Synthesis, characterization, docking study and antimicrobial activity of 2-(4-benzoylphenoxy)-1-[2-(1-methyl-1H-indol-3-yl)methyl)-1H-benzo[d]imidazol-1-yl] ethanone derivatives

Article abstract of DOI:10.1007/s13738-021-02230-y

The occurrence of drug-resistant bacterial infections impulses the development of new antibacterial agents that own a mechanism of action different from traditional antibiotics. From the earlier days, benzophenone, indole and benzimidazole moieties alone

Full text of DOI:10.1007/s13738-021-02230-y

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-021-02230-y
ORIGINAL PAPER
Synthesis, characterization, docking study and antimicrobial
activity of 2‑(4‑benzoylphenoxy)‑1‑[2‑(1‑methyl‑1H‑indol‑3‑yl)
methyl)‑1H‑benzo[d]imidazol‑1‑yl] ethanone derivatives
T. Prashanth1,2 · V. Lakshmi Ranganatha3 · Ramith Ramu4 · Subhankar P. Mandal5 · C. Mallikarjunaswamy6 ·
Shaukath Ara Khanum1
Received: 9 September 2020 / Accepted: 26 February 2021
© Iranian Chemical Society 2021
Abstract
The occurrence of drug-resistant bacterial infections impulses the development of new antibacterial agents that own a
mechanism of action diferent from traditional antibiotics. From the earlier days, benzophenone, indole and benzimidazole
moieties alone are one of the most important frameworks in the discovery of innovative drugs. In this present study, we have
described a detailed synthesis and structural elucidation of new benzimidazole bridged benzophenone substituted indole
scafolds 11a–k. Further, all the newly synthesized compounds were tested for in vitro antimicrobial activity by disk difusion
and serial dilution method and the compounds 11b, 11e, 11f and 11h were revealed as potent compounds among the tested
strains in the series11a–k. Further, compounds 11b, 11e, 11f and 11h were subjected for in silico studies and FtsZ has been
recognized as a key functional protein in bacterial cell division and it is currently considered to be a potential target for the
growth of novel antibacterial agents. In continuation, the results obtained from docking studies were in accordance with in
vitro results and compounds 11b, 11e, 11f and 11h emerged as potent molecules in the series 11a–k.
Introduction
Antibiotics are of our most important weapons in fghting
bacterial infections and have greatly benefted the health-
related quality of human life since their introduction [1].
Conversely, over the past few decades, these health ben-
efts are at risk as many commonly used antibiotics have
become less and less efective against certain diseases not
only because many of them produce toxic reactions but also
due to the emergence of drug resistant bacteria. In this view,
it is highly essential to investigate newer drugs, with lesser
resistance [2]. Over the past several years, the emergence
of organisms resistant to nearly all the class of antimicro-
bial agents has become a serious public health concern [3].
Normally, bacteria have the genetic ability to transmit and
attain resistance to drugs, which are utilized as therapeutic
agents[4]. In the past two decades, there has been a signif-
cant increase in the frequency of systematic fungal infec-
tion in man. The frst orally active antifungal agent that was
efective against a broad array of systematic and superfcial
fungal infections was ketoconazole [5]. Further, a number
of azole antifungal agents, viz. itraconazole, fuconazole
[6], voriconazole [7], ravuconazole [8] and glucan synthesis
inhibitor caspofungin [9], have been introduced to the clinic.
* Shaukath Ara Khanum
shaukathara@yahoo.co.in
1
Department of Chemistry, Yuvaraja’s College
(Autonomous), University of Mysore, Mysuru 570005,
Karnataka, India
2
Department of Chemistry, Vidya Vikas Institute
of Engineering and Technology, Bannur Road,
Mysore 570028, Karnataka, India
3
4
Department of Chemistry, The National Institute
of Engineering, Manandavadi Road, Mysore 57008,
Karnataka, India
Division of Biotechnology and Bioinformatics, Department
of Water and Health Sciences, Faculty of Life Sciences, JSS
Academy of Higher Education and Research (JSS AHER),
Mysuru, Karnataka, India
5
6
Department of Pharmaceutical Chemistry, JSS College
of Pharmacy, JSS Academy of Higher Education
and Research, Mysuru 570 015, Karnataka, India
PG Department of Chemistry, JSS College of Arts,
Commerce and Science, Ooty Road, Mysore 570025,
Karnataka, India
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
In addition, benzophenone derivatives are having good phar-
macological properties [10]. For instance, during the past
years, extensive evidence has been accumulated to establish
the efciency of benzophenone analogs as an antimicrobial
agent [11, 12]. Furthermore, benzophenone analogs (gar-
cinol) have been isolated from the stem bark of Garcinia
huillensis grown in Zaire and used in central-African tradi-
tional medicine and this has been shown to exhibit chemo-
therapeutic activity against gram-positive and gram-negative
cocci, mycobacteria and fungi. Recently, Selviet al. have
reported antifungal activity of benzophenone analogs, at its
lower concentration and the results displayed that chloro-
substituted benzophenones have exhibited more antifungal
activity [13].
constriction during division and biosynthesis of peptidogly-
can, this protein complex is gaining focus for the develop-
ment of antibiotics. The flamentous temperature-sensitive
protein Z (FtsZ) is one such target protein with proven ef-
cacy. Several studies have validated the inhibition of this
protein as a platform for the development of broad spectrum-
antibiotics [45–47]. Despite its potential, small molecules
with inhibitory potential against this protein are lacking in
clinical trials, thereby opening newer avenues for research on
molecular scafolds with inhibitiory potential against FtsZ.
With this background (potential of benzimidazole
nucleus) and in continuation of our previous work [48–53],
it was thought that it would be worthwhile to design and syn-
thesize some new benzimidazole derivatives bearing indole
and benzophenone moieties and screen them for potential
antimicrobial agents.
Besides, metrafenone, a novel benzophenone-derived fun-
gicide, recently registered in several countries for control
of powdery mildews in diferent crops [14] and eyespot in
cereals.
Subsequently, benzimidazoles are outstandingly success-
ful compounds, with respect to their both inhibitory activity
and encouraging selectivity ratio. The broad biochemical
and pharmacological studies have verifed that benzimi-
dazole molecules are efective against various strains of
microorganisms [15–21]. Benzimidazoles are considered a
capable class of bioactive heterocyclic compounds with a
wide range of biological activities. Specifcally, this nucleus
is a constituent of vitamin-B12 [22]. This ring system is pre-
sent in numerous antioxidant [23–25], antiparasitic [26, 27],
antihelmintics [28], antiproliferative [29], anti-HIV [30],
anticonvulsant [31], anti-infammatory [32–35], antihyper-
tensive [36], antineoplastic [37, 38] and antitrichinellosis
analogs. Based on the immense signifcance and diverse
bioactivities exhibited by benzimidazoles, eforts have been
made from time to time to create libraries of these com-
pounds and screened them for potential biological activities.
