Molecular properties prediction, synthesis, and antimicrobial activity of bis(azolyl)sulfonamidoacetamides

Article abstract of DOI:10.1002/ardp.202000483

A library of bis(azolyl)sulfonamidoacetamides was prepared by the reaction of azolylsulfonylamines with azolylchloroacetamides in the presence of pyridine/4-(dimethylamino)pyridine (DMAP) under ultrasonication. The reaction proceeded well with DMAP, resulting in a higher yield of the products. The antimicrobial activity of the compounds indicated that N-{5-[N-(2-{[4-(4-chloro-1H-pyrrol-2-yl)-1H-imidazol-2-yl)amino}-2-oxoethyl)sulfamoyl]-4-phenylthiazol-2-yl}benzamide (22a), N-{5-[N-(2-{[4-(4-chloro-1H-pyrrol-2-yl)-1H-imidazol-2-yl]amino}-2-oxoethyl)sulfamoyl]-4-(4-chlorophenyl)thiazol-2-yl}benzamide (22c), and N-{5-[N-(2-{[4-(4-chloro-1H-pyrrol-2-yl)-1H-imidazol-2-yl]amino}-2-oxoethyl)sulfamoyl]-4-(4-chloro-phenyl)-1H-imidazol-2-yl}benzamide (24c) exhibited a low minimal inhibitory concentration (MIC) against Bacillus subtilis, equal to the standard drug, chloramphenicol. Compounds 22c and 24c also showed low MICs against Aspergillus niger, equal to the standard drug, ketoconazole. The molecular properties of the synthesized molecules were studied to identify druglikeness properties of the target compounds. On the basis of molecular properties prediction, 19a, 19b, 20b, 20c, 21a–c, 22b, 22c, and 23a–c can be treated as drug candidates.

Full text of DOI:10.1002/ardp.202000483

Received: 6 January 2021
Revised: 11 April 2021
Accepted: 16 April 2021
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DOI: 10.1002/ardp.202000483
F U L L P A P E R
Molecular properties prediction, synthesis, and antimicrobial
activity of bis(azolyl)sulfonamidoacetamides
Siva sankar P | Narendra babu K | Tamatam Rekha | Adivireddy Padmaja
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Venkatapuram Padmavathi
Department of Chemistry, Sri Venkateswara
University, Tirupati, Andhra Pradesh, India
Abstract
A library of bis(azolyl)sulfonamidoacetamides was prepared by the reaction of
azolylsulfonylamines with azolylchloroacetamides in the presence of pyridine/4‐
(dimethylamino)pyridine (DMAP) under ultrasonication. The reaction proceeded
well with DMAP, resulting in a higher yield of the products. The antimicrobial ac-
tivity of the compounds indicated that N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐
imidazol‐2‐yl)amino}‐2‐oxoethyl)sulfamoyl]‐4‐phenylthiazol‐2‐yl}benzamide (22a),
N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐oxoethyl)
sulfamoyl]‐4‐(4‐chlorophenyl)thiazol‐2‐yl}benzamide (22c), and N‐{5‐[N‐(2‐{[4‐(4‐
chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐oxoethyl)sulfamoyl]‐4‐(4‐chloro‐
Correspondence
Venkatapuram Padmavathi, Department of
Chemistry, Sri Venkateswara University,
Tirupati, Andhra Pradesh 517502, India.
Email: vkpuram2001@yahoo.com
phenyl)‐1H‐imidazol‐2‐yl}benzamide (24c) exhibited
a low minimal inhibitory
concentration (MIC) against Bacillus subtilis, equal to the standard drug, chlor-
amphenicol. Compounds 22c and 24c also showed low MICs against Aspergillus niger,
equal to the standard drug, ketoconazole. The molecular properties of the synthe-
sized molecules were studied to identify druglikeness properties of the target
compounds. On the basis of molecular properties prediction, 19a, 19b, 20b, 20c,
21a–c, 22b, 22c, and 23a–c can be treated as drug candidates.
K E Y W O R D S
antibacterial activity, antifungal activity, bis(azolyl)sulfonamidoacetamides, molecular
properties, ultrasonication
and antifungal[13] activities. Azoles are also valuable precursors in
various biochemical and synthetic transformations in addition to a
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1
INTRODUCTION
Microbial world has always had the molecular tools to drive re-
sistance, thus stimulating the need to discover novel antimicrobial
agents.[1] As classic heterocycles, azole derivatives exhibit a broad
spectrum of biological activities. The oxazole nucleus is ubiquitous in
natural products such as pyrronazol,[2] ulapualide,[3] diazonamide,[4]
and rhizopodin.[5] Thiazole is an essential core found in thiamine
(vitamin B1), thiamine pyrophosphate, and medicinally important
molecules.[6,7] Imidazole derivatives are associated with antitumor,[8]
antibacterial,[9] antiviral,[10] antioxidant,[11] anti‐inflammatory,[12]
part of the unit in many drugs such as oxaprozin, bengazole‐A,
inthomycin‐C, meloxicam, tiazofurin, cimetidine, ketoconazole, ome-
praole[14] (Figure 1), and so forth.
Drug absorption and drug delivery are the main factors for the
development of oral drugs.[15] About 30% of oral drugs fail in usage
due to poor pharmacokinetics,[16] mainly bioavailability.[17] Thus, the
prediction of bioavailability and bioavailability‐related properties
such as solubility and lipophilicity are the main factors for the mo-
lecules to be treated as drugs.[17] An in silico model for predicting
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Arch Pharm. 2021;e2000483.
wileyonlinelibrary.com/journal/ardp © 2021 Deutsche Pharmazeutische Gesellschaft
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SANKAR ET AL.
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FIGURE 1 Drugs containing oxazole,
thiazole, and imidazole units
oral bioavailability is very important in the early stage of drug dis-
covery to select the most promising compounds for further optimi-
zation and in the later stage to identify candidates for clinical
development. In the present investigation, a new class of bisazoles
(19–24a–c) linked by amido‐sulfonamido group is synthesized and
subjected to druglikeness by MolSoft (MolSoft 2007) software to
identify the compounds as promising drug agents, and their anti-
microbial activity is also studied.
the presence of H2SO4. The latter compound was prepared by the
treatment of phenacyl bromide with acetyl guanidine.[19] N‐Arylation
of 1, 2, and 3 with benzoyl chloride furnished N‐(4‐aryloxazol‐2‐yl)
benzamide (4), N‐(4‐arylthiazol‐2‐yl)benzamide (5), and N‐(4‐aryl‐1H‐
imidazol‐2‐yl)benzamide (6). Chlorosulfonylation of 4, 5, and 6 with
chlorosulfonic acid under ultrasonication at a frequency of 46 kHz
resulted in trisubstituted azoles N‐[5‐(chlorosulfonyl)‐4‐aryloxazol‐2‐
yl]benzamide (7), N‐[5‐(chlorosulfonyl)‐4‐arylthiazol‐2‐yl]benzamide
(8), and N‐[5‐(chlorosulfonyl)‐4‐aryl‐1H‐imidazol‐2‐yl]benzamide
(9)[20] (Scheme 1). Functionalization of sulfonyl chloride in 7, 8, and
9 to sulfonamide was effected by treating with 25% NH4OH, which
led to the formation of N‐[5‐(aminosulfonyl)‐4‐aryloxazol‐2‐yl]
benzamide (10), N‐[5‐(aminosulfonyl)‐4‐arylthiazol‐2‐yl]benzamide
(11), and N‐[5‐(aminosulfonyl)‐4‐aryl‐1H‐imidazol‐2‐yl]benzamide
(12)[20] (Scheme 1).
