 (Ar–H), 1654 (C=N) cm^-1; ¹H NMR (400 MHz,

CDCl₃) d ppm: 2.21 (s, 6H, 2CH₃), 5.85 (s, 2H, pyrrole–C₃

and C₄–H), 7.31–7.34 (m, 2H, Ph–C₃and C₅–H), 7.38 (s,

1H, thiazole–C₅–H), 7.76–7.79 (m, 2H, Ph–C₂and C₆–H);

¹³C NMR (400 MHz, CDCl₃) d ppm: 158.87 (thiazole–C₂),

151.54 (thiazole–C₄), 134.23 (Ph–C₄), 132.59 (Ph–C₁),

129.89 (Ph–C₃and C₅), 129.04 (Ph–C₂and C₆), 127.50

(pyrrole–C₂and C₅), 112.75 (pyrrole–C₃and C₄), 108.26

(thiazole–C₅), 13.53 (2CH₃); MS (ESI): m/z = found

288.05 [M^?], 290.05 [M^??2], 210, 176, 95, 85; calcd.

288.80. Anal. C₁₅H₁₃ClN₂S.

4-(3,4-Dimethoxyphenyl)-2-(1H-pyrrol-1-yl)thiazole (12k)

Yield 62 %. mp 132–134 °C; FTIR (KBr): 2923, 2849 (Ar–

H), 1601 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d ppm:

3.90 (s, 6H, 2OCH₃), 6.39 (dd, 2H, pyrrole–C₃and C₄–H),

7.11 (s, 1H, thiazole–C₅–H), 7.21–8.03 (m, 5H, Ph–C₂, C₅

and C₆–H, pyrrole–C₂and C₅–H); ¹³C NMR (400 MHz,

CDCl₃) d ppm: 159.84 (thiazole–C₂), 151.27 (thiazole–C₄),

150.85 (Ph–C₃), 150.31 (Ph–C₄), 130.22 (Ph–C₁), 117.11

(pyrrole–C₂and C₅), 115.27 (Ph–C₆), 113.03 (Ph–C₅),

110.27 (pyrrole–C₃, C₄and Ph–C₂), 109.15 (thiazole–C₅),

56.81 (3,4-(OCH₃)₂); MS (ESI): m/z = found 286.08 [M^?],

254, 220, 150, 137; calcd. 286.35. Anal. C₁₅H₁₄N₂O₂S.

4-(4-Hydroxyphenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thi-

azole (13c) Yield 75 %. mp 108–110 °C; FTIR (KBr):

3221 (OH), 2920 and 2854 (Ar–H), 1655 (C=N) cm^-1; ¹H

NMR (400 MHz, DMSO-d₆) d ppm: 2.17 (s, 6H, 2CH₃),

5.79 (s, 2H, pyrrole–C₃and C₄–H), 6.79 (d, 2H,

J = 11 Hz, Ph–C₃and C₅–H), 7.44 (s, 1H, thiazole–C₅–

H), 7.67 (d, 2H, J = 11 Hz, Ph–C₂and C₆–H), 9.25 (bs,

1H, OH); ¹³C NMR (400 MHz, DMSO-d₆) d ppm: 157.53

(thiazole–C₂and Ph–C₄),152.12 (thiazole–C₄), 128.92

(Ph–C₂and C₆), 127.06 (pyrrole–C₂and C₅), 125.02 (Ph–

C₁), 115.34 (Ph–C₃and C₅), 110.42 (pyrrole–C₃and C₄),

107.57 (thiazole–C₅), 12.96 (2CH₃); MS (ESI): m/

z = found 270.08 [M^?], 192, 177, 176, 161, 95, 85; calcd.

270.35. Anal. C₁₅H₁₄N₂OS.

4-(3-Nitrophenyl)-2-(1H-pyrrol-1-yl)thiazole (12l) Yield

59 %. mp 107–109 °C; FTIR (KBr): 2920, 2879 (Ar–H),

1607 (C=N), 1502, 1331 (NO₂) cm^-1; ¹H NMR (400 MHz,

CDCl₃) d ppm: 6.35 (dd, 2H, pyrrole–C₃and C₄–H), 7.03

(s, 1H, thiazole–C₅–H), 7.41–8.19 (m, 6H, Ph–C₂, C₄, C₅

and C₆–H, pyrrole C₂and C₅–H); ¹³C NMR (400 MHz,

CDCl₃) d ppm: 160.09 (thiazole–C₂), 150.33 (thiazole–C₄),

149.11 (Ph–C₃), 134.21 (Ph–C₁), 133.29 (Ph–C₆), 131.45

(Ph–C₂), 125.25 (Ph–C₄), 123.81 (Ph–C₅), 115.19 (pyr-

role–C₂and C₅), 109.10 (pyrrole–C₃and C₄), 108.81

(thiazole–C₅); MS (ESI): m/z = found 271.04 [M^?], 205,

150, 149, 124, 122; calcd. 271.29. Anal. C₁₃H₉N₃O₂S.

4-(4-Bromophenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thia-

zole (13d) Yield 87 %. mp 84–86 °C; FTIR (KBr):

General procedure for the preparation of 4-(4-substituted

2981 and 2952 (Ar–H), 1617 (C=N) cm^-^{1 1}H NMR

;

phenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiazoles (13a–l)

(400 MHz, CDCl₃) d ppm: 2.20 (s, 6H, 2CH₃), 5.84 (s,

2H, pyrrole–C₃and C₄–H), 7.39 (s, 1H, thiazole–C₅–H),

7.46–7.48 (m, 2H, Ph–C₃and C₅–H), 7.70–7.72 (m, 2H,

Ph–C₂and C₆–H); ¹³C NMR (400 MHz, CDCl₃) d ppm:

158.90 (thiazole–C₂), 151.57 (thiazole–C₄), 133.03 (Ph–

C₃and C₅), 132.01 (Ph–C₁), 129.89 (Ph–C₂and C₆),

127.81 (pyrrole–C₂and C₅), 122.48 (Ph–C₄), 112.87

(pyrrole–C₃and C₄), 108.32 (thiazole–C₅), 13.59

(2CH₃); MS (ESI): m/z = found 332.00 [M^?], 334.00

[M^??2], 176, 160, 157, 95, 85; calcd. 332.00. Anal.