Further, indole derivatives are an important class of het-
erocyclic compounds with a wide range of biological activi-
ties [39]. Indole is a substructural element of many natural
products and is widely used as a scafold in agricultural and
medicinal chemistry. For example, indole-3-acetic acid is a
key plant growth hormone [40] and tryptophan, an essential
amino acid, participates in many essential biological pro-
cesses [41]. Indomethacin is a nonsteroidal anti-infamma-
tory drug [42]. Sumatriptan, frovatriptan and zolmitriptan
are used to treat acute migraine attacks and headaches [43].
Besides, the indole alkaloid reserpine is an antipsychotic and
antihypertensive drug that has been used for the manage-
ment of high blood pressure and for the relief of psychotic
symptoms [44].
Experimental Section
All reagents were of commercial quality and were purifed
before use, and some of the starting materials were synthe-
sized according to standard procedure. The organic solvents
were of analytical grade and purifed by standard procedure.
The chemicals used for the synthesis of intermediates and
end products were purchased from Sigma-Aldrich, Merck,
Ranbaxy, Spectrochem and SD fne chemicals. Analytical
thin layer chromatography (TLC) was performed on Merck
pre-coated silica gel-G F254 aluminum plates. Visualization
of the spots on TLC plates was achieved by either exposure
to iodine vapor or UV light. The completion of the reac-
tion was checked by using TLC plates, varying the solvent
proportions and by the multiple irrigations. All evapora-
tion of solvents was carried out under reduced pressure on
IKA rotary evaporator. Melting points were determined on
a Thomas Hoover capillary melting point apparatus with
a digital thermometer. IR spectra were recorded on FTIR
Shimadzu 8300 spectrophotometer using nujol mull or
potassium bromide water. NMR spectra were recorded on a
Bruker 400 MHz (1H NMR) and 100 MHz (13C NMR) spec-
trophotometer, respectively, in deuterated dimethyl sulfoxide
(DMSO-d6), deuterated chloroform, and the chemical shifts
were recorded in parts per million down feld from tetra-
methylsilane. Mass spectra were obtained with a VG70-70H
mass spectrometer, and important fragments are given with
the relative intensities in the brackets. Microanalyses were
performed by the Regional Sophisticated Instrumentation
Centre, C.D.R.I, Lucknow, and the results are within 0.5%
of the calculated value.
Progress in the discovery of antimicrobial agents has
led to the identifcation of an array of compounds targeting
the bacterial divisiome. Comprising of a series of highly
conserved proteins responsible for cell division, membrane
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Journal of the Iranian Chemical Society
to give compound 10. Finally, substituted (4-benzoyl-
phenoxy)-acetic acids (6a–k)and2-((1-methyl-1H-indol-
3-yl)methyl)-1H-benzo[d]imidazole (10) were treated
with thionyl chloride in the presence of triethyl amine
and 1,4-dioxane as solvent and the reaction mixture was
refuxed to deliver the expected fnal products 11a–k in a
good yield.
Chemistry: plan of the synthesis
Synthesis of the title compounds 10a–k was accomplished
by a synthetic procedure as shown in Scheme 1. The ben-
zoylated products 3a–k were synthesized by the benzo-
ylation of substituted phenols 1a–b under low tempera-
ture, and these on Fries rearrangement using anhydrous
aluminum chloride as a catalyst under neat condition
gave hydroxy benzophenones 4a–k. Compounds 4a–k on
etherifcation with ethyl chloroacetate using dry acetone
as a solvent gave substituted ethyl esters 5a–k, and com-
pounds 5a–k on refuxing with aqueous sodium hydroxide
in ethanol gave (4-benzoyl-phenoxy)-acetic acids 6a–k.
Further, N-(2-aminophenyl)-2-(1-methyl-1H-indol-3-yl)
acetamide (9) was obtained by the reaction of 2-(1-methyl-
1H-indol-3-yl)acetic acid (7) and 1,2-diaminobenzene (8)
in the presence of lutidine as a base and dichloromethane
as a solvent to give the compound 9. Then this compound
9 on refuxing with neat acetic acid undergoes cyclization
Detailed synthetic procedures
Procedure for the synthesis of phenyl benzoates
(3a–k)
Benzoic acid-2-bromo phenyl ester (3a) was synthesized by
benzoylation of 2-bromo phenol (1a) with benzoyl chloride
(2a, 1:1) using 10% sodium hydroxide solution. The reac-
tion mass was stirred for 2–3 h at 0 °C. The reaction was
monitored by TLC using 4:1 n-hexane/ethyl acetate solvent
mixture. After completion of the reaction, the oily product
R4
Scheme 1 Synthesis of
R4
ii
R3
R4
R3
R4
R3
2-(4-benzoylphenoxy)-1-(2-((1-
COCl
OH
O
O
O
methyl-1H-indol-3-yl)methyl)-1
H-benzo[d]imidazol-1-yl)
R3
R1
R2
+
i
iii
R3
iv
ethanone derivatives (11a-k)
O
O
R1
R4
2a-f
1a-b
R2
R2
R1
R2
R1
O
R2
R1
OH
4a-k
O
O
O
O
3a-k
OH
a: R1=Br, R2=H a: R3=R4=H
b: R1=R2=CH3
b: R3=H, R4=CH3
c: R3=Cl, R4=H
d: R3=H, R4=Br
e: R3=H, R4=F
5a-k
6a-k
f: R3=H, R4=OCH3
OH
HN
H2N
H2N
N
O
NH2
v
vi
O
+
1
HN
N
2
N
H3C
2
10
CH3
N
8
7
1
CH3
9
R4
R3
O
N
O
N
N
O
R2
vii
2
HN
+
N
H3C
1
R1
N
H3C
R2
R1
R4
O
O
10
O
R3
OH
11 a-k
6a-k
a: R1=Br, R2=R3=R4=H
g: R 1=R2=R4=CH3, R3=H
b: R1=Br, R2=R3=H, R4=CH3
c: R1=Br, R2=R4=H, R3=Cl
d: R1=R4=Br, R2=R3=H
h: R1=R2=CH3, R3=Cl, R4=H
i: R 1=R2=CH3, R3=H, R4=Br
j: R 1=R2=CH3, R3=H, R4=F
k: R1=R2=CH3, R3=H, R4=OCH3
e: R1=Br, R2=R3=H, R4=F
f: R1=R2=CH3, R3=R4=H
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Journal of the Iranian Chemical Society
was extracted with ether layer (3×30 mL). Ether layer was
washed with 10% sodium hydroxide solution (3× 50 mL)
followed by water (3×30 mL) and then dried over anhydrous
sodium sulfate and evaporated the solvent under pressure to
aford a desired compound (3a). Compounds (3b–k) were
synthesized analogously starting with compounds (1a–b)
and (2b–f).