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2
RESULTS AND DISCUSSION
Chemistry
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2.1
The azolyl amines 4‐aryloxazolyl‐2‐amine (1) and 4‐arylthiazolyl‐2‐
amine (2) were synthesized by the reaction of phenacyl bromide with
urea and thiourea in methanol.[18] 4‐Arylimidazolyl‐2‐amine (3) was
obtained by the hydrolysis of N‐4‐aryl‐1H‐imidazol‐2‐yl acetamide in
However, the reaction of 2‐bromo‐1‐(4‐chloroheteroaryl)ethan‐1‐
one with acetyl guanidine resulted in N‐[4‐(4‐chlorofuran‐2‐yl)‐1H‐
imidazol‐2‐yl]acetamide/N‐[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]
Ar
Ar
Ar
Ar
N
O
O
N
N
N
O
i
ii
iii
Cl
H2N
NH2
S
PPh
X
Ph
N
H
N
H
X
S
X
N
H
Ph
X
O2
O2
1 / 2 / 3
4 / 5 / 6
7 / 8 / 9
10 / 11 / 12
(i) PhCOCl
(ii) ClSO3H
(iii) 25 % N
/
/
H
Toluene / Δ
CHCl3 / )))
Ar
= a) Ph
X= O, S, NH
b) 4-Me.Ph
c) 4-Cl.Ph
SCHEME 1 Synthesis of N‐(4‐aryl‐5‐sulfamoyloxazol/thiazol/1H‐imidazol‐2‐yl)benzamide

SANKAR ET AL.
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acetamide, which on hydrolysis in the presence of sulfuric acid gave 4‐(4‐
chlorofuran‐2‐yl)‐1H‐imidazol‐2‐amine (15)/4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐
1H‐imidazol‐2‐amine (16) (Scheme 2). Functionalization of hetero-
arylamines was reported by several methods.[18,21] In fact, we have
achieved N‐sulfonylation of heteroarylamines with ethyl chloroacetate in
the presence of dispersed sodium in tetrahydrofuran (THF).[22] It was
observed that the reaction proceeded effectively with dispersed Na. As
such, we have carried out the reaction of 15 with methyl 2‐chloroacetate
in the presence of dispersed sodium under ultrasonication at a frequency
of 46 kHz wherein 2‐chloro‐N‐[4‐(4‐chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]
acetamide (17) was obtained in an excellent yield. Adopting a similar
methodology, 2‐chloro‐N‐[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]
acetamide (18) was prepared by the treatment of 16 with methyl 2‐
chloroacetate (Scheme 2). In the presence of dispersed sodium, carbonyl
free radical generated from methyl chloroacetate reacted with hetero-
aryl amine to obtain the corresponding amide by the expulsion of H2
(Scheme 3).
amino}‐2‐oxoethyl)sulfamoyl]‐4‐aryl‐1H‐imidazol‐2‐yl}benzamide
(24) were prepared by the reaction of 10/11/12 with 17/18 in the
presence of pyridine (Method A) and also DMAP (Method B) (-
Scheme 4). The 1H nuclear magnetic resonance (NMR) spectra of
19a, 21a displayed four broad singlets at 7.86, 7.90 (SO2NH), 9.54,
9.85 (CH2CONH), 11.69, 11.76 (CONH), 12.23, 12.41 (imidazole
NH). The compounds 20a, 22a showed five broad singlets at 7.80,
7.92 (SO2NH), 9.65, 9.94 (CH2CONH), 11.34, 11.47 (pyrrole NH),
11.70, 11.68 (CONH), 12.31, 12.49 (imidazole NH), whereas 23a and
24a exhibited four broad singlets at 7.86, 8.10 (SO2NH), 9.91, 9.89
(CH2CONH), 11.68, 11.84 (CONH), 12.37, 12.48 (imidazole NH).
Besides, 24a showed another broad singlet at 11.36 due to pyrrole
NH. The signals of NH disappeared on deuteration.
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2.2
Biology
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The reaction of heteroarylamines and heteroarylmethyl chlor-
ides was reported in the presence of diisopropyl ethylamine,[23]
triethylamine,[24] potassium carbonate,[25] and sodium hydride[26]
under conventional methods. However, most of the reactions re-
quired longer reaction times and maintenance of anhydrous condi-
tions, and also in some instances, they led to lower yields. Recently,
we have reported the reaction of heteroarylmethyl halides with
heteroarylamines in the presence of pyridine in dichloromethane
(DCM)[27] and 4‐(dimethylamino)pyridine (DMAP) in DCM under
ultrasonication.[27] As such, the reaction was performed by both
methods. It was observed that the reaction proceeded at a faster
rate in the presence of DMAP, leading to the formation of a higher
yield of the products. This may be due to the more basicity of DMAP
enhanced by the presence of N,N‐dimethylamino group at 4‐position.
Thus compounds N‐{5‐[N‐(2‐{[4‐(4‐chlorofuran‐2‐yl)‐1H‐imidazol‐
2‐yl]amino}‐2‐oxoethyl)sulfamoyl]‐4‐aryloxazol‐2‐yl}benzamide (19),
N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐aryloxazol‐2‐yl}benzamide (20), N‐{5‐[N‐(2‐{[4‐
(4‐chloro‐furan‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐oxoethyl)sulfamoyl]‐
4‐arylthiazol‐2‐yl}benzamide (21), N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐
2‐yl)‐1H‐imidazol‐2‐yl)amino}‐2‐oxoethyl)sulfamoyl]‐4‐aryl‐thiazol‐2‐
yl}benzamide (22), N‐{5‐[N‐(2‐{[4‐(4‐chlorofuran‐2‐yl)‐1H‐imidazol‐2‐
yl]amino}‐2‐oxo‐ethyl)sulfamoyl]‐4‐aryl‐1H‐imidazol‐2‐yl}benzamide
(23), and N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]
2.2.1
Antibacterial activity
The results of antibacterial activity depicted in Table 1 and Figure 2
revealed that all the compounds except 19b displayed more activity
against Gram‐positive bacteria than against Gram‐negative bacteria.
The imidazolylthiazole derivatives (21, 22) exhibited greater activity
than imidazolyloxazoles (19, 20) and bis(imidazolyl) derivatives (23,
24). Among the latter compounds, 23, 24 showed more activity than
19, 20. It was noticed that 4‐chloropyrrolyl compounds 20, 22, and
24 exhibited slightly higher activity than 4‐chlorofuryl derivatives 19,
21, and 23. The presence of an electron‐withdrawing group on the
aromatic ring enhanced the activity. In fact, 4‐chloro‐substituted
compounds showed higher activity than methyl and unsubstituted
ones in the respective series. Compounds 22a, 22c, and 24c dis-
played excellent antibacterial activity against Bacillus subtilis, greater
than the standard drug, chloramphenicol.