C₁₅H₁₃BrN₂S.

To a solution of 2-amino-4-(4-substituted phenyl)thiazoles

(10 mmol) in 20 mL glacial acetic acid, acetonyl acetone

(15 mmol) was added slowly at room temperature and was

reﬂuxed for 1 h (monitored by TLC). The reaction mixture

was poured into ice-cold water and basiﬁed with ammo-

nium carbonate solution. The separated solid was collected,

washed with water, and dried. The compounds were puri-

ﬁed by column chromatography using chromatotron (hex-

ane/ethyl acetate 70:30).

123

Med Chem Res (2014) 23:1123–1147

1137

Table 3 In vitro antibacterial activity of pyrrole derivatives (5a–m,

8a–m, 12a–l, and 13a–l) against the selected strains (MIC in lg/mL)

Table 3 continued

Compound

Gram-positive bacteria

Gram-negative bacteria

K. pneumoniae E. coli

Compound

Gram-positive bacteria

Gram-negative bacteria

S. aureus

B. subtilis

S. aureus

B. subtilis

K. pneumoniae E. coli

13i

0.8

25

12.5

1.6

2

0.4

25

6.25

1.6

2

6.25

50

12.5

50

5a

12.5

6.25

3.125

6.25

3.125

6.25

12.5

6.25

12.5

3.125

6.25

3.125

6.25

3.125

12.5

6.25

12.5

0.8

3.125

6.25

1.6

13j

5b

3.125

0.8

12.5

0.8

13k

100

1

50

5c

13l

100

2

5d

1.6

0.8

Ciproﬂoxacin

Norﬂoxacin

5e

0.4

1.6

3

1

12

5f

1.6

12.5

3.125

1.6

12.5

0.8

5g

0.4

5h

0.2

4-(4-Methoxyphenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thia-

zole (13e) Yield 80 %. mp 61–63 °C; FTIR (KBr): 3092

and 2925 (Ar–H), 1609 (C=N) cm^-1; ¹H NMR (500 MHz,

CDCl₃) d ppm: 2.30 (s, 6H, 2CH₃), 3.88 (s, 3H, OCH₃),

5.94 (s, 2H, pyrrole–C₃and C₄–H), 6.99 (d, 2H, J = 9 Hz,

Ph–C₃and C₅–H), 7.36 (s, 1H, thiazole–C₅–H), 7.89 (d,

2H, J = 9 Hz, Ph–C₂and C₆–H); ¹³C NMR (400 MHz,

CDCl₃) d ppm: 159.82 (Ph–C₄), 158.46 (thiazole–C₂),

152.56 (thiazole–C₄), 129.90 (Ph–C₂and C₆), 127.52

(pyrrole–C₂and C₅), 127.04 (Ph–C₁), 114.18 (Ph–C₃and

C₅), 110.68 (pyrrole–C₃and C₄), 107.91 (thiazole–C₅),

55.38 (OCH₃), 13.40 (2CH₃); MS (ESI): m/z = found

284.10 [M^?], 242, 207, 95, 85; calcd. 284.38. Anal.

C₁₆H₁₆N₂OS.

5i

0.8

12.5

3.125

6.25

3.125

6.25

12.5

1.6

12.5

1.6

5j

3.125

1.6

5k

5l

3.125

1.6

12.5

1.6

5m

8a

8b

8c

8d

1.6

8e

0.8

12.5

0.8

8f

0.4

8g

1.6

3.125

1.6

8h

0.2

1.6

8i

3.125

1.6

3.125

12.5

3.125

6.25

12.5

25

12.5

6.25

12.5

25

4-(4-Nitrophenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole

8j

(13f) Yield 64 %. mp 65–67 °C; FTIR (KBr): 2921 and

8k

1

2858 (Ar–H), 1646 (C=N), 1506, 1339 (NO₂) cm^-1; H

8l

1.6

NMR (400 MHz, CDCl₃) d ppm: 2.31 (s, 6H, 2CH₃), 5.95

(s, 2H, pyrrole–C₃and C₄–H), 7.69 (s, 1H, thiazole–C₅–H),

8.06–8.10 (m, 2H, Ph–C₃and C₅–H), 8.28–8.32 (m, 2H,

Ph–C₂and C₆–H); ¹³C NMR (300 MHz, DMSO) d = ¹³C

NMR (400 MHz, CDCl₃) d ppm: 160.13 (Ph–C₄), 158.03

(thiazole–C₂), 151.27 (thiazole–C₄), 130.11 (Ph–C₃and

C₅), 129.47 (Ph–C₂and C₆), 128.01 (pyrrole–C₂and C₅),

127.33 (Ph–C₁), 111.09 (pyrrole–C₃and C₄), 107.93 (thi-

azole–C₅), 13.43 (2CH₃); MS (ESI): m/z = found 299.07

[M^?], 95, 85; calcd. 299.35. Anal. C₁₅H₁₃N₃O₂S.