2,6-Dimethylphenyl-4-bromobenzoate (3i): Yield 90%.
IR (neat): 1722 cm−1 (C=O). 1H NMR (DMSO-d6):δ 2.26
(s, 6H, 2CH3), 6.7–7.7 (m, 7H, Ar–H). LC–MS m/z 305.01
(M + 1), 307.01 (M + 2). Anal. calcd. for C15H13BrO2: C,
59.04; H, 4.29. Found: C, 59.07; H, 4.25%.
2,6-Dimethylphenyl-4-fuorobenzoate (3j): Pale brown
1
solid, yield 85%. IR (neat): 1715 cm−1 (C=O). H NMR
Reagents and reaction conditions: (i) Aq. NaOH, stirring
0–5 °C for 2–3 h, (ii) Anhy. AlCl3, neat 150–170 °C for
2–3 h, (iii) ClCH2COOC2H5/K2CO3/dry acetone, refux, for
8–14 h, (iv) Aq. NaOH/ethanol, refux, for 5–8 h, (v) TBTU/
Lutidine, dry DCM, cold stirring, (vi) acetic acid, refux,
(vii) thionyl chloride, 1,4-dioxane, triethyl amine, refux.
2-Bromophenyl benzoate (3a): Yield 90%. Colorless vis-
cous liquid, IR (neat): 1715 cm−1 (C=O). 1H NMR (DMSO-
d6):δ 7.3–7.8 (m, 9H, Ar–H). LC–MS m/z 276.98 (M+1),
278.98 (M+2). Anal. calcd. for C13H9 BrO2: C, 56.34; H,
3.27. Found: C, 56.37; H, 3.24%.
(DMSO-d6):δ 2.28 (s, 6H, 2CH3), 6.9–7.6 (m, 7H, Ar–H).
LC–MS m/z 245.09 (M+1). Anal. calcd. for C15H13FO2: C,
73.76; H, 5.36. Found: C, 73.78; H, 5.37%.
2,6-Dimethylphenyl-4-methoxybenzoate (3 k): White
1
solid, yield 90%. IR (neat): 1718 cm−1 (C=O). H NMR
(DMSO-d6):δ 2.24 (s, 6H, 2CH3), 3.80 (s, 3H, OCH3),
6.8–7.7 (m, 7H, Ar–H). LC–MS m/z 257.11(M+1). Anal.
calcd. for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.95;
H, 6.26%.
2-Bromophenyl-4-methylbenzoate (3b): Pale yellow
Procedure for the synthesis of 4‑Hydroxy benzophe‑
nones (4a–k)
1
solid, yield 95%. IR (neat): 1720 cm−1 (C=O). H NMR
(DMSO-d6):δ2.30 (s, 3H, CH3), 7.4–7.9 (m, 8H, Ar–H).
LC–MS m/z 290.99 (M+1), 292.99 (M+2). Anal. calcd. for
C14H11BrO2: C, 57.76; H, 3.81. Found: C, 57.72; H, 3.85%.
2-Bromophenyl-2-chlorobenzoate (3c): Pale yellow
Substituted 4-hydroxy-diarylmethanone commonly known
as hydroxy benzophenones (4a–k) was synthesized by Fries
rearrangement. For instance, (3-bromo-4-hydroxyphenyl)
(phenyl)methanone (4a) was obtained by treating com-
pound (3a,0.001 mol) with anhydrous aluminum chloride
(0.002 mol) as a catalyst at 150–170 °C under without sol-
vent condition for about 2–3 h. Then the reaction mixture
was cooled to room temperature and quenched with 6 N HCl
in the presence of ice water. The reaction mixture was stirred
for about 2–3 h, fltered the solid and recrystallized it with
methanol to obtain desired compounds (4a). Compounds
(4b–k) were synthesized analogously starting with (3b–k).
(3-Bromo-4-hydroxyphenyl)(phenyl)methanone (4a): Pale
yellow solid, yield 72%. mp 125–128 °C. IR: (KBr) 1640
1
solid, yield 85%. IR (neat): 1725 cm−1 (C=O). H NMR
(DMSO-d6):δ 7.4–7.9 (m, 8H, Ar–H). LC–MS m/z 310.94
(M + 1), 312.94 (M + 2), 314.94 (M + 4). Anal. calcd. for
C13H8BrClO2: C, 50.12; H, 2.59. Found: C, 50.15; H, 2.55%.
2-Bromophenyl-4-bromobenzoate (3d): Yellow solid,
yield 80%. IR (neat): 1705 cm−1 (C=O). 1H NMR (DMSO-
d6):δ 7.2–7.8 (m, 8H, Ar–H). LC–MS m/z 354.89 (M+1),
356.89 (M+2). Anal. calcd. for C13H8Br2O2: C, 43.86; H,
2.26. Found: C, 43.82; H, 2.29%.
2-Bromophenyl-4-fuorobenzoate (3e): Pale yellow solid,
yield 92%. IR (neat): 1725 cm−1 (C=O). 1H NMR (DMSO-
d6):δ 7.2–7.8 (m, 8H, Ar–H). LC–MS m/z 294.97 (M+1),
296.97 (M+2). Anal. calcd. for C13H8BrFO2: C, 52.91; H,
2.73. Found: C, 52.95; H, 2.75%.
1
(C=O),3510–3600 (O–H) cm−1. H NMR (DMSO-d6):δ
4.50 (bs, 1H, OH) 6.71–7.80 (m, 8H, Ar–H). LC–MS m/z
276.98 (M+1), 278.98 (M+2). Anal. calcd. for C13H9BrO2:
C, 56.18; H, 3.69. Found: C,55.92; H, 3.70%.
2,6-Dimethylphenyl benzoate (3f): White solid, yield
85%. IR (neat): 1730 cm−1 (C=O). 1H NMR (DMSO-d6):δ
2.33 (s, 6H, 2CH3), 6.9–7.6 (m, 8H, Ar–H). LC–MS m/z
227.1 (M+1). Anal. calcd. for C15H14O2: C, 79.62; H, 6.24.
Found: C, 79.65; H, 6.22%.
(3-Bromo-4-hydroxyphenyl)(4-methylphenyl)metha-
none (4b): Pale yellow solid, yield 90%. mp 120–122 °C.
IR: (KBr) 1645 (C=O),3520–3610 (O–H) cm−1. 1H NMR
(DMSO-d6):δ 2.30 (s, 3H, CH3), 4.60 (bs, 1H, OH), 7.4–7.9
(m, 7H, Ar–H). LC–MS m/z 290.99 (M+1), 292.99 (M+2).
Anal. calcd. for C14H11BrO2: C, 57.76; H, 3.81. Found: C,
57.73; H, 3.86%.