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2.2.2
Antifungal activity
All the compounds inhibited the spore germination of tested fungi
except 19a, 19b, 20a, and 20b (Table 2 and Figure 3). The tested
compounds showed higher activity against Aspergillus niger than
against Penicillium chrysogenum. The bis(imidazolyl) derivatives
Cl
Cl
O
Y
Y
O
i & ii
Br
iii
N
N
Cl
Cl
Y
NH2
N
H
N
H
N
H
13 / 14
15 / 16
17 / 18
SCHEME 2 Synthesis of 2‐chloro‐N‐[4‐(4‐
(i) (NH2)2C=NHAc / DMF
(ii)) dil.H2SO4 MeOH
(iii) ClCH2CO2Me / Dispersed Na / )))
chlorofuran‐2‐yl/4‐chloropyrrol‐2‐yl)‐1H‐
imidazol‐2‐yl]acetamide. DMF,
dimethylformamide
Y = O. NHH
/

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O
SCHEME 3 Mechanism
OO
))))
Cl
Na
NaOMe
Cl
Cl
OMe
Cl
O
Y
))))
Y
H
Cl
O
N
N
Cl
N
NH2
N
H
N
H
H
H
H2
H
Cl
Cl
SCHEME 4 Synthesis of N‐{5‐[N‐(2‐{[4‐(4‐
chlorofuran‐2‐yl)‐pyrrol‐2‐yl‐imidazol‐2‐
yl]amino}‐2‐oxoethyl)sulfamoyl]‐4‐arylazol‐2‐
yl}benzamide. DCM, dichloromethane; DMAP,
4‐(dimethylamino)pyridine
4''
5''
Ar
3''
1''
Y
O
Ar
N
O
Y
O
N
5 X
O
i
N
2'
4'
5'
4
H2N
N
Cl
H
N
Ph
2
S
N
H
Ph
X
N
O2
N
H
N
H
S
N
H
N
H
H
O2
10
/ 11 / 12 a-c
17 / 18
19-24 a-c
19 X=O, Y=O
Ar = a) Ph
(i) MMethod A : Pyridine / DCM / )))
Method B
20 X=O, Y=NH
21 X=S, Y=O
22 X=S, Y=NH
23 X=NH, Y=O
24 X=NH, Y=NH
M
b) 4-Me. Ph
c) 4-Cl. Ph
: DMAP / DCM / )))
(23, 24) showed greater activity than imidazolyloxazoles (19, 20) and
imidazolylthiazoles (21, 22). Compounds 21, 22 showed higher ac-
tivity than 19, 20. Furthermore, compounds with 4‐chloropyrrole
substituent showed higher activity than those with 4‐chlorofuran.
Among the compounds with substituents on aromatic ring, those
with 4‐chlorophenyl moiety displayed greater activity in the re-
spective series due to the electron‐withdrawing effect. Compounds
22c and 24c showed excellent antifungal activity against A. niger
higher than the standard drug, ketoconazole.
found to be 2 × MIC. The structure–activity relationship of these
molecules indicated that thiazolylimidazoles (22) and bisimidazoles
(24) having 4‐chloropyrrole substituent displayed excellent anti-
microbial activity against B. subtilis and A. niger.
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2.3
Molecular properties and druglikeness
Molecular property prediction depends on various features such as
hydrophobicity, molecular size, flexibility, and bioavailability that
influence the behavior of molecules in living organs. Good bioavail-
ability can be achieved with an appropriate balance between solu-
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2.2.3
Minimal inhibitory concentration (MIC),
minimum bactericidal concentration (MBC), and
minimum fungicidal concentration (MFC) of
compounds 22a, 22c, and 24c
bility and partitioning properties. A wide array of tools and
approaches are available for the assessment of molecular diversity,
which is an important factor to design drugs. As such, computational
sensitivity analysis and structural analysis have been used to study
the druglikeness of the molecules. Thus, to achieve good oral drugs,
we have subjected a series of bisazoles linked by amido‐sulfonamido
group (19–24a–c) for the prediction of absorption, polar surface area
(PSA), and other properties.
The MIC (the lowest concentration of an antimicrobial that inhibits
the visible growth of a microorganism), MBC (the lowest con-
centration of antibiotic required to kill a particular bacterium), and
MFC (the lowest concentration of antibiotic required to kill a parti-
cular fungus) of the compounds tested are listed in Table 3. When
MIC is determined, MBC/MFC can be known by performing addi-
tional set of steps. The antimicrobials are usually regarded as bac-
tericidal/fungicidal if the MBC/MFC is not greater than four times
the MIC.[28] Compounds 22a, 22c, and 24c exhibited a low MIC
against B. subtilis, equal to standard drug chloramphenicol. The MBC
was found to be 2 × MIC. Moreover, 22c and 24c showed a low MIC
against A. niger, equal to standard drug ketoconazole. The MFC was
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2.3.1
Absorption, PSA, and other properties
High oral bioavailability is the major factor for the development of
bioactive molecules as therapeutic agents. Good oral bioavailability
can be predicted from good intestinal absorption, reduced molecular
flexibility, low PSA, and total hydrogen bond count (sum of donors

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FIGURE 2 The in vitro antibacterial
activity of compounds 19–24a–c. DMSO,
dimethyl sulfoxide
TABLE 2 The in vitro antifungal
activity of compounds 19–24a–c
Zone of inhibition (mm)
Aspergillus niger
Penicillium chrysogenum
Compound no.
50 µg/well 75 µg/well 100 µg/well 50 µg/well 75 µg/well 100 µg/well
19a
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
19b
‐
‐
‐
19c
8
1.0
10 1.2
13 2.2
‐
8
1.8
10 2.3
‐
20a
‐
‐
‐
‐
‐
20b
‐
‐
‐
20c
9
1.5
12 2.6
20 2.0
14 2.8
24 1.3
11 1.2
26 2.0
32 2.7
23 2.4
38 1.7
27 2.7
24 2.3
27 1.5
34 1.4
28 1.8
41 1.6
36 2.1
‐
8
1.7
10 2.3
16 2.5
13 2.5
18 2.8
12 1.4
21 1.3
29 2.7
14 2.2
19 2.4
23 1.0
20 1.8
25 1.2
18 2.3
14 2.1
26 2.8
38 1.4
‐
21a
18 2.1
‐
14 2.4
‐
21b
9
1.8
9 1.8
21c
21 1.0
28 2.5
16 2.1
33 1.5
22 1.3
18 1.0
23 1.5
29 1.7
23 1.8
36 2.4
31 2.0
‐
24 1.4
29 2.8
19 1.9
35 2.3
25 1.6
20 2.4
25 1.7
31 2.5
26 2.2
38 2.7
33 1.6
‐
16 2.2
24 2.9
‐
17 2.4
26 2.6
10 1.3
21 1.5
20 2.1
17 1.2
21 2.4
16 1.9
13 1.4
22 1.7
36 2.5
‐
22a
22b
22c
15 1.6
17 2.5
14 2.1
19 1.8
13 2.7
10 2.5
19 2.3
35 1.7
‐
23a
23b
23c
24a
24b
24c
Ketoconazole
Control (DMSO)
Note: Data are presented as SD.
Abbreviations: DMSO, dimethyl sulfoxide; ‐, no activity.
and acceptors).[29,30] Molecular properties, namely membrane per-
meability and bioavailability, are associated with basic molecular
descriptors like log P (partition coefficient), hydrogen bond accep-
tors, and hydrogen bond donors in a molecule.[31]
Lipinski's rule[32] states that molecules with good membrane
permeability should have log P ≤ 5, molecular weight ≤500, number
of hydrogen bond acceptors ≤10, and number of hydrogen bond
donors ≤5. This rule is used to identify drug‐like properties of

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FIGURE 3 The in vitro antifungal activity
of compounds 19–24a–c
TABLE 3 MIC, MBC, and MFC of compounds 22a, 22c, and 24c
MIC (MBC/MFC) μg/well
Staphylococcus
aureus
Bacillus
subtilis
Pseudomonas
aeruginosa
Klebsiella
Penicillium
Compound no.