8m

12a

12b

12c

12d

12e

12f

12g

12h

12i

12j

12k

12l

13a

13b

13c

13d

13e

13f

13g

13h

3.125

0.4

1.6

0.4

12.5

100

50

12.5

1.6

25

1.6

50

12.5

0.4

3.12

0.2

100

50

6.25

12.5

3.12

12.5

50

12.5

25

12.5

1.6

25

0.2

12.5

25

1.6

12.5

1.6

3.12

6.25

1.6

50

4-(4-Aminophenyl)-2-(2,5-dimethyl-1H-pyrrol-1-yl)thia-

zole (13g) Yield 88 %. mp 137–139 °C; FTIR (KBr):

3437 (NH₂), 2920 and 2852 (Ar–H), 1612 (C=N) cm^-1; ¹H

NMR (400 MHz, CDCl₃) d ppm: 2.22 (s, 6H, 2CH₃), 5.84

(s, 2H, NH₂), 5.85 (s, 2H, pyrrole–C₃and C₄–H), 7.17 (s,

1H, thiazole–C₅–H), 7.19–7.21 (m, 2H, Ph–C₃and C₅–H),

7.93–7.95 (m, 2H, Ph–C₂and C₆–H); ¹³C NMR (400 MHz,

CDCl₃) d ppm: 158.92 (thiazole–C₂), 151.84 (thiazole–C₄),

138.96 (Ph–C₄), 129.91 (Ph–C₂and C₆), 128.63 (pyrrole–

C₂and C₅), 126.85 (Ph–C₁), 112.96 (Ph–C₃and C₅),

108.14 (pyrrole–C₃and C₄), 105.94 (thiazole–C₅), 13.47

50

12.5

50

1.6

0.8

12.5

50

12.5

0.8

6.25

12.5

0.8

100

50

0.8

100

1.6

50

0.4

0.2

3.12

50

12.5

50

0.4

1.6

0.4

0.2

3.12

12.5

123

1138

Med Chem Res (2014) 23:1123–1147

Table 4 Antimycobacterial and cytotoxicity activity of pyrrole

derivatives (5a–m, 8a–m, 12a–l, and 13a–l)

Table 4 continued

Compound M. tuberculosis H₃₇Rv^aIC₅₀(lM)^b

MV cell lines^cA₅^d₄₉

Compound M. tuberculosis H₃₇Rv^aIC₅₀(lM)^b

MV cell lines^cA₅^d₄₉

13i

0.4

12.5

50

221.34 0.5 231.67 0.5

5a

6.25

0.8

NT

13j

NT

5b

13k

NT

5c

13l

0.8

NT

5d

3.125

0.4

Isoniazid

Cisplatin

0.25

[450

1.29

[450

9.90

5e

251.22 0.3 254.31 0.3

NT NT

–

5f

0.8

NT not tested, ^cMV mammalian Vero cell lines, A₅₄₉lung adeno-

carcinoma cell lines

d

5g

0.4

259.19 0.2 255.11 0.3

265.40 0.3 261.12 0.4

5h

0.2

a

Minimal inhibition concentration is expressed in lg/mL

5i

0.8

NT

b

Cytotoxicity is expressed as IC₅₀, is the concentration of com-

5j

3.125

pound, which is reduced by 50 % of the optical density of treated

cells with respect to untreated cells using the MTT assay, values are

mean SEM of three independent experiments

5k

5l

5m

8a

(2CH₃); MS (ESI): m/z = found 269.10 [M^?], 239, 175,

12.5

3.125

8b

118, 95, 85; calcd. 269.36. Anal. C₁₅H₁₅N₃S.

8c

8d

3.125

0.4

4-(4-Fluorophenyl)-2-(1H-pyrrol-1-yl)thiazole (13h) Yield

57 %. mp 116–118 °C; FTIR (KBr): 2986 and 2920 (Ar–H),

1631 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d ppm: 2.29

(s, 6H, 2CH₃), 5.83 (s, 2H, pyrrole–C₃and C₄–H), 7.29 (d,

2H, J = 8 Hz, Ph–C₃and C₅–H), 7.41 (s, 1H, thiazole–C₅–

H), 7.63 (d, 2H, J = 8 Hz, Ph–C₂and C₆–H); ¹³C NMR

(400 MHz, CDCl₃) d ppm: 163.01 (Ph–C₄), 161.11 (thia-

zole–C₂), 151.29 (thiazole–C₄), 133.20 (Ph–C₂and C₆),

129.01 (pyrrole–C₂and C₅), 128.63 (Ph–C₁), 117.27 (Ph–C₃

and C₅), 111.08 (pyrrole–C₃and C₄), 108.21 (thiazole–C₅),

12.76 (2CH₃); MS (ESI): m/z = found 272.08 [M^?], 178,

146, 95; calcd. 272.34. Anal. C₁₅H₁₃FN₂S.

8e

251.52 0.3 234.82 0.4

251.34 0.6 251.12 0.3

252.29 0.5 250 0.4

260.13 0.2 260.33 0.3

8f

0.4

8g

0.4

8h

0.2

8i

0.8

NT

8j

6.25

0.4

8k

8l

8m

12a

12b

12c

12d

12e

12f

12g

12h

12i

12j

12k

12l

13a

13b

13c

13d

13e

13f

13g

13h

233.21 0.4 231.22 0.4

242.42 0.5 244.61 0.3

0.4

50

NT

4-(3,4-Dichlorophenyl)-2-(1H-pyrrol-1-yl)thiazole

(13i)

0.8

12.5

0.4

25

Yield 75 %. mp 140–142 °C; FTIR (KBr): 2990 and 2957

(Ar–H), 1627 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d

ppm: 2.20 (s, 6H, 2CH₃), 5.87 (s, 2H, pyrrole–C₃and C₄–

H), 7.31–7.69 (m, 4H, thiazole–C₅–H, Ph–C₃, C₅, C₆–H);

¹³C NMR (400 MHz, CDCl₃) d ppm: 159.81 (thiazole–C₂),

150.78 (thiazole–C₄), 135.43 (Ph–C₄), 133.09 (Ph–C₃),

132.83 (Ph–C₁), 131.52 (Ph–C₅), 129.88 (Ph–C₂), 128.01

(Ph–C₆), 127.89 (pyrrole–C₂and C₅), 110.22 (pyrrole–C₃

and C₄), 109.02 (thiazole–C₅), 12.82 (2CH₃); MS (ESI): m/

z = found 322.01 [M^?], 324.01 [M^??2], 232/230, 178,

144/146, 95; calcd. 323.24. Anal. C₁₅H₁₂Cl₂N₂S.