2,6-Dimethylphenyl-4-methylbenzoate(3 g): White
1
solid, yield 90%. IR (neat): 1735 cm−1 (C=O). H NMR
(DMSO-d6):δ 2.2 (s, 6H, 2CH3), 2.3 (s, 3H, CH3), 6.8–7.7
(m, 7H, Ar–H). LC–MS m/z 241.12 (M+ 1). Anal. calcd.
for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.95; H, 6.76%.
2,6-Dimethylphenyl-2-chlorobenzoate (3 h): White
(3-Bromo-4-hydroxyphenyl)(2-chlorophenyl)methanone
(4c): White solid, yield 80%. mp 121–122 °C. IR: (KBr)
1
1635 (C=O), 3515–3620 (O–H) cm−1. H NMR (DMSO-
1
solid, yield 95%. IR (neat): 1733 cm−1 (C=O). H NMR
d6):δ 4.55 (bs, 1H, OH), 7.4–7.9 (m, 7H, Ar–H). LC–MS
m/z 310.94 (M+1), 312.94 (M+2), 314.94 (M+4). Anal.
calcd. for C13H8BrClO2: C, 50.12; H, 2.59. Found: C, 50.16;
H, 2.56%.
(DMSO-d6):δ 2.25 (s, 6H, 2CH3), 6.7–7.7 (m, 7H, Ar–H).
LC–MS m/z 261.06 (M+1), 263.06 (M+2). Anal. calcd. for
C15H13ClO2: C, 69.10; H, 5.03. Found: C, 69.15; H, 5.07%.
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Journal of the Iranian Chemical Society
(3-Bromo-4-hydroxyphenyl)(4-bromophenyl)metha-
none (4d): Pale yellow solid, yield 85%. mp 118–120 °C.
IR: (KBr) 1630 (C=O),3505–3605 (O–H) cm−1. 1H NMR
(DMSO-d6):δ 4.45 (bs, 1H, OH), 7.2–7.8 (m, 7H, Ar–H).
LC–MS m/z 354.89 (M+1), 356.89 (M+2), 358.89 (M+4).
Anal. calcd. for C13H8Br2O2: C, 43.86; H, 2.26. Found: C,
43.82; H, 2.29%.
Procedure for the synthesis of (4‑Ben‑
zoyl‑phenoxy)‑acetic acid ethyl esters (5a–k)
(4-Benzoyl-2-bromo-phenoxy)-acetic acid ethyl ester (5a)
was obtained by refluxing a mixture of compound (4a,
0.013 mol), ethyl chloroacetate (0.026 mol) and anhydrous
potassium carbonate (0.019 mol) in dry acetone (50 mL)
for 8–9 h. The reaction mixture was cooled, and solvent
was removed by distillation. The residual mass was tritu-
rated with cold water to remove potassium carbonate and
extracted with ether (3×50 mL). The ether layer was washed
with 10% sodium hydroxide solution (3×50 mL) followed
by water (3×30 mL) and then dried over anhydrous sodium
sulfate and evaporated to dryness to obtain crude solid,
which on recrystallization with ethanol aforded desired
compound (5a).Similarly, compounds (5b–k) were synthe-
sized analogously starting with (4b–k).
(3-Bromo-4-hydroxyphenyl)(4-fluorophenyl)metha-
none (4e): Pale yellow solid, yield 90%. mp 107–110 °C.
IR: (KBr) 1625 (C=O),3530–3615 (O–H) cm−1. 1H NMR
(DMSO-d6):δ 4.35 (bs, 1H, OH), 7.2–7.8 (m, 7H, Ar–H).
LC–MS m/z 294.97 (M+1), 296.97 (M+2). Anal. calcd. for
C13H8BrFO2: C, 52.91; H, 2.73. Found: C, 52.94; H, 2.76%.
(3,5-Dimethyl-4-hydroxyphenyl)(phenyl)methanone
(4f): White solid, yield 88%. mp 113–115 °C. IR: (KBr)
1
1635 (C=O),3540–3630 (O–H) cm−1. H NMR (DMSO-
d6):δ 2.33 (s, 6H, 2CH3), 4.25 (bs, 1H, OH), 6.9–7.6 (m,
7H, Ar–H). LC–MS m/z 227.1 (M + 1). Anal. calcd. for
C15H14O2: C, 79.62; H, 6.24. Found: C, 79.66; H, 6.21%.
(3,5-Dimethyl-4-hydroxyphenyl)(4-methylphenyl)meth-
anone (4g): White solid, yield 92%. mp 115–117 °C. IR:
(4-Benzoyl-2-bromo-phenoxy)-acetic acid ethyl ester
(5a): Pale brown solid, yield 90%. mp 49–52 °C. IR (Nujol):
1664 (C=O), 1760 (ester, C=O) cm−1. 1H NMR (DMSO-
d6): δ 1.2 (t, 3H, CH3 of ester, J=6.6 Hz),4.1 (q, 2H, CH2
of ester, J = 6.6 Hz), 4.9 (s, 2H, OCH2), 6.9–7.7 (m, 8H,
Ar–H). LC–MS m/z 363.02 (M+1), 365.02 (M+2). Anal.
calcd. For C17H15BrO4: C, 56.47; H, 4.04. Found: C, 56.26;
H, 4.12%.
1
(KBr) 1645 (C=O), 3510–3620 (O–H) cm−1. H NMR
(DMSO-d6):δ 2.2 (s, 6H, 2CH3), 2.3 (s, 3H, CH3), 4.44
(bs, 1H, OH), 6.8–7.7 (m, 6H, Ar–H). LC–MS m/z 241.12
(M + 1). Anal. calcd. for C16H16O2: C, 79.97; H, 6.71.
Found: C, 79.96; H, 6.75%.
[4-(4-Methylbenzoyl-2-bromo)phenoxy]acetic acid ethyl
ester (5b): Pale brown solid, yield 95%. mp 45–47 °C. IR
(3,5-Dimethyl-4-hydroxyphenyl)(2-chlorophenyl)meth-
anone (4h): White solid, yield 90%. mp 121–122 °C. IR:
(Nujol): 1666 (C=O), 1765 (ester, C=O) cm−1. H NMR
1
1
(KBr) 1645 (C=O), 3525–3615 (O–H) cm−1. H NMR
(DMSO-d6): δ 1.3 (t, 3H, CH3 of ester, J=6.6 Hz),2.33 (s,
3H, CH3), 4.2 (q, 2H, CH2 of ester, J=6.6 Hz), 4.8 (s, 2H,
OCH2), 6.8–7.8 (m, 7H, Ar–H). LC–MS m/z 377.02 (M+1),
379.02 (M+2). Anal. calcd. For C18H17BrO4: C, 57.31; H,
4.54. Found: C, 57.33; H, 4.56%.
(DMSO-d6):δ 2.25 (s, 6H, 2CH3), 4.39 (bs, 1H, OH), 6.7–7.7
(m, 6H, Ar–H). LC–MS m/z 261.06 (M+1), 263.06 (M+2).