22a
pneumoniae
Aspergillus niger
12.5 (50)
6.25 (12.5)
6.25 (12.5)
‐
chrysogenum
25 (100)
12.5 (100)
12.5 (100)
6.25
6.25 (12.5)
6.25 (12.5)
6.25 (12.5)
6.25
12.5 (50)
12.5 (50)
12.5 (50)
6.25
100 (>200)
100 (>200)
100 (>200)
12.5
100 (>200)
200 (‐)
200 (‐)
‐
22c
24c
Chloramphenicol
Ketoconazole
‐
‐
‐
‐
6.25
12.5
Note: Data are presented as MIC (SD)
Abbreviations: MBC, minimum bactericidal concentration; MFC, minimum fungicidal concentration; MIC, minimal inhibitory concentration; ‐, no activity.
molecules. Although the molecular weight of the compounds is
higher than 500, most of the compounds satisfied the other prop-
erties (Table 4). The magnitude of absorption is expressed by the
percentage of absorption. Absorption percent was calculated using
the following expression: % ABS = 109 − 0.345 PSA.[33] PSA was
determined by the fragment‐based method reported by Ertl and co‐
workers.[34,35] The presence of more than 5 H‐bond donors and
10 H‐bond acceptors indicates poor permeation or absorption.
Hydrogen‐bonding capacity has been also identified as an important
parameter for describing drug permeability.[19] Molecules 19a–c,
20a–c, 21a–c, 22a–c, and 23a–c except 24a–c possess ≤5 hydrogen
bond donors and all the compounds have ≤10 hydrogen bond ac-
ceptors (Table 4).
considered as drug‐like. The druglikeness score was found to be
0.08–0.71 for compounds 19a, 19b, 20b, 20c, 21a–c, 22b, 22c,
23a–c, 24b, and 24c under investigation. However, 24a–c have hy-
drogen bond donors >5. Thus, based on the molecular properties
prediction, 19a, 19b, 20b, 20c, 21a–c, 22b, 22c, and 23a–c can be
treated as drug candidates.
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3
CONCLUSION
A new class of bis(azolyl)sulfonamidoacetamides was prepared by
the reaction of azolylsulfonylamines with azolylchloroacetamides in
the presence of pyridine/DMAP under ultrasonication. The reaction
proceeded well with DMAP, resulting in higher yield of the products.
This may be due to the presence of electron‐donating N,N‐
dimethylamino group at 4‐position, which enhances the basicity of
DMAP. The antimicrobial activity of the compounds indicated that
N‐{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl)amino}‐2‐
oxoethyl)sulfamoyl]‐4‐phenylthiazol‐2‐yl}benzamide (22a), N‐{5‐[N‐
(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐oxoethyl)
sulfamoyl]‐4‐(4‐chloro‐phenyl)thiazol‐2‐yl}benzamide (22c), and N‐
{5‐[N‐(2‐{[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)‐1H‐imidazol‐2‐yl}benzamide
(24c) exhibited a low MIC against B. subtilis, equal to standard drug
chloramphenicol. Compounds 22c and 24c also showed a low MIC
against A. niger, equal to standard drug ketoconazole. Molecular
Molecular PSA indicates the prediction of drug transport prop-
erties of a molecule. PSA is the sum of surfaces of polar atoms
(usually oxygen and nitrogen) in a molecule. PSA and volume are
inversely proportional to % ABS. Compounds 21a–c and 22a–c have
maximum absorption (64.25–64.18%), as their corresponding PSA
and volume are least among the series (Table 4). The druglikeness
model score (a combined effect of physicochemical properties,
pharmacokinetics, and pharmacodynamics of
a compound re-
presented by a numerical value) was computed by MolSoft (MolSoft
2007) software for the molecules under study, and the values are
presented in Table 4. As depicted in Figure 4, those with green color
indicates non‐drug‐like behavior and with blue color are considered
as drug‐like. Compounds having zero or negative value cannot be

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TABLE 4 Calculated absorption, polar surface area, and druglikeness model score of compounds 19–24a–c
No.
of
No.
of
Mol log S log
Mol
Mol
Mol
(mol/l) 0.00 (in Formula
Druglikeness
Compound no. Molecular formula % ABS Vol (Å3)
PSA (Å2) log P
HBA
HBD
mg/L)
−8.37
−8.82
−9.32
−8.55
−9.00
−9.50
−8.25
−8.70
−9.21
−8.43
−8.88
−9.39
−8.98
−9.44
−9.94
−9.16
−9.61
−10.12
weight
566.08
580.09
600.04
565.09
579.11
599.05
582.05
596.07
616.02
581.07
595.09
615.03
565.09
579.11
599.05
564.11
578.13
598.07
model score
19a
19b
19c
20a
20b
20c
21a
21b
21c
22a
22b
22c
23a
23b
23c
24a
24b
24c
C
C
C
C
25H19ClN6O6S
26H21ClN6O6S
25H18Cl2N6O6S
25H20ClN7O5S
61.08 490.21
61.08 511.15
61.08 507.40
61.00 493.82
61.00 514.76
61.00 511.02
64.25 494.28
64.25 515.22
138.89
138.89
138.89
139.11
139.11
139.11
129.69
129.69
129.69
129.91
129.91
129.91
140.92
140.92
140.92
141.13
141.13
141.13
3.68
4.08
4.39
3.40
3.80
4.12
4.69
5.09
5.40
4.41
4.81
5.13
3.78
4.18
4.49
3.50
3.90
4.21
9
9
9
8
8
8
9
9
9
8
8
8
8
8
8
7
7
7
4
4
4
5
5
5
4
4
4
5
5
5
5
5
5
6
6
6
0.09
0.34
−0.66
−0.17
0.08
C26H22ClN7O5S
25H19Cl2N7O5S
C25H19ClN6O5S2
26H21ClN6O5S2
C
0.38
0.15
C
0.38
C25H18Cl2N6O5S2 64.25 511.47
0.71
C25H20ClN7O4S2
C26H22ClN7O4S2
64.18 497.89
64.18 518.83
−0.08
0.16
C25H19Cl2N7O4S2 64.18 515.09
0.46
C
25H20ClN7O5S
C26H22ClN7O5S
25H19Cl2N7O5S
60.38 488.97
60.38 509.91
60.38 506.17
45.49 492.58
45.49 513.52
45.49 509.78
0.13
0.36
C
0.68
C25H21ClN8O4S
C26H23ClN8O4S
C25H20Cl2N8O4S
−0.09
0.15
0.44
Abbreviations: HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; Mol log P, octanol/water partition coefficient; Mol log S, water solubility;
Mol PSA, molecular polar surface area; Mol Vol, molecular volume % ABS, percentage of absorption.
properties of synthesized molecules were studied to identify dru-
glikeness behavior of the molecules. Molecules 19a–c, 20a–c, 21a–c,
22a–c, and 23a–c possess ≤5 hydrogen bond donors and ≤10 hy-
drogen bond acceptors. However, 24a–c have hydrogen bond donors
>5. Furthermore, PSA and volume indicated that the compounds
21a–c and 22a–c have maximum absorption. The druglikeness score
was found to be 0.08–0.71 for compounds 19a, 19b, 20b, 20c, 21a–c,
22b, 22c, 23a–c, 24b, and 24c. Thus, based on molecular properties
prediction, 19a, 19b, 20b, 20c, 21a–c, 22b, 22c, and 23a–c can be
treated as drug candidates.
the wavenumbers were given in cm−1. The 1H and 13C NMR spectra
(see the Supporting Information) were recorded in dimethyl sulfoxide
(DMSO)‐d6 on
a Bruker spectrometer operating at 400 and
100 MHz. The chemical shifts are reported in δ (ppm) using tetra-
methylsilane as an internal standard. The high‐resolution mass
spectra are recorded on micromass Q‐TOF micromass spectrometer
using electrospray ionization. Ultrasonication was performed in a
Bandelin SONOREX RK 12 H ultrasonic bath operating at a fre-
quency of 46 kHz. The microanalyses were performed on a Perki-
nElmer 240C elemental analyzer. The progress of the reaction was
monitored by TLC using silica gel plates (silica gel 60 F254 0.25 mm),
and components were visualized by observation under UV light (254
and 365 nm). Compounds 4‐phenyloxazol‐2‐amine (1), 4‐
phenylthiazol‐2‐amine (2), 4‐phenyl‐1H‐imidazol‐2‐amine (3), 4‐(4‐
chlorofuran‐2‐yl)‐1H‐imidazol‐2‐amine (15), and 4‐(4‐chloro‐1H‐
pyrrol‐2‐yl)‐1H‐imidazol‐2‐amine (16) were prepared as per the lit-
erature procedures.[14,28] Compounds 4‐(4‐chlorophenyl)‐1H‐pyrrol‐
2‐amine (7), 2‐bromo‐1‐(4‐chlorofuran‐2‐yl)ethan‐1‐one (13), and 2‐
bromo‐1‐(4‐chloro‐1H‐pyrrol‐2‐yl)ethan‐1‐one (14) were purchased
from Sigma‐Aldrich.
|
4
EXPERIMENTAL
Chemistry
|
4.1
|
4.1.1
General
Melting points were determined in open capillaries on a Mel‐Temp
apparatus and were uncorrected. The purity of the compounds was
evaluated by thin‐layer chromatography (TLC) (silica gel H, BDH,
ethyl acetate/hexane, 1:3). The infrared (IR) spectra were recorded
on a Thermo Nicolet IR 200 FT‐IR spectrometer as KBr pellets and
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting
Information.