243.17 0.6 246.09 0.7

NT NT

261.31 0.3 262.57 0.3

0.2

0.8

50

NT

50

0.8

0.4

0.8

12.5

0.4

257.07 0.6 253.29 0.5

NT NT

252.81 0.7 253.13 0.9

NT NT

265.53 0.3 268.34 0.5

2-(1H-pyrrol-1-yl)-4-(3,4,5-trimethoxyphenyl)thiazole (13j)

Yield 65 %. mp 159–161 °C; FTIR (KBr): 2977 and 2913

(Ar–H), 1605 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d

ppm: 2.27 (s, 6H, 2CH₃), 3.89 (s, 9H, (OCH₃)₃), 5.97 (s,

2H, pyrrole–C₃and C₄–H), 7.97 (s, 1H, thiazole–C₅–H),

6.25

0.4

12.5

0.2

123

Med Chem Res (2014) 23:1123–1147

1139

7.63 (d, 2H, J = 7.5 Hz, Ph–C₂and C₆–H); ¹³C NMR

(400 MHz, CDCl₃) d ppm: 159.37 (thiazole–C₂), 154.07

(Ph–C₃and C₅), 150.21 (thiazole–C₄), 140.81 (Ph–C₄),

128.09 (Ph–C₁), 127.31 (pyrrole–C₂and C₅), 110.21

(pyrrole–C₃and C₄), 109.59 (thiazole–C₅), 103.19 (Ph–C₂

and C₆), 60.53 (4-OCH₃), 57.22 (3,5-(OCH₃)₂), 12.90

(2CH₃); MS (ESI): m/z = found 344.12 [M^?], 312, 178,

167, 95; calcd. 344.43. Anal. C₁₈H₂₀N₂O₃S.

Escherichia coli) by broth microdilution method (Goto

et al., 1981). Serial dilutions of the test compounds and

reference drugs were prepared in Mueller–Hinton agar.

Drugs (10 mg) were dissolved in DMSO (1 mL). Further

progressive dilutions with melted Mueller–Hinton agar

were performed to obtain the required concentrations of

0.2, 0.4, 0.8, 1.6, 3.125, 6.25, 12.5, 25, 50, and

100 lg mL^-1. The tubes were inoculated with 10⁵

CFU mL^-1(colony forming unit/mL) and incubated at

37 °C for 18 h. The MIC was the lowest concentration of

the tested compound that yield no visible growth on the

plate. To ensure that solvent had no effect on the bacterial

growth, a control was performed with the test medium

supplemented with DMSO at the same dilutions as used in

the experiments and DMSO had no effect on the micro-

organisms in the concentrations studied. Table 3 reveals

the antibacterial activity (MIC values) of the compounds.

MIC values were determined for the newly synthesized

compounds (5a–m, 8a–m, 12a–l, and 13a–l) against MTB

strain H₃₇Rv using the microplate alamar blue assay

(Franzblau et al., 1998). Isoniazid was used as the standard

drug. The 96-wells plate received 100 lL of the Middle-

brook 7H9 broth and serial dilution of compounds were

made directly on plate. The ﬁnal drug concentrations tested

were 0.2, 0.4, 0.8, 1.6, 3.125, 6.25, 12.5, 25, 50, and

100 lg mL^-1. Plates were covered and sealed with para-

ﬁlm and incubated at 37 °C for 5 days. After this, 25 lL of

freshly prepared 1:1 mixture of alamar blue reagent and

10 % Tween 80 was added to the plate and incubated for

24 h. A blue color in the well was interpreted as no bac-

terial growth and pink color was scored as growth. The

MIC was deﬁned as the lowest drug concentration which

prevented the color change from blue to pink. Table 4

reveals the antitubercular activity (MIC) of the newly

synthesized compounds.

4-(3,4-Dimethoxyphenyl)-2-(1H-pyrrol-1-yl)thiazole (13k)

Yield 67 %. mp 146–148 °C; FTIR (KBr): 2939 and 2887

(Ar–H), 1621 (C=N) cm^-1; ¹H NMR (400 MHz, CDCl₃) d

ppm: 2.21 (s, 6H, 2CH₃), 3.83 (s, 6H, (OCH₃)₂), 5.84 (s,

2H, pyrrole–C₃and C₄–H), 7.39–7.83 (m, 4H, thiazole–

C₅–H, Ph–C₂, C₅and C₆–H); ¹³C NMR (400 MHz, CDCl₃)

d ppm: 159.51 (thiazole–C₂), 150.87 (thiazole–C₄), 150.09

(Ph–C₃), 149.29 (Ph–C₄), 130.12 (Ph–C₁), 128.17 (pyr-

role–C₂and C₅), 123.01 (Ph–C₆), 120.19 (Ph–C₅), 117.81

(Ph–C₂), 111.19 (pyrrole–C₃, C₄), 109.27 (thiazole–C₅),

57.11 (3,4-(OCH₃)₂), 12.80 (2CH₃); MS (ESI): m/

z = found 314.11 [M^?], 220, 178, 152, 137; calcd. 314.40.

Anal. C₁₇H₁₈N₂O₂S.