Anal. calcd. for C15H13ClO2: C, 69.10; H, 5.03. Found: C,
68.15; H, 5.06%.
(3,5-Dimethyl-4-hydroxyphenyl)(4-bromophenyl)meth-
anone (4i): White solid, yield 95%. mp 127–128 °C. IR:
[4-(2-Chlorobenzoyl-2-bromo-)phenoxy]acetic acid ethyl
ester (5c): Pale brown solid, yield 85%. mp 51–53 °C. IR
1
(KBr) 1640 (C=O), 3515–3635 (O–H) cm−1. H NMR
(Nujol): 1662 (C=O), 1769 (ester, C=O) cm−1. H NMR
1
(DMSO-d6):δ 2.26 (s, 6H, 2CH3), 4.29 (bs, 1H, OH), 6.7–7.7
(m, 6H, Ar–H). LC–MS m/z 305.01 (M+1), 307.01 (M+2).
Anal. calcd. for C15H13BrO2: C, 59.04; H, 4.29. Found: C,
59.06; H, 4.24%.
(DMSO-d6): δ 1.4 (t, 3H, CH3 of ester, J=6.6 Hz),4.5 (q,
2H, CH2 of ester, J=6.6 Hz), 4.8 (s, 2H, OCH2), 6.8–7.8 (m,
7H, Ar–H). LC–MS m/z 396.98 (M + 1), 398.98 (M + 2),
400.98 (M + 4).Anal. calcd. For C17H14BrClO4: C, 51.35;
H, 3.55. Found: C, 51.37; H, 3.58%.
(3,5-Dimethyl-4-hydroxyphenyl)(4-fuorophenyl)meth-
anone (4j): White solid, yield 88%. mp 120–122 °C. IR:
[4-(4-Bromobenzoyl-2-bromo-)phenoxy]acetic acid ethyl
ester (5d): Pale yellow solid, yield 80%. mp 54–56 °C. IR
1
(KBr) 1605 (C=O), 3545–3630 (O–H) cm−1. H NMR
(Nujol): 1668 (C=O), 1762 (ester, C=O) cm−1. H NMR
1
(DMSO-d6):δ 2.28 (s, 6H, 2CH3), 4.22 (bs, 1H, OH), 6.9–7.6
(m, 6H, Ar–H). LC–MS m/z 245.09 (M+1). Anal. calcd. for
C15H13FO2: C, 73.76; H, 5.36. Found: C, 73.77; H, 5.36%.
(3,5-Dimethyl-4-hydroxyphenyl)(4-methoxyphenyl)
methanone (4 k): White solid, yield 95%. mp 119–121 °C.
IR: (KBr) 1635 (C=O), 3510–3610 (O–H) cm−1. 1H NMR
(DMSO-d6):δ 2.24 (s, 6H, 2CH3), 3.85 (s, 3H, OCH3),
4.32 (bs, 1H, OH), 6.8–7.7 (m, 6H, Ar–H). LC–MS m/z
257.11(M+1). Anal. calcd. for C16H16O3: C, 74.98; H, 6.29.
Found: C, 74.96; H, 6.25%.
(DMSO-d6): δ 1.2 (t, 3H, CH3 of ester, J=6.6 Hz),4.1 (q,
2H, CH2 of ester, J=6.6 Hz), 4.9 (s, 2H, OCH2), 6.6–7.7 (m,
7H, Ar–H). LC–MS m/z 440.93 (M + 1), 442.93 (M + 2),
444.93 (M+4). Anal. calcd. For C17H14Br2O4: C, 46.18; H,
3.19. Found: C, 46.19; H, 3.17%.
[4-(4-Fluorobenzoyl-2-bromo)phenoxy]acetic acid
ethyl ester (5e): Pale brown solid, yield 82%. mp
50–52 °C. IR (Nujol): 1662 (C=O), 1770 (ester, C=O)
1
cm−1. H NMR (DMSO-d6): δ 1.3 (t, 3H, CH3 of ester,
1 3

Journal of the Iranian Chemical Society
J = 6.6 Hz),4.1 (q, 2H, CH2 of ester, J = 6.6 Hz), 4.8 (s,
2H, OCH2), 7.1–7.8 (m, 7H, Ar–H). LC–MS m/z 381.02
(M+1), 383.02 (M+2). Anal. calcd. For C17H14BrFO4: C,
53.56; H, 3.70. Found: C, 53.58; H, 3.75%.
Procedure for the synthesis of (4‑Ben‑
zoyl‑phenoxy)‑acetic acids (6a–k):
(4-Benzoyl-2-bromo-phenoxy)-acetic acid (6a) was synthe-
sized from a compound (5a, 6.0 mmol) in ethanol (15 mL)
and treated with 15 mmol of sodium hydroxide solution. The
reaction mixture was refuxed for 5–6 h, cooled and acidi-
fed with 1 N hydrochloric acid. The precipitate was fltered,
washed with water and fnally recrystallized from methanol
to aford desired compounds (6a) with good yield. Com-
pounds (6b–k) were synthesized analogously from (5b–k).
The characterization data of the compounds (6a–k) are given
below. The compounds 3a–k to 6a–k were synthesized from
the reported procedure [49].
(4-Benzoyl-2,6-dimethylphenoxy) acetic acid ethyl
ester (5f): Pale yellow solid, yield 88%. mp 55–57 °C. IR
1
(Nujol): 1665 (C=O), 1775 (ester, C=O) cm−1. H NMR
(DMSO-d6): δ 1.4 (t, 3H, CH3 of ester, J = 6.6 Hz), 2.34
(s, 6H, 2CH3), 4.2 (q, 2H, CH2 of ester, J= 6.6 Hz), 4.7 (s,
2H, OCH2), 6.9–7.8 (m, 7H, Ar–H). LC–MS m/z 313.14
(M + 1). Anal. calcd. For C19H20O4: C, 73.06; H, 6.45.
Found: C, 73.09; H, 6.42%.
[4-(4-Methylbenzoyl-2,6-dimethyl)phenoxy]acetic
acid ethyl ester (5g): Pale brown solid, yield 88%. mp
54–56 °C. IR (Nujol): 1666 (C=O), 1779 (ester, C=O)
(4-Benzoyl-2-bromo-phenoxy)-acetic acid (6a): White
solid, yield 75%. mp 130–132 °C. FT-IR (KBr): 1675
1
cm−1. H NMR (DMSO-d6): δ 1.5 (t, 3H, CH3 of ester,
(C=O), 1730 (acid C=O), 3400–3500 (acid O–H) cm−1
.