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FIGURE 4 (a) phenyl, (b) 4‐methyl phenyl (Toluene), (c) means‐ 4‐chloro phenyl. Graph showing compounds 19–24a–c of the druglikeness
model score using Molsoft 2007

10 of 14
SANKAR ET AL.
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|
4.1.2
Preparation of dispersed sodium
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 44.2 (CH2–C), 167.6
(C═O), 105.4, 108.7, 117.5, 121.9, 130.4, 141.6, 149.3 (aromatic
carbon C2ʹ, C4ʹ, C5ʹ, C1″, C3″, C4″, and C5″) ppm. HRMS (m/z):
282.0804 [M+Na]+; anal. calcd. for C9H8Cl2N4O: C, 41.72; H, 3.11; N,
21.62; found: C, 41.78; H, 3.08; N, 21.73%.
Clean sodium metal (10 g) was weighed under dry ether and in-
troduced into a 500‐ml round‐bottomed flask containing sodium‐
dried xylene (100 cm3) fitted with an air condenser carrying a cal-
cium chloride guard tube and placed on a sand bath. The flask was
covered with a dry cloth and the sand bath was heated slowly. The
ring of condensed vapors of xylene was carefully observed. When the
ring of condensed vapor had risen to the neck of the flask, the flame
was extinguished. The condenser was replaced by the stopper and
the flask was wrapped with a pre‐dried cloth. The stopper was then
held firmly and shaken vigorously for 2–3 min until the molten so-
dium was converted into a fine dispersion. Immediately the stopper
was removed and the flask was placed on the cork ring. The sodium
was obtained in the form of small spheres, depending upon the time
and rapidity of shaking. Then the contents were cooled to room
temperature, xylene was decanted, and sodium was washed with
sodium‐dried ether. The dispersed sodium as small spheres was
preserved in absolute ether.[31]
|
4.1.4
General procedure for the synthesis of N‐{5‐
[N‐(2‐{[4‐(4‐chlorofuran‐2‐yl)‐pyrrol‐2yl‐imidazol‐2‐yl]‐
amino}‐2‐oxoethyl)sulfamoyl]‐4‐arylazol‐2‐yl}‐
benzamide (19–24)
Method A: N‐(4‐Phenyl‐5‐sulfamoyloxazol/thiazol/1H‐imidazol‐2‐yl)
benzamide (10/11/12) (1 mmol) and 2‐chloro‐N‐[4‐(4‐chlorofuran‐2‐yl)‐
1H‐imidazol‐2‐yl]acetamide (17)/2‐chloro‐N‐[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐
1H‐imidazol‐2‐yl]acetamide (18) (1 mmol) were dissolved in DCM (20 ml),
and pyridine (3 mmol) was added dropwise to this. The contents were
subjected to ultrasound irradiation at a frequency of 46 kHz for
45–60 min at room temperature. After completion of the reaction
(checked by TLC), the residue was poured on crushed ice and solid se-
parated was filtered, dried, and recrystallized from ethanol.
|
4.1.3
General procedure for the synthesis of
Method B: Compounds 10–12 (1 mmol) and 17, 18 (1 mmol)
were dissolved in DCM (15 ml). To this, DMAP (1 mmol) and trie-
thylamine (1 mmol) were added dropwise and sonicated at a fre-
quency of 46 kHz at room temperature for 35–40 min. After the
reaction was completed, the contents were poured on crushed ice
and the solid was filtered, dried, and recrystallized from ethanol.
2‐chloro‐N‐[4‐(4‐chlorofuran/1H‐pyrrol‐2‐yl)‐1H‐
imidazol‐2‐yl]acetamide (17/18)
A mixture of methyl 2‐chloroacetate (0.001 mol), dispersed sodium
(1.8 mg atom), and THF (3 ml) was sonicated for 15 min in a sonic bath at
a frequency of 46 kHz at 35°C. To this, 4‐(4‐chlorofuran‐2‐yl)‐1H‐
imidazol‐2‐amine (15)/4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐amine
(16) was added, and sonication was continued for 15–22 min. After
completion of the reaction (monitored by TLC), the organic matter was
filtered, washed with water, extracted with ether, and dried. Removal of
the solvent under reduced pressure gave a solid that was recrystallized
from ethanol.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐phenyloxazol‐2‐yl}benzamide (19a)
Yield 64% (Method A), 71% (Method B); mp 142–144°C. IR (KBr):
3384 (NH), 1688 (C═O), 1639 (C═C), 1579 (C═N), 1340–1135 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.42 (s, 2H, CH2), 6.44
(s, 1H, C5″–H), 7.46–7.72 (m, 12H, Ar–H, C3″–H, and C5ʹ–H), 7.82 (br
s, 1H, SO2NH), 9.54 (br s, 1H, CH2CONH), 11.69 (br s, 1H, CONH),
12.23 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6):
δ 45.6 (CH2–C), 152.3 (C‐2), 153.7 (C‐2ʹ), 160.4 (C‐1″), 165.1
(CONH), 169.3 (CH2CONH), 109.3, 114.9, 119.6, 125.4, 127.1, 129.0,
132.5, 134.7, 136.3, 137.2, 138.1, 139.6, 141.3, 142.8, 144.1 (aro-
matic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
589.9621 [M+Na]+; anal. calcd. for C25H19ClN6O6S: C, 52.96; H,
3.38; N, 14.82; found: C, 53.04; H, 3.33; N, 14.93%.
2‐Chloro‐N‐[4‐(4‐chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]acetamide (17)
Yield 65%; mp 132–134°C. IR (KBr): 3376 (NH), 1676 (C═O), 1645
(C═C), 1583 (C═N) (cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 4.38
(s, 2H, CH2), 7.09–7.41 (m, 3H, C5″–H, C5ʹ–H and C3″–H), 10.23 (br s,
1H, CONH), 12.46 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz,
DMSO‐d6): δ 43.4 (CH2–C), 168.3 (C═O), 112.5, 115.9, 122.3, 137.8,
140.1, 153.7, 157.0 (aromatic carbon C2ʹ, C4ʹ, C5ʹ, C1″, C3″, C4″, and
C5″) ppm. HRMS (m/z): 283.0632 [M+Na]+; anal. calcd. for
C9H7Cl2N3O2: C, 41.56; H, 2.71; N, 16.16; found: C, 41.64; H, 2.75;
N, 16.25%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(p‐tolyl)oxazol‐2‐yl}benzamide (19b)
Yield 65% (Method A), 73% (Method B); mp 155–157°C. IR (KBr):
3374 (NH), 1678 (C═O), 1634 (C═C), 1573 (C═N), 1325–1128 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 2.29 (s, 3H, CH3), 3.40
(s, 2H, CH2), 6.39 (s, 1H, C5″–H), 7.40–7.68 (m, 11H, Ar–H, C3″–H and
C5ʹ–H), 7.78 (br s, 1H, SO2NH), 9.50 (br s, 1H, CH2CONH), 11.61 (br s,
1H, CONH), 12.18 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz,
DMSO‐d6): δ 20.3 (CH3–C), 43.6 (CH2–C), 151.9 (C‐2), 152.6 (C‐2ʹ),
2‐Chloro‐N‐[4‐(4‐chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐
yl]acetamide (18)
Yield 68%; mp 146–148°C. IR (KBr): 3369 (NH), 1680 (C═O), 1638
(C═C), 1575 (C═N) (cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 4.42
(s, 2H, CH2), 6.57–7.43 (m, 3H, C5″–H, C5ʹ–H and C3″–H), 10.31 (br s,
1H, CONH), 11.65 (br s, 1H, pyrrole NH), 12.52 (br s, 1H, imidazole

SANKAR ET AL.