4-(3-Nitrophenyl)-2-(1H-pyrrol-1-yl)thiazole (13l) Yield

50 %. mp 150–152 °C; FTIR (KBr): 2981 and 2909 (Ar–

H), 1609 (C=N), 1507, 1333 (NO₂) cm^-^{1 1}H NMR

;

(400 MHz, CDCl₃) d ppm: 2.30 (s, 6H, 2CH₃), 5.87 (s, 2H,

pyrrole–C₃and C₄–H), 7.61–8.21 (m, 5H, thiazole–C₅–H,

Ph–C₂, C₄, C₅and C₆–H); ¹³C NMR (400 MHz, CDCl₃) d

ppm: 159.23 (thiazole–C₂), 150.31 (thiazole–C₄), 149.01

(Ph–C₃), 134.03 (Ph–C₁), 133.27 (Ph–C₆), 131.13 (Ph–C₂),

127.59 (pyrrole–C₂and C₅), 125.49 (Ph–C₄), 124.51 (Ph–

C₅), 110.01 (pyrrole–C₃and C₄), 109.03 (thiazole–C₅),

12.77 (2CH₃); MS (ESI): m/z = found 299.07 [M^?], 205,

178, 152, 145, 122, 95; calcd. 299.35. Anal. C₁₅H₁₃N₃O₂S.

Biological activities

MTT-based cytotoxic activity

In vitro antibacterial activity

The cellular conversion of MTT [3-(4,5-dimethylthiazo-2-

yl)-2,5-diphenyl-tetrazolium bromide] into a formazan

product (Mosmann, 1983) was used to evaluate the cyto-

toxic activity (IC₅₀) of some synthesized compounds

against mammalian Vero cell lines and A₅₄₉(lung adeno-

carcinoma) cell lines up to concentrations of 62.5 lg/mL

using the Promega Cell Titer 96 non-radioactive cell

MIC determination of the test compounds (5a–m, 8a–m,

12a–l, and 13a–l) was investigated in side-by-side com-

parison with ciproﬂoxacin and norﬂoxacin against Gram-

positive (Staphylococcus aureus and Bacillus subtilis) and

Gram-negative bacteria (Klebsiella pneumoniae and

Table 5 Statistical results of Topomer CoMFA including various parameters

q²

StdErr

r²

SEE

F value

Intercept

5.09

r_p²_red

PLS components

6

0.815

0.36

0.973

0.14

86.757

0.689

q²LOO cross-validation correlation coefﬁcient, r²non-cross-validation correlation coefﬁcient, StdErr standard error of prediction, SEE standard

error of estimate, F Fischer test value, Intercept Y-intercept for the CoMFA model, r_p²_redpredictive correlation coefﬁcient, PLS components

optimum number of components

123

1140

Med Chem Res (2014) 23:1123–1147

Table 6 Actual and predicted antitubercular activity of the training

set and the test set molecules with R₁and R₂fragments contributions

Table 6 continued

Compound

Fragments Actual

pMIC

Predicted

pMIC

Fragment

contributions

Compound

Fragments Actual

pMIC

Predicted

pMIC

Fragment

contributions

R₁

R₂

R₁

R₂

5k

A1

A2

5.33

5.10

5.36

4.60

4.30

4.90

6.40

5.33

5.10

5.36

4.86

4.15

4.44

6.23

0.52 -0.27

0.41 -0.40

0.67 -0.40

-0.37 0.14

-1.08 0.14

-0.91 0.26

0.89 0.26

Training set

8b

5a

5b

5c

5d

5e

5f

A1

5.20

6.10

5.51

6.40

6.10

6.70

6.10

5.51

4.90

5.51

6.40

6.70

6.10

5.20

6.40

4.30

6.10

4.90

6.40

6.70

6.40

4.30

6.10

6.40

6.10

4.90

6.40

5.20

6.40

4.90

6.70

6.40

4.30

5.12

5.23

5.87

5.56

6.47

6.34

6.74

6.15

5.43

5.49

5.42

4.99

5.74

5.43

6.34

6.21

6.37

6.61

6.02

5.30

5.20

5.29

6.31

6.17

4.52

6.20

5.01

6.33

6.67

6.35

4.32

6.12

6.42

6.29

4.63

6.31

5.12

6.45

4.97

6.78

6.46

4.26

0.30 -0.27

0.41 -0.27

1.05 -0.27

0.74 -0.27

1.65 -0.27

1.52 -0.27

1.92 -0.27

1.33 -0.27

0.61 -0.27

0.67 -0.27

0.60 -0.27

0.30 -0.40

1.05 -0.40

0.74 -0.40

1.65 -0.40

1.52 -0.40

1.68 -0.40

1.92 -0.40

1.33 -0.40

0.61 -0.40

0.52 -0.40

0.60 -0.40

1.08 0.14

0.94 0.14

-0.71 0.14

0.97 0.14

-0.22 0.14

1.11 0.14

1.44 0.14

1.12 0.14

-0.91 0.14

0.89 0.14

1.08 0.26

0.94 0.26

-0.71 0.26

0.97 0.26

-0.22 0.26

1.11 0.26

-0.37 0.26

1.44 0.26

1.12 0.26

-1.08 0.26

8l

12g

12k

13j

13l

5h(template) T1

5i

A1

A2

proliferation assay was employed (Gundersen et al., 2002).

Cisplatin was used as a positive control. The IC₅₀values

are the averages SEM of three independent experiments

and are presented in Table 4.