J=6.6 Hz), 2.3 (s, 6H, 2CH3), 2.4 (s, 3H, CH3), 4.5 (q, 2H,
CH2 of ester, J = 6.6 Hz), 4.9 (s, 2H, OCH2), 6.8–7.7 (m,
6H, Ar–H). LC–MS m/z 327.15 (M + 1). Anal. calcd. For
C20H22O4: C, 73.60; H, 6.79. Found: C, 73.64; H, 6.77%.
[4-(2-Chlorobenzoyl)-2,6-dimethylphenoxy]acetic
acid ethyl ester (5h): Pale brown solid, yield 95%. mp
57–60 °C. IR (Nujol): 1665 (C=O), 1775 (ester, C=O)
1H NMR (DMSO-d6): δ 4.86 (s, 2H, OCH2), 6.9–7.7 (m,
8H, Ar–H), 9.0 (s, 1H, COOH). LC–MS m/z 334.9 (M+1),
336.9 (M + 2). Anal. calcd. for C15H11BrO4: C, 53.71; H,
3.30. Found: C, 53.68; H, 3.34%.
[4-(4-Methyl-benzoyl-2-bromo-phenoxy)]-acetic acid
(6b): White solid, yield 70%. mp 125–128 °C. FT-IR (KBr):
1670 (C=O), 1735 (acid C=O), 3410–3510 (acid O–H)
1
cm−1. H NMR (DMSO-d6): δ 1.6 (t, 3H, CH3 of ester,
1
cm−1. H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 4.86 (s,
J = 6.6 Hz), 2.31 (s, 6H, 2CH3), 4.6 (q, 2H, CH2 of ester,
J = 6.6 Hz), 4.9 (s, 2H, OCH2), 6.9–7.9 (m, 6H, Ar–H).
LC–MS m/z 347.10 (M + 1), 349.10 (M + 2). Anal. calcd.
For C19H19ClO4: C, 65.80; H, 5.52. Found: C, 65.84; H,
5.55%.
2H, OCH2), 6.8–7.7 (m, 7H, Ar–H), 9.5 (s, 1H, COOH).
LC–MS m/z 349 (M + 1) 351 (M + 2). Anal. calcd. for
C16H13BrO4: C, 55.71; H, 3.30. Found: C, 55.68; H, 3.35%.
[4-(2-Chloro-benzoyl-2-bromo-phenoxy)]-acetic acid
(6c): White solid, yield 73%. mp 160–162 °C. FT-IR (KBr):
1665 (C=O), 1725 (acid C=O), 3405–3550 (acid O–H)
cm−1. 1H NMR (DMSO-d6): δ 4.86 (s, 2H, OCH2), 6.7–7.7
(m, 7H, Ar–H), 9.2 (s, 1H, COOH). LC–MS m/z 368.95
(M + 1), 370.90 (M + 2), 372.90. A (M + 4). Anal. calcd.
for C15H10BrClO4: C, 48.71; H, 2.30. Found: C, 48.68; H,
2.34%.
[4-(4-Bromobenzoyl)-2,6-dimethylphenoxy]acetic acid
ethyl ester (5i): Pale brown solid, yield 80%. mp 52–54 °C.
IR (Nujol): 1650 (C=O), 1768 (ester, C=O) cm−1. 1H NMR
(DMSO-d6): δ 1.2 (t, 3H, CH3 of ester, J=6.6 Hz), 2.31 (s,
6H, 2CH3), 4.2 (q, 2H, CH2 of ester, J=6.6 Hz), 4.9 (s, 2H,
OCH2), 7.1–7.7 (m, 6H, Ar–H). LC–MS m/z 391.05 (M+1),
393.05 (M+2). Anal. calcd. For C19H19BrO4: C, 58.33; H,
4.89. Found: C, 58.38; H, 4.86%.
[4-(4-Bromo-benzoyl-2-bromo-phenoxy)]-acetic acid
(6d): White solid, yield 78%. mp 178–180 °C. FT-IR (KBr):
1660 (C=O), 1720 (acid C=O), 3415–3520 (acid O–H)cm−1.
1H NMR (DMSO-d6): δ 4.86 (s, 2H, OCH2), 6.7–7.8 (m,
7H, Ar–H), 9.3 (s, 1H, COOH). LC–MS m/z 412.9 (M+1),
414.9 (M+2), 416.9 (M+4). Anal. calcd. for C15H10Br2O4:
C, 43.71; H, 2.30. Found: C, 43.68; H, 2.35%.
[4-(4-Fluorobenzoyl)-2,6-dimethylphenoxy]acetic acid
ethyl ester (5j): Pale brown solid, yield 82%. mp 58–59 °C.
IR (Nujol): 1656 (C=O), 1778 (ester, C=O) cm−1. 1H NMR
(DMSO-d6): δ 1.25 (t, 3H, CH3 of ester, J=6.6 Hz), 2.36 (s,
6H, 2CH3), 4.25 (q, 2H, CH2 of ester, J=6.6 Hz), 4.8 (s, 2H,
OCH2), 7.1–7.7 (m, 6H, Ar–H). LC–MS m/z 331.13 (M+1).
Anal. calcd. For C19H19FO4: C, 69.08; H, 5.80. Found: C,
69.05; H, 5.85%.
[4-(4-Fluoro-benzoyl-2-bromo-phenoxy)]-acetic acid
(6e): White solid, yield 75%. mp 210–212 °C. FT-IR (KBr):
1665 (C=O), 1735 (acid C=O), 3450–3560 (acid O–H)cm−1.
1H NMR (DMSO-d6): δ 4.88 (s, 2H, OCH2), 6.9–7.7 (m, 7H,
Ar–H), 9.1 (s, 1H, COOH). LC–MS m/z 353 (M+1), 355
(M+2). Anal. calcd. for C15H10BrFO4: C, 51.71; H, 2.85.
Found: C, 51.68; H, 2.56%.
[4-(4-Methoxybenzoyl)-2,6-dimethylphenoxy]acetic acid
ethyl ester (5k): Pale brown solid, yield 87%. mp 45–48 °C.
IR (Nujol): 1645 (C=O), 1765 (ester, C=O) cm−1. 1H NMR
(DMSO-d6): δ 1.30 (t, 3H, CH3 of ester, J=6.6 Hz), 2.35
(s, 6H, 2CH3), 3.71 (s, 3H, OCH3), 4.2 (q, 2H, CH2 of ester,
J = 6.6 Hz), 4.8 (s, 2H, OCH2), 7.0–7.8 (m, 6H, Ar–H).
LC–MS m/z 343.15 (M+1). Anal. calcd. For C20H22O5: C,
70.16; H, 6.48. Found: C, 70.18; H, 6.45%.