11 of 14
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159.4 (C‐1″), 163.2 (CONH), 167.1 (CH2CONH), 110.6, 113.4, 116.7,
119.0, 121.2, 122.8, 124.1, 128.9, 133.7, 135.0, 137.6, 138.5, 139.3,
140.5, 143.4 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm.
HRMS (m/z): 603.9890 [M+Na]+; anal. calcd. for C26H21ClN6O6S: C,
53.75; H, 3.64; N, 14.47; found: C, 53.67; H, 3.60; N, 14.38%.
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)oxazol‐2‐yl}
benzamide (20c)
Yield 62% (Method A), 73% (Method B); mp 185–187°C. IR (KBr):
3375 (NH), 1679 (C═O), 1645 (C═C), 1580 (C═N), 1342–1141 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.51 (s, 2H, CH2), 6.48 (s,
1H, C5″‐H), 6.95 (s, 1H, C3″–H), 7.45–7.73 (m, 10H, Ar–H and C5ʹ–H),
7.88 (br s, 1H, SO2NH), 9.72 (br s, 1H, CH2CONH), 11.52 (br s, 1H,
pyrrole NH), 11.83 (br s, 1H, CONH), 12.43 (br s, 1H, imidazole
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 44.4 (CH2–C), 150.0 (C‐
2), 152.2 (C‐2ʹ), 164.7 (CONH), 167.0 (CH2CONH), 109.8, 111.2,
115.0, 118.6, 121.7, 126.4, 127.6, 128.5, 129.8, 130.4, 132.6, 135.2,
137.7, 139.0, 140.5, 142.9 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C1″,
C3″, C4″, and C5″) ppm. HRMS (m/z): 623.4212 [M+Na]+; anal. calcd.
for C25H19Cl2N7O5S: C, 50.01; H,3.19; N, 16.33; found: C, 50.09; H,
3.14; N, 16.26%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)oxazol‐2‐yl}benzamide (19c)
Yield 62% (Method A), 76% (Method B); mp 161–163°C. IR (KBr):
3386 (NH), 1683 (C═O), 1648 (C═C), 1581 (C═N), 1342–1139 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.48 (s, 2H, CH2), 6.47
(s, 1H, C5″–H), 7.49–7.76 (m, 11H, Ar–H, C3″–H and C5ʹ–H), 7.89 (br
s, 1H, SO2NH), 10.08 (br s, 1H, CH2CONH), 11.93 (br s, 1H, CONH),
12.25 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6):
δ 44.2 (CH2–C), 152.4 (C‐2), 153.6 (C‐2ʹ), 161.7 (C‐1″), 164.0
(CONH), 168.9 (CH2CONH), 112.3, 114.7, 119.1, 120.5, 121.4, 122.8,
127.3, 130.4, 133.2, 134.7, 136.3, 138.2, 139.5, 140.7, 142.2 (aro-
matic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
624.4054 [M+Na]+; anal. calcd. for C25H18Cl2N6O6S: C, 49.93; H,
3.02; N, 13.97; found: C, 49.85; H, 3.08; N, 13.84%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐phenylthiazol‐2‐yl}benzamide (21a)
Yield 59% (Method A), 71% (Method B); mp 162–164°C. IR (KBr):
3369 (NH), 1675 (C═O), 1636 (C═C), 1591 (C═N), 1330–1125 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.52 (s, 2H, CH2), 6.58 (s,
1H, C5″–H), 7.41–7.80 (m, 12H, Ar–H, C3″–H and C5ʹ–H), 7.97 (br s,
1H, SO2NH), 9.85 (br s, 1H, CH2CONH), 11.76 (br s, 1H, CONH),
12.41 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6):
δ 43.9 (CH2–C), 151.2 (C‐2ʹ), 157.6 (C‐1″), 159.3 (C‐2), 163.4
(CONH), 167.4 (CH2CONH), 104.8, 109.4, 112.3, 115.1, 119.5, 124.6,
128.5, 129.7, 130.0, 131.4, 136.2, 138.9, 140.4, 141.5, 143.8 (aro-
matic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
606.0238 [M+Na]+; anal. calcd. for C25H19ClN6O5S2: C, 51.50; H,
3.28; N, 14.41; found: C, 51.48; H, 3.31; N, 14.45%.
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐phenyloxazol‐2‐yl}benzamide (20a)
Yield 60% (Method A), 75% (Method B); mp 150–152°C. IR (KBr):
3370 (NH), 1678 (C═O), 1640 (C═C), 1577 (C═N), 1334–1124 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.45 (s, 2H, CH2), 6.43 (s,
1H, C5″–H), 6.82 (s, 1H, C3″–H), 7.39–7.66 (m, 11H, Ar–H and
C5ʹ–H), 7.80 (br s, 1H, SO2NH), 9.68 (br s, 1H, CH2CONH), 11.34 (br
s, 1H, pyrrole NH), 11.70 (br s, 1H, CONH), 12.31 (br s, 1H, imidazole
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 44.7 (CH2–C), 149.1
(C‐2), 151.6 (C‐2ʹ), 163.8 (CONH), 166.5 (CH2CONH), 106.5, 107.6,
109.4, 111.7, 115.2, 119.1, 120.4, 127.7, 129.4, 132.0, 133.8, 135.3,
136.5, 138.2, 139.6, 140.1 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C1″,
C3″, C4″, and C5″) ppm. HRMS (m/z): 588.9783 [M+Na]+; anal. calcd.
for C25H20ClN7O5S: C, 53.05; H, 3.56; N, 17.32; found: C, 53.00; H,
3.61; N, 17.45%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(p‐tolyl)thiazol‐2‐yl}benzamide (21b)
Yield 65% (Method A), 73% (Method B); mp 167–169°C. IR (KBr):
3365 (NH), 1672 (C═O), 1632 (C═C), 1576 (C═N), 1326–1133 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 2.38 (s, 3H, CH3), 3.54 (s,
2H, CH2), 6.53 (s, 1H, C5″–H), 7.35–7.69 (m, 11H, Ar–H, C3″–H and
C5ʹ–H), 7.85 (br s, 1H, SO2NH), 9.76 (br s, 1H, CH2CONH), 11.70 (br
s, 1H, CONH), 12.36 (br s, 1H, imidazole NH) ppm; 13C NMR
(100 MHz, DMSO‐d6): δ 22.5 (CH3–C), 44.7 (CH2–C), 151.0 (C‐2ʹ),
156.3 (C‐1″), 158.7 (C‐2), 162.9 (CONH), 166.7 (CH2CONH), 105.1,
108.3, 110.6, 114.0, 119.2, 123.5, 128.1, 129.4, 131.2, 133.4, 135.0,
137.3, 139.5, 141.2, 143.3 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″,
C4″, and C5″) ppm. HRMS (m/z): 620.0513 [M+Na]+; anal. calcd. for
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐(p‐tolyl)oxazol‐2‐yl}benzamide (20b)
Yield 66% (Method A), 76% (Method B); mp 164–166°C. IR (KBr):
3357 (NH), 1674 (C═O), 1637 (C═C), 1572 (C═N), 1331–1135
(SO2) (cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 2.35 (s, 3H, CH3),
3.43 (s, 2H, CH2), 6.45 (s, 1H, C5″–H), 6.78 (s, 1H, C3″–H),
7.30–7.65 (m, 10H, Ar–H, and C5ʹ–H), 7.82 (br s, 1H, SO2NH),
9.61 (br s, 1H, CH2CONH), 11.46 (br s, 1H, pyrrole NH), 11.75 (br
s, 1H, CONH), 12.28 (br s, 1H, imidazole NH) ppm; 13C NMR
(100 MHz, DMSO‐d6): δ 21.1 (CH3–C), 43.2 (CH2–C), 148.3 (C‐2),
150.8 (C‐2ʹ), 162.3 (CONH), 166.2 (CH2CONH), 106.1, 107.4,
112.5, 118.3, 119.8, 121.2, 123.1, 125.6, 127.3, 128.5, 129.0,
131.4, 134.8, 138.1, 139.9, 141.5 (aromatic carbons, C4, C5, C4ʹ,
C5ʹ, C1″, C3″, C4″, and C5″) ppm. HRMS (m/z): 603.0064 [M+Na]+;
anal. calcd. for C26H22ClN7O5S: C, 53.84; H, 3.82; N, 16.90;
found: C, 53.74; H, 3.75; N, 16.98%.