5j

5l

5m

8a

8c

Results and discussion

8d

8e

Synthetic and spectral studies

8f

8g

Structures of the compounds were assigned on the basis of

their spectral and analytical data. The physical data, FTIR,

8h

8i

8j

8k

Topomer CoMFA

8m

12a

12b

12c

12d

12e

12f

12h

12i

12j

12l

13a

13b

13c

13d

13e

13f

13g

7

6.5

6

5.5

5

Training set

Test set

4.5

4

4.5

5

5.5

6

6.5

7

Actual pMIC

Fig. 3 Scatter plot diagram for Topomer CoMFA analysis

Table 7 Topomer CoMFA contour map for the R₁and R₂fragments

Contours

R₁

R₂

Contour Color Volume Contour Color Volume

level estimate level estimate

13h(template) T2

Steric

-0.072 Yellow 3.5

-0.005 Yellow 4.1

0.003 Green 22.4

13i

13k

A2

0.030 Green 72.0

Electrostatic -0.042 Red

14.8

72.4

-0.003 Red

23.2

7.2

Test set

5g

0.041 Blue

0.003 Blue

A1

6.40

6.50

1.68 -0.27

123

Med Chem Res (2014) 23:1123–1147

1141

NMR, and MS are reported in the experimental protocols.

The disappearance of NH₂stretching band in the FTIR

spectrum of 5e conﬁrmed the formation of pyrrolylimide.

A strong stretching band at 1,728 cm^-1was related to

In the FTIR spectrum of 12c, a broad absorption band

observed at 3,351 cm^-1was due to OH, while a strong

stretching band at 1,606 cm^-1was assigned to C=N. The ¹H

NMR spectrum of 12c showed a singlet at d 8.50, which was

accounted for hydroxyl group on the phenyl ring. A singlet at

d 6.99 was assigned to C₅proton of thiazole; four protons of

pyrrole moiety resonated as two doublet of doublets at d 7.42

and 6.37. Multiplets between d 6.89–6.92 and 7.78–7.82

were due to four aromatic protons. The MS of 12c showed a

molecular ion peak at m/z 242, which conﬁrmed its molec-

ular weight. Electron impact MS showed accurate molecular

ion peaks at m/z 226.06, 260.02, 242.05, 305.96, 256.07,

271.04, 241.07, 244.05, 295.98, 316.09, 286.08, 271.04,

254.09, 288.05, 270.08, 332.00, 284.10, 299.07, 269.10,

272.08, 322.01, 344.12, 314.11, and 299.07 for compounds

12a–l and 13a–l, respectively.

1

ketonic carbonyl. The H NMR spectrum of 5e showed a

D₂O exchangeable singlet at d 11.20 due to NH proton.

The four protons of pyrrole ring appeared as two doublet of

doublets at d 6.35 and 7.32. The four protons of phenyl

moiety resonated as two doublets at d 7.64 and 8.13; the

multiplets between d 7.89 and 7.97 were assigned for four

protons—C₄, C₅, C₆, and C₇protons of isoindoline. For-

mation of pyrrolylimides was further conﬁrmed by ¹³C

NMR and MS. The ¹³C NMR spectrum of 5e showed

signals at d 167.18, 165.38, and 164.52 due to isoindoline–

C₅, isoindoline–C₂, and amide carbonyl carbons, respec-

tively. MS showed accurate molecular ion peaks at m/z

281.08, 283.10, 296.10, 295.10, 331.10, 646.73, 468.94,

403.06, 400.02, 345.11, 376.08, 376.08, 337.14, 309.11,

311.13, 323.13, 323.13, 359.13, 674.76, 496.97, 431.09,

428.05, 373.14, 404.11, 404.11, and 365.17 for compounds

5a–m and 8a–m, respectively.

Antimicrobial activity

The results of antimicrobial activities (expressed in MIC)

of the compounds against the selected two Gram-positive,

Fig. 4 Steric and electrostatics

stdev* coefﬁcient contour map

for compound 13h by Topomer

CoMFA analysis. a Steric

contour map for the R₁

fragment. b Electrostatic

contour map for the R₁

fragment. c Steric contour map

for the R₂fragment. d

Electrostatics contour map for

the R₂fragment. Sterically

favored/unfavored areas are

shown in green/yellow contour,

while the blue/red polyhedra

depict the favorable sites for the

positively/negatively charged

groups (Color ﬁgure online)

123

1142

Med Chem Res (2014) 23:1123–1147

two Gram-negative bacteria and MTB H₃₇Rv are illustrated

in Tables 3 and 4, respectively. The activity of ciproﬂox-

acin and norﬂoxacin are used for comparison. All the

compounds showed moderate to signiﬁcant microbial

inhibition. Pyrrolylimide compounds showed antibacterial

activity between MIC of 0.2 and 12.5 lg/mL. Compounds

have shown better activity against B. subtilis than the other

tested microorganisms. In pyrrolylimide series, compounds

5h and 8h showed the highest activity against B. subtilis at

MIC of 0.2 lg/mL. Compounds 5c, d, h, and 8f showed the

highest activity against E. coli at MIC of 0.8 lg/mL.

Pyrrolylthiazole compounds have exhibited antibacterial

activity at MIC between 0.2 and 100 lg/mL and the

compounds were more active against Gram-positive bac-

teria than Gram-negative bacteria. Compounds 12f, h, 13f,

and h have shown the highest activity against B. subtilis at

MIC of 0.2 lg/mL (Table 3).

Antitubercular activity

The tested compounds (Schemes 1, 2) showed activities

against mycobacteria with the MIC values ranging from 0.2

to 50 lg/mL (Table 4). The pyrrolylimide compounds

showed antitubercular activity between MIC of 0.2 and

12.5 lg/mL. Among the pyrrolylimide derivatives, com-

pounds 5h and 8h exhibited the highest activity against the

tested mycobacteria at a MIC of 0.2 lg/mL. Similarly,

pyrrolylthiazole compounds 12h and 13h have shown the

highest activity at MIC of 0.2 lg/mL against the tested

mycobacteria.