[4-(Benzoyl-2,6-dimethyl-phenoxy)]-acetic acid (6f):
White solid, yield 80%. mp 121–125 °C. FT-IR (KBr): 1670
(C=O), 1735 (acid C=O), 3410–3550 (acid O–H)cm−1. 1H
1 3

Journal of the Iranian Chemical Society
NMR (DMSO-d6): δ 2.34 (s, 6H, 2CH3), 4.9 (s, 2H, OCH2),
7.2–7.7 (m, 7H, Ar–H), 9.5 (s, 1H, COOH). LC–MS m/z
285.2 (M+1). Anal. calcd. for C17H16O4: C, 71.71; H, 5.30.
Found: C, 71.68; H, 5.34%.
monitored by TLC using chloroform/methanol (9:1). The
reaction mixture was diluted with 20 mL of dichlorometh-
ane and treated with 1.5 N hydrochloric acid (20 mL). The
organic layer was washed with water (3×25 mL), dried over
anhydrous sodium sulfate, concentrated to a syrupy liquid
and recrystallized twice from diethyl ether to aford com-
pound 9.
[4-(4-Methylbenzoyl-2,6-dimethyl-phenoxy)]-acetic acid
(6g): White solid, yield 85%. mp 178–180 °C. FT-IR (KBr):
1660 (C=O), 1740 (acid C=O), 3420–3560 (acid O–H)
1
cm−1. H NMR (DMSO-d6): δ 2.2 (s, 6H, 2CH3), 2.3 (s,
N-(2-Aminophenyl)-2-(1-methyl-1H-indol-3-yl)aceta-
mide (9): White solid, yield 80%. mp 180–182 °C. FT-IR
(KBr,): 1690 (amide C=O), 3120–3335 (NH & NH2)cm−1.
1H NMR (DMSO-d6): δ3.60 (s, 3H, N–CH3), 3.69 (s, 2H,
CH2), 4.59 (s, 2H, NH2), 6.3 (s, 1H, 2nd position indole ring
H), 6.80–7.75 (m, 8H, Ar–H), 9.80 (s, 1H, NH). LC–MS
m/z 280.1 (M+1). Anal. calcd. for C17H17N3O: C, 73.10; H,
6.13; N, 15.04. Found: C, 73.15; H, 6.15; N, 15.08%.
3H, CH3), 4.9 (s, 2H, OCH2), 7.2–7.6 (m, 6H, Ar–H), 9.2
(s, 1H, COOH). LC–MS m/z 299 (M+1). Anal. calcd. for
C18H18O4: C, 72.71; H, 6.30. Found: C, 72.68; H, 6.33%.
[4-(2-Chlorobenzoyl-2,6-dimethyl-phenoxy)]-acetic
acid (6h): White solid, yield 88%. mp 165–169 °C. FT-IR
(KBr): 1660 (C=O), 1735 (acid C=O), 3460–3550 (acid
1
O–H)cm−1. H NMR (DMSO-d6): δ 2.34 (s, 6H, 2CH3),
4.8 (s, 2H, OCH2),, 7.25–7.65 (m, 6H, Ar–H), 9.3 (s, 1H,
COOH). LC–MS m/z 319.75 (M+1), 321. 75 (M+2). Anal.
calcd. for C17H15ClO4: C, 64.06; H, 4.74. Found: C, 64.08;
H, 4.71%.
Procedure for the synthesis of 2‑((1‑methyl‑1H‑in‑
dol‑3‑yl)methyl)‑1H‑benzo[d]imidazole (10):
[4-(4-Bromobenzoyl-2,6-dimethyl-phenoxy)]-acetic acid
(6i): White solid, yield 74%. mp 140–145 °C. FT-IR (KBr):
1655 (C=O), 1715 (acid C=O), 3450–3510 (acid O–H)
cm−1. 1H NMR (DMSO-d6): δ 2.34 (s, 6H, 2CH3), 4.86 (s,
2H, OCH2), 7.1–7.6 (m, 6H, Ar–H), 9.2 (s, 1H, COOH).
LC–MS m/z 363.1 (M+1), 365.1 (M+2). Anal. calcd. for
C17H15BrO4: C, 56.71; H, 4.30. Found: C, 56.68; H, 4.34%.
[4-(4-Fluorobenzoyl-2,6-dimethyl-phenoxy)]-acetic acid
(6j): White solid, yield 69%. mp 218–220 °C. FT-IR (KBr):
1660 (C=O), 1725 (acid C=O), 3470–3560 (acid O–H)
cm−1. 1H NMR (DMSO-d6): δ 2.34 (s, 6H, 2CH3), 4.85 (s,
2H, OCH2), 7.0–7.6 (m, 6H, Ar–H), 9.4 (s, 1H, COOH).
LC–MS m/z 303.1 (M+1). Anal. calcd. for C17H15FO4: C,
67.54; H, 5.00. Found: C, 67.68; H, 5.14%.
Compound 10 was synthesized via cyclization of compound
9 (0.001 mol) using acetic acid as the cyclizing agent under
refuxing conditions for 5–6 h. The reaction was monitored
by TLC using n-hexane/dichloromethane/acetone (5:3:2).
After completion of the reaction, the reaction mixture was
cooled to room temperature, poured into crushed ice and
neutralized with a 10% sodium bicarbonate solution. After
fltration, the solid was recrystallized from acetonitrile.
2-[(1-Methyl-1H-indol-3-yl)methyl]-1H-benzo[d]imida-
zole (10): White solid, yield 70%. mp 195–198 °C. FT-IR
(KBr): 1650 (C=N), 3130–3210 (N–H) cm−1.1H NMR
(DMSO-d6): δ 3.60 (s, 3H, N–CH3), 3.70 (s, 2H, CH2), 6.25
(s, 1H, 2nd position indole ring H), 6.7–7.71 (m, 8H, Ar–H),
9.81 (s, 1H, NH). LC–MS m/z 262.1 (M+1). Anal. calcd.
for C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C, 78.15;
H, 5.75; N, 16.05%.
[4-(4-Methoxybenzoyl-2,6-dimethyl-phenoxy)]-acetic
acid (6k): White solid, yield 75%. mp 201–204 °C. FT-IR
(KBr): 1670 (C=O), 1730 (acid C=O), 3420–3515 (acid
O–H)cm−1. 1H NMR (DMSO-d6): δ 2.34 (s, 6H, 2CH3), 3.72
(s, 3H, OCH3), 4.86 (s, 2H, OCH2), 6.7–7.7 (m, 6H, Ar–H),
9.2 (s, 1H, COOH). LC–MS m/z 315.1 (M+1). Anal. calcd.
for C18H18O5: C, 68.71; H, 5.30. Found: C, 68.61; H, 5.35%.