C26H21ClN6O5S2: C, 52.30; H, 3.55; N, 14.08; found: C, 52.38; H,
3.49; N, 14.17%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)thiazol‐2‐yl}benzamide (21c)
Yield 63% (Method A), 76% (Method B); mp 173–175°C. IR (KBr):
3375 (NH), 1680 (C═O), 1641 (C═C), 1593 (C═N), 1341–1140 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.60 (s, 2H, CH2), 6.61

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(s, 1H, C5″–H), 7.46–7.85 (m, 11H, Ar–H, C3″–H, and C5ʹ–H), 7.94 (br
s, 1H, SO2NH), 9.90 (br s, 1H, CH2CONH), 11.84 (br s, 1H, CONH),
12.45 (br s, 1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6):
δ 46.3 (CH2–C), 152.5 (C‐2ʹ), 156.8 (C‐1″), 159.7 (C‐2), 165.1
(CONH), 167.7 (CH2CONH), 103.5, 109.6, 112.7, 116.3, 119.7, 123.1,
129.2, 130.8, 134.6, 135.4, 137.0, 139.3, 140.5, 142.7, 144.1 (aro-
matic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
640.4653 [M+Na]+; anal. calcd. for C25H18Cl2N6O5S2: C, 48.63; H,
2.94; N, 13.61; found: C, 48.55; H, 2.98; N, 13.76%.
114.7, 118.3, 120.8, 123.1, 125.0, 126.4, 128.2, 129.7, 131.6, 133.1,
135.5, 137.2, 139.8, 141.7 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″,
C3″, C4″, and C5″) ppm. HRMS (m/z): 639.4823 [M+Na]+; anal. calcd.
for C25H19Cl2N7O4S2: C, 48.71; H, 3.11; N, 15.90; found: C, 48.80; H,
3.09; N, 15.98%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐phenyl‐1H‐imidazol‐2‐yl}benzamide (23a)
Yield 63% (Method A), 74% (Method B); mp 166–168°C. IR (KBr):
3363 (NH), 1687 (C═O), 1650 (C═C), 1582 (C═N), 1332–1136 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.51 (s, 2H, CH2), 6.63
(s, 1H, C5″–H), 7.32–7.72 (m, 12H, Ar–H, C3″–H and C5ʹ–H), 7.86 (br
s, 1H, SO2NH), 9.91 (br s, 1H, CH2CONH), 11.72 (br s, 1H, CONH),
12.37 (br s, 2H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6):
δ 44.1 (CH2–C), 150.1 (C‐2 and C‐2ʹ), 157.3 (C‐1″), 164.7 (CONH),
168.3 (CH2CONH), 110.6, 113.4, 118.1, 120.5, 122.7, 126.2, 127.7,
129.5, 130.8, 132.5, 135.0, 137.6, 139.4, 141.3, 143.7 (aromatic
carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
588.9783 [M+Na]+; anal. calcd. for C25H20ClN7O5S: C, 53.05; H,
3.56; N, 17.32; found: C, 53.14; H, 3.49; N, 17.24%.
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl)amino}‐
2‐oxoethyl)sulfamoyl]‐4‐phenylthiazol‐2‐yl}benzamide (22a)
Yield 66% (Method A), 74% (Method B); mp 158–160°C. IR (KBr):
3377 (NH), 1676 (C═O), 1629 (C═C), 1585 (C═N), 1337–1128 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.56 (s, 2H, CH2), 6.64 (s,
1H, C5″–H), 6.88 (s, 1H, C3″–H), 7.38–7.90 (m, 11H, Ar–H and
C5ʹ–H), 7.92 (br s, 1H, SO2NH), 9.94 (br s, 1H, CH2CONH), 11.47 (br
s, 1H, pyrrole NH), 11.68 (br s, 1H, CONH), 12.48 (br s, 1H, imidazole
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 44.5 (CH2–C), 152.9
(C‐2ʹ), 160.2 (C‐2), 164.1 (CONH), 167.4 (CH2CONH), 104.2, 108.7,
113.4, 116.1, 119.0, 123.9, 125.7, 127.2, 129.5, 131.3, 133.6, 135.2,
137.6, 139.5, 140.2, 143.6, (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C1″,
C3″, C4″, and C5″) ppm. HRMS (m/z): 605.0393 [M+Na]+; anal. calcd.
for C25H20ClN7O4S2: C, 51.59; H, 3.46; N, 16.85; found: C, 51.65; H,
3.40; N, 16.79%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(p‐tolyl)‐1H‐imidazol‐2‐yl}benzamide (23b)
Yield 61% (Method A), 75% (Method B); mp 155–157°C. IR (KBr):
3356 (NH), 1676 (C═O), 1633 (C═C), 1578 (C═N), 1328–1129 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 2.41 (s, 3H, CH3), 3.52
(s, 2H, CH2), 6.47 (s, 1H, C5″–H), 7.27–7.68 (m, 11H, Ar–H, C3″–H
and C5ʹ–H), 7.84 (br s, 1H, SO2NH), 10.05 (br s, 1H, CH2CONH),
11.87 (br s, 1H, CONH), 12.45 (br s, 2H, imidazole NH) ppm; 13C
NMR (100 MHz, DMSO‐d6): δ 21.8 (CH3–C), 42.8 (CH2–C), 149.6
(C‐2 and C‐2ʹ), 157.1 (C‐1″), 163.7 (CONH), 166.3 (CH2CONH),
109.0, 112.7, 115.5, 120.8, 125.2, 126.3, 128.6, 129.5, 131.0, 133.9,
135.1, 136.3, 138.6, 139.4, 143.6 (aromatic carbons, C4, C5, C4ʹ, C5ʹ,
C3″, C4″, and C5″) ppm. HRMS (m/z): 603.0062 [M+Na]+; anal. calcd.
for C26H22ClN7O5S: C, 53.84; H, 3.82; N, 16.90; found: C, 53.76; H,
3.87; N, 16.78%.
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐(p‐tolyl)thiazol‐2‐yl}benzamide (22b)
Yield 59% (Method A), 73% (Method B); mp 149–151°C. IR (KBr):
3370 (NH), 1682 (C═O), 1635 (C═C), 1570 (C═N), 1329–1135 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 2.30 (s, 3H, CH3), 3.60 (s,
2H, CH2), 6.58 (s, 1H, C5″–H), 6.83 (s, 1H, C3″–H), 7.35–7.81 (m, 10H,
Ar–H and C5ʹ–H), 7.87 (br s, 1H, SO2NH), 9.89 (br s, 1H, CH2CONH),
11.38 (br s, 1H, pyrrole NH), 11.70 (br s, 1H, CONH), 12.40 (br s, 1H,
imidazole NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 22.4 (CH3–C),
43.2 (CH2–C), 151.4 (C‐2ʹ), 159.3 (C‐2), 163.4 (CONH), 166.5
(CH2CONH), 103.7, 107.3, 109.2, 116.0, 119.5, 122.4, 123.2, 124.7,
127.9, 129.2, 130.8, 132.4, 134.7, 137.1, 139.5, 141.2 (aromatic
carbons, C4, C5, C4ʹ, C5ʹ, C1″, C3″, C4″, and C5″) ppm. HRMS (m/z):
619.0674 [M+Na]+; anal. calcd. for C26H22ClN7O4S2: C, 52.39; H,
3.72; N, 16.45; found: C, 52.46; H, 3.75; N, 16.55%.