Fig. 5 Steric and electrostatics stdev* coefﬁcient contour map for

compound 5h by Topomer CoMFA analysis. a Steric contour map for

the R₁fragment. b Electrostatic contour map for the R₁fragment. c

Steric contour map for the R₂fragment. d Electrostatics contour map

for the R₂fragment. Sterically favored/unfavored areas are shown in

green/yellow contour, while the blue/red polyhedra depict the

favorable sites for the positively/negatively charged groups (Color

ﬁgure online)

123

Med Chem Res (2014) 23:1123–1147

1143

Fig. 6 Steric and electrostatics stdev* coefﬁcient contour map for

compound 12h by Topomer CoMFA analysis. a Steric contour map

for the R₁fragment. b Electrostatic contour map for the R₁fragment.

c Steric contour map for the R₂fragment. d Electrostatics contour

map for the R₂fragment. Sterically favored/unfavored areas are

shown in green/yellow contour, while the blue/red polyhedra depict

the favorable sites for the positively/negatively charged groups (Color

ﬁgure online)

Cytotoxic activity

activity against mammalian Vero cell line at concentra-

tions \100 lM. Among the test compounds, pyrrolylimide

derivatives showed inferior toxicity with IC₅₀values

of [250 lM against both mammalian Vero cell lines and

A₅₄₉(lung adenocarcinoma) cell lines.

Some compounds were further examined for toxicity (IC₅₀)

in mammalian Vero cell lines and A₅₄₉(lung adenocarci-

noma) cell lines up to 62.5 lg/mL concentrations. After

72 h of exposure, viability was assessed on the basis of

cellular conversion of MTT into a formazan product using

the Promega Cell Titer 96 non-radioactive cell proliferation

assay and the results are summarized in Table 4. The 15

derivatives tested showed IC₅₀values ranging from 221.34

to 265.53 lM against mammalian Vero cell lines. How-

ever, all the compounds did not show any signiﬁcant

QSAR study

Topomer CoMFA model analysis The model displayed a

q²= 0.815 and r²= 0.973 with 0.36 StdErr and 0.14

standard error of estimate (SEE). The number of compo-

nents that provided the highest q²was six. The summary of

123

1144

Med Chem Res (2014) 23:1123–1147

Fig. 7 Steric and electrostatics stdev* coefﬁcient contour map for

compound 8h by Topomer CoMFA analysis. a Steric contour map for

the R₁fragment. b Electrostatic contour map for the R₁fragment. c

Steric contour map for the R₂fragment. d Electrostatics contour map

for the R₂fragment. Sterically favored/unfavored areas are shown in

green/yellow contour, while the blue/red polyhedra depict the

favorable sites for the positively/negatively charged groups (Color

ﬁgure online)

Hydrophobic groups, H-bond acceptors

favored region

Negatively charged

substituents,H-bond

acceptors favored

region

R₂

R

O

N

Bulky,Negatively charged

substituents,H-bond

acceptors favored

region

R

HN N

R₁

N

R

N

S

O

R

Bulky substituents

favored region

Bulky substituents

favored region

Fig. 8 Summary of structure–activity relationship

123

Med Chem Res (2014) 23:1123–1147

1145

PLS results is provided in Table 5. The predictive ability of

the developed Topomer CoMFA model was assessed by

the test set (eight molecules) predictions, which were

excluded during the Topomer CoMFA model generation.

The predictive ability of the test set was 0.689. The actual

and predicted activities of the training set and test set

molecules along with R₁and R₂fragment contributions are

given in Table 6. The graph of predicted versus actual

activity for training set and test set molecules is shown in

Fig. 3.

effect. For compound 5e, the unsubstituted phenyl ring was

less favored for activity and the compound displayed less

inhibitory potency than compound 5h. For compounds 5j–

l, removal of halo groups from R₁fragment produced a

decreased activity compared to compound 5h, indicting the

necessity of the halo groups for the inhibitory effect.

Compound 5i showed better activity than compounds 5j–l

due to the presence of 5,6-dichloro group. In compound

5m, the phenyl group of compound 5e was replaced by the

cyclohexyl group, which showed lesser inhibitory effect.

Steric and electrostatic contour maps for compound 12h

are shown in Fig. 6. Fragment R₂consisted of hydrogen at

the second and ﬁfth positions of pyrrole ring. The steric

contour map (Fig. 6c) revealed that the whole of pyrrole

ring was favored for inhibitory potency. Fragment R₂

contribution in compounds 13a–l revealed that bulky nat-

ure of 2,5-dimethylpyrrole ring was favorable for inhibi-

tory potency than compounds 12a–l.

Contour map analysis Contour level along with color

scheme and estimated volume of contour are summarized

in Table 7. The 3D-QSAR contours and their relationship

with the biological activity of molecule are described in

Figs. 4, 5, 6, and 7. In the steric contour map, green color

denotes sterically bulky groups favored for activity and the

yellow color indicates sterically bulky groups unfavored

for activity. In the electrostatics contour map, red indicates

electronegative favored groups and blue indicates electro-

positive favored group. The steric contours of compound

13h R₁fragment (Fig. 4a) revealed that large green-col-

ored contours favor the substitution of electronegative 4-

ﬂuoro group on phenyl moiety. The electrostatics contour

map depicted that electronegative groups (red contour,

Fig. 4b) are favored at the para position of phenyl group

and hence, compound 13h displayed the highest activity

(pMIC = 6.70) among all the tested compounds in the

series. For compounds 13b, d, and i (pMIC = 6.40), the 4-

ﬂuoro group of compound 13h was replaced by 4-chloro,

4-bromo, and 2,4-dichloro groups, respectively, that pro-

duced smaller inhibitory effect. Electropositive nature of

the hydroxyl, methoxy, and amino groups was not favor-

able for activity when located at the 4-position on phenyl

ring, but showed decreased inhibitory potency. For com-

pound 13a, the unsubstituted phenyl ring was less favored

for activity and the compound displayed less inhibitory

potency than 13h. For the R₂fragment, green contours

(Fig. 4c) near the methyl group of pyrrole indicated that

bulky group was favored for the inhibitory effect, while the

red color near the thiazole indicated that an electronegative

substitution could retain molecular activity.