N‐{5‐[N‐(2‐{[4‐(4‐Chlorofuran‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐2‐
oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)‐1H‐imidazol‐2‐yl}
benzamide (23c)
Yield 60% (Method A), 73% (Method B); mp 181–183°C. IR (KBr):
3364 (NH), 1681 (C═O), 1641 (C═C), 1587 (C═N), 1348–1142
(SO2) (cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.65 (s, 2H, CH2),
6.62 (s, 1H, C5″–H), 7.45–7.90 (m, 11H, Ar–H, C3″–H and C5ʹ–H),
8.13 (br s, 1H, SO2NH), 9.87 (br s, 1H, CH2CONH), 11.79 (br s,
1H, CONH), 12.50 (br s, 2H, imidazole NH) ppm; 13C NMR
(100 MHz, DMSO‐d6): δ 45.6 (CH2–C), 151.5 (C‐2 and C‐2ʹ), 158.6
(C‐1″), 165.0 (CONH), 169.4 (CH2CONH), 112.3, 115.2, 118.6,
125.5, 127.3, 129.1, 132.3, 134.8, 137.1, 139.7, 140.5, 142.3,
143.7, 145.0, 146.1 (aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″,
and C5″) ppm. HRMS (m/z): 623.4205 [M+Na]+; anal. calcd. for
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐(4‐chlorophenyl)thiazol‐2‐yl}
benzamide (22c)
Yield 65% (Method A), 78% (Method B); mp 165–167°C. IR (KBr):
3383 (NH), 1677 (C═O), 1646 (C═C), 1596 (C═N), 1345–1147 (SO2)
(cm−1); 1H NMR (400 MHz, DMSO‐d6): δ 3.63 (s, 2H, CH2), 6.67 (s,
1H, C5″–H), 6.97 (s, 1H, C3″–H), 7.41–7.85 (m, 10H, Ar–H and
C5ʹ–H), 7.97 (br s, 1H, SO2NH), 10.02 (br s, 1H, CH2CONH), 11.55 (br
s, 1H, pyrrole NH), 11.73 (br s, 1H, CONH), 12.52 (br s, 1H, imidazole
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 46.9 (CH2–C), 152.7
(C‐2ʹ), 159.0 (C‐2), 165.2 (CONH), 168.3 (CH2CONH), 106.5, 109.2,
C
25H19Cl2N7O5S: C, 50.01; H, 3.19; N, 16.33; found: C, 49.92; H,
3.24; N, 16.45%.

SANKAR ET AL.
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N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐phenyl‐1H‐imidazol‐2‐yl}benzamide (24a)
Yield 65% (Method A), 77% (Method B); mp 186–188°C. IR (KBr): 3373
(NH), 1674 (C═O), 1639 (C═C), 1572 (C═N), 1335–1137 (SO2) (cm−1);
1H NMR (400 MHz, DMSO‐d6): δ 3.58 (s, 2H, CH2), 6.57 (s, 1H, C5″–H),
6.84 (s, 1H, C3″–H), 7.43–7.84 (m, 11H, Ar–H, and C5ʹ–H), 8.10 (br s, 1H,
SO2NH), 9.89 (br s, 1H, CH2CONH), 11.36 (br s, 1H, pyrrole NH), 11.84
(br s, 1H, CONH), 12.48 (br s, 2H, imidazole NH) ppm; 13C NMR
(100 MHz, DMSO‐d6): δ 46.1 (CH2–C), 150.7 (C‐2 and C‐2ʹ), 158.0 (C‐1″),
165.8 (CONH), 168.6 (CH2CONH), 106.8, 108.2, 117.5, 120.4, 122.0,
126.3, 128.7, 129.4, 131.6, 133.2, 136.5, 138.7, 140.3, 142.8, 145.8
(aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
587.9943 [M+Na]+; anal. calcd. for C25H21ClN8O4S: C, 53.15; H, 3.75; N,
19.83; found: C, 53.06; H, 3.79; N, 19.97%.
using chloramphenicol for antibacterial activity and ketoconazole for
antifungal activity as standard drugs.[36–39]
ACKNOWLEDGMENT
The authors are grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial assistance under major
research project.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
ORCID
Adivireddy Padmaja
http://orcid.org/0000-0003-4015-8163
Venkatapuram Padmavathi
https://orcid.org/0000-0003-
3448-1423
N‐{5‐[N‐(2‐{[4‐(4‐Chloro‐1H‐pyrrol‐2‐yl)‐1H‐imidazol‐2‐yl]amino}‐
2‐oxoethyl)sulfamoyl]‐4‐(p‐tolyl)‐1H‐imidazol‐2‐yl}benzamide (24b)
Yield 62% (Method A), 74% (Method B); mp 175–177°C. IR (KBr): 3358
(NH), 1671 (C═O), 1628 (C═C), 1575 (C═N), 1339–1132 (SO2) (cm−1);
1H NMR (400 MHz, DMSO‐d6): δ 2.46 (s, 3H, CH3), 3.62 (s, 2H, CH2),
6.52 (s, 1H, C5″–H), 6.84 (s, 1H, C3″–H), 7.37–7.90 (m, 10H, Ar–H, and
C5ʹ–H), 8.11 (br s, 1H, SO2NH), 9.98 (br s, 1H, CH2CONH), 11.42 (br s,
1H, pyrrole NH), 11.76 (br s, 1H, CONH), 12.40 (br s, 2H, imidazole
NH) ppm; 13C NMR (100 MHz, DMSO‐d6): δ 23.2 (CH3–C), 45.4 (CH2–C),
149.3 (C‐2 and C‐2ʹ), 157.2 (C‐1″), 164.2 (CONH), 167.9 (CH2CONH),
105.3, 107.6, 118.3, 119.5, 121.2, 123.7, 125.4, 127.0, 128.7, 131.3,
134.1, 136.4, 138.9, 140.5, 143.1 (aromatic carbons and C4, C5, C4ʹ, C5ʹ,
C3″, C4″, C5″) ppm. HRMS (m/z): 602.0213 [M+Na]+; anal. calcd. for
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(NH), 1673 (C═O), 1643 (C═C), 1594 (C═N), 1347–1145 (SO2) (cm−1);
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6.98 (s, 1H, C3″–H), 7.35–8.10 (m, 10H, Ar–H and C5ʹ–H), 8.24 (br s, 1H,
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(100 MHz, DMSO‐d6): δ 46.5 (CH2–C), 151.8 (C‐2 and C‐2ʹ), 158.4 (C‐1″),
166.5 (CONH), 169.8 (CH2CONH), 107.2, 109.5, 119.0, 121.4, 122.6,
125.8, 127.7, 129.1, 132.3, 135.6, 137.2, 138.5, 139.1, 141.6, 144.3
(aromatic carbons, C4, C5, C4ʹ, C5ʹ, C3″, C4″, and C5″) ppm. HRMS (m/z):
622.4374 [M+Na]+; anal. calcd. for C25H20Cl2N8O4S: C, 50.09; H, 3.36; N,
18.69; found: C, 50.00; H, 3.32; N, 18.79%.
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4.2
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in the sup-
porting information tab for this article.
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