Steric and electrostatic contour maps for compound 8h

are presented in Fig. 7. The steric contour map for frag-

ment R₂(Fig. 7c) revealed that phenyl group with pyrrole

ring were favorable for activity. Fragment R₂contribution

in compounds 5a–m revealed that 2,5-unsubstituted pyr-

role ring was favorable for the inhibitory potency than the

compounds 8a–m.

Summary of structure–activity relationship The struc-

ture–activity relationship revealed by 3D-QSAR studies are

illustrated in Fig. 8. According to Topomer CoMFA anal-

ysis, we observed that not only the negatively charged

substituents, H-bond acceptors at R₁and R₂positions

showed increase in activity (like in compounds 5h and

13h) but also the hydrophobic substituent at the position of

the linker showed increased activity in cyclic imide series.

The hydrophobic property of benzene, pyrrole, cyclic

imide, and thiazole rings plays a key role in exhibiting

antimycobacterial activities.

Conclusion

The present study reports on the synthesis of novel pyrrole

derivatives and their in vitro antibacterial and antituber-

cular activities against MTB H₃₇Rv strain by broth dilution

assay method have been evaluated. Among all the com-

pounds, 5a, c, e, h, 8h, 12f, h, 13f, and h have shown better

activity against the tested microorganisms and mycobac-

teria. Further, some of the compounds were assessed for

their cytotoxicity (IC₅₀) against mammalian Vero cell lines

and A₅₄₉(lung adenocarcinoma) cell lines using the MTT

assay method. The compounds exhibited antitubercular

activity at non-cytotoxic concentrations. Some of the

compounds of this study could be further developed as a

Steric and electrostatic contour maps for compound 5h

are shown in Fig. 5. Fragment R₁consisted of cyclic imide

moiety. In the steric contour map (Fig. 5a), the green color

indicates less bulky and electronegative group at the ortho,

meta, and para positions at the phenyl group of cyclic

imide moiety was favored for activity. The electrostatic

contour map (Fig. 5b) revealed that electron withdrawing

nature of ﬂuorine group substituted at 4,5,6,7-positions of

cyclic imide was favored for activity. The replacement of

4,5,6,7-tetraﬂuoro group of compound 5h with 4,5,6,7-

tetrabromo or tetrachloro group produced lesser inhibitory

123

1146

Med Chem Res (2014) 23:1123–1147

Duncan K, Barry CE (2004) Prospects for new antitubercular drugs.

Curr Opin Microbiol 7:460–465

novel class of antibacterial and antitubercular agents, even

though further structural modiﬁcation is necessary. It was

found that the 3D structural information is useful in drug

design and the Topomer CoMFA model exhibited good

internal and external consistency. The Topomer CoMFA

model showed a good correlation between the actual and

predicted values for training set molecules. The ability of

QSAR model to accurately predict the property value

(pMIC) along with other important information gathered

from 3D contour maps are valuable in the design of new

pyrrolylimides and pyrrolylthiazoles having improved

antitubercular activity.

Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G,

Hernandez A, Degnan MT, Cook MB, Quenzer VK, Ferguson

RM, Gilman RH (1998) Rapid, low-technology MIC determi-

nation with clinical Mycobacterium tuberculosis isolates by

using the microplate Alamar Blue assay. J Clin Microbiol

36:362–366

Gorczynski MJ, Leal RM, Mooberry SL, Bushweller JH, Brown ML

(2004) Synthesis and evaluation of substituted 4-aryloxy- and 4-

arylsulfanyl-phenyl-2-aminothiazoles as inhibitors of human

breast cancer cell proliferation. Bioorg Med Chem 12:1029–

1036

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Tanami H (1981) Determination method of minimum inhibitory

concentrations. Chemotherapy 29:76–79

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antimycobacterial activity of 6-arylpurines: the requirements for

the N-9 substituent in active antimycobacterial purines. J Med

Chem 45:1383–1386

Jones RA (1992) Pyrroles, Vinyl Pyrroles, Part II, the chemistry of

heterocyclic compounds, vol 48. Wiley, New York, pp 131–298

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Press, London, pp 51–57

Joshi SD, Vagdevi HM, Vaidya VP, Gadaginamath GS (2008)

Synthesis of new 4-pyrrol-1-yl benzoic acid hydrazide analogs

and some derived oxadiazole, triazole and pyrrole ring systems,

a novel class of potential antibacterial and antitubercular agents.

Eur J Med Chem 43:1989–1996

Acknowledgments Authors immensely thank the Indian Council of

Medical Research, New Delhi, India for ﬁnancial support [File No.

64/4/2011-BMS, IRIS Cell No. 2010-08710]. We also thank Dr. V. H.

Kulkarni, Principal and Mr. H. V. Dambal, President, S.E.T.’s Col-

lege of Pharmacy, Dharwad, India, for providing facilities. We thank

Dr. K. G. Bhat, Maratha Mandal’s Dental College, Hospital and

Research Centre, Belgaum, India for providing facilities for anti-

bacterial, antitubercular, and cytotoxic activities; Director, SAIF,

Indian Institute of Technology, Chennai, Tamil Nadu, India and the

Director, SAIF, Panjab University, Chandigarh, Panjab, India for

providing the NMR and mass spectral data. We thank Mr. Shrikant A.

Tiwari for his technical assistance.

Joshi SD, Joshi A, Vagdevi HM, Vaidya VP, Gadaginamath GS

(2010) Microwave assisted synthesis of some new quinolinyl-

pyrrole derivatives as potential antibacterial and antitubercular

agents. Indian J Heterocycl Chem 19:221–224

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Synthesis, characterization, biological activity, and 3D-QSAR studies on some novel class of pyrrole derivatives as antitubercular agents

DOI: 10.1007/s00044-013-0709-y

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