Procedure for the synthesis of 2‑(4‑benzoylphenox
y)‑1‑[2‑((1‑methyl‑1H‑indol‑3‑yl)methyl)‑1H‑benzo
[d]imidazol‑1‑yl]ethanones(11a‑k)
2-(4-Benzoyl-2-bromo-phenoxy)-1-(2-((1-methyl-1H-
indol-3-yl)methyl)-1H-benzoimidazol-1-ylethanone
(11a) was synthesized by the reaction of compound (10,
0.001 mol) with 2-(4-benzoyl-2-bromo-phenoxy) acetic
acid (6a, 0.001 mol)in 1,4-dioxane and then thionyl chlo-
ride (0.002 mol) and triethyl amine (15 mL) were added.
The reaction mixture was refuxed for 5 h, and the comple-
tion of the reaction was monitored by TLC using n-hexane/
dichloromethane/acetone (5:3:2). After completion of the
reaction, the mixture was quenched with ice cold water and
washed with distilled water and dried. Obtained solid was
further purifed by recrystallization by using methanol to
achievecompound 11a in a pure state.
Procedure for the synthesis of N‑(2‑aminophenyl)‑2‑
(1‑methyl‑1H‑indol‑3‑yl)acetamide (9):
To 2-(1-methyl-1H-indol-3-yl)acetic acid (7, 0.0037 mol) in
dry dichloromethane (15 mL), lutidine (1.2 vol.) was added
at 25–30 °C, followed by the addition of 1,2-diaminoben-
zene (8, 0.0037 mol) and the reaction mixture was stirred at
25–30 °C for 30 min. Then the reaction mixture was cooled
to 0–5 °C, and o-(benzotriazol-1-yl)- N,N,N’,N’-tetrame-
thyl aminium tetrafuoroborate (TBTU) (0.0037 mol) was
added over a period of 30 min while maintaining the tem-
perature below 5 °C. The reaction was stirred overnight and
1 3

Journal of the Iranian Chemical Society
2-(4-Benzoyl-2-bromo-phenoxy)-1-[2-(1-methyl-1H-in-
dol-3-yl)methyl-1H-benzo [d]imidazol-1-yl]ethanone (11a):
White solid, yield 85%. mp 230–232 °C. FT-IR (KBr):
1675 (C=O),1680 (C=N), 1730 (N–C=O) cm−1. 1H NMR
(DMSO-d6): δ 3.60 (s, 3H, N–CH3), δ 3.69 (s, 2H, CH2),
5.05 (s, 2H, OCH2), 6.35 (s, 1H, 2nd position indole ring
H), 6.9–7.71 (m, 16H, Ar–H). 13C NMR (DMSO-d6):δ 31.3,
38.0, 73.1, 101.4, 111.9, 115.3, 116.2, 118.1, 123.0, 124.1,
126.9, 128.5, 130.3, 130.8, 132.5, 134.2, 134.8, 138.9,
139.0, 139.7, 140.7, 140.8, 141.5, 142.4, 160.7, 196.3,
200.0. LC–MS m/z 578.46 (M+1), 580.46 (M+2). Anal.
calcd. for C32H24BrN3O3: C, 66.44; H, 4.18; N, 7.26. Found:
C, 66.40; H, 4.15; N, 7.22%.
[2-(4–4-Fluoro-benzoyl-2-bromo-phenoxy)]-1-[2-(1-
methyl-1H-indol-3-yl)methyl)-1H-benzo [d]imidazol-1-yl]
ethanone (11e): White solid, yield 75%. mp 210–212 °C.
FT-IR (KBr): 1660 (C=O),1670 (C=N),1725 (N–C=O)
1
cm−1. H NMR (DMSO-d6): δ 3.45 (s, 3H, N-CH3), 3.60
(s, 2H, CH2), 5.15 (s, 2H, OCH2), 6.4 (s, 1H, 2nd posi-
tion indole ring H), 6.90–7.75 (m, 15H, Ar–H).13C NMR
(DMSO-d6):δ 30.3, 35.0, 75.1, 100.4, 109.9, 114.2, 115.2,
117.7, 119.1, 122.0, 123.1, 125.9, 129.3, 130.1, 130.5,
131.8, 134.5, 134.7, 134.9, 137.3, 138.9, 149.7, 143.5,
161.7, 163.6, 198.3, 201.3. LC–MS m/z 596.1 (M + 1),
598.1 (M + 2). Anal. calcd. for C32H23BrFN3O3: C, 64.44;
H, 3.89; N, 7.05. Found: C, 64.42; H, 3.92; N, 7.10%.
2-(4-Benzoyl-2,6-dimethyl-phenoxy)-1-(2-[(1-methyl-
1H-indol-3-yl)methyl)-1H-benzo [d]imidazol-1-yl]etha-
none (11f): White solid, yield 80%. mp 121–125 °C. FT-IR
[2–4-(4-Methyl-benzoyl-2-bromo-phenoxy)]-1-[2-(1-
methyl-1H-indol-3-yl)methyl-1H-benzo [d]imidazol-1-yl]
ethanone (11b): White solid, yield 70%. mp 175–178 °C.
FT-IR (KBr): 1675 (C=O), 1685 (C=N), 1730 (N–C=O)
(KBr): 1675 (C=O),1675 (C=N),1740 (N–C=O) cm−1
.
1
cm−1. H NMR (DMSO-d6): δ 2.30 (s, 3H, CH3), 3.60 (s,
1H NMR (DMSO-d6): δ 2.30 (s, 6H, 2CH3), 3.67 (s, 3H,
N–CH3), 3.65 (s, 2H, CH2), 5.25 (s, 2H, OCH2), 6.3 (s, 1H,
3H, N–CH3), 3.69 (s, 2H, CH2), 5.05 (s, 2H, OCH2), 6.25 (s,
1H, 2nd position indole ring H), 6.9–7.75 (m, 15H, Ar–H).
13C NMR (DMSO-d6):δ 24.3, 31.5, 36.0, 73.6, 102.4, 112.8,
115.2, 116.7, 119.1, 123.6, 124.8, 126.6, 128.4, 130.8,
131.0, 134.6, 135.2, 136.7, 138.3, 140.4, 141.1, 141.8,
159.4, 159.9, 160.2, 161.0, 195.3, 201.0. LC–MS m/z 592.1
(M+1), 594.1 (M+2). Anal. calcd. for C33H26BrN3O3: C,
66.90; H, 4.42; N, 7.09. Found: C, 66.80; H, 4.45; N, 7.12%.
[2-[4-(2-Chloro-benzoyl]-2-bromo-phenoxy)]-1-[2-(1-
methyl-1H-indol-3-yl)methyl-1H-benzo [d]imidazol-1-yl]
ethanone (11c): White solid, yield 73%. mp 160–162 °C.
FT-IR (KBr): 1665 (C=O),1675 (C=N), 1735 (N–C=O)
2nd position indole ring H), 6.9–7.75 (m, 15H, Ar–H). 13
C
NMR (DMSO-d6):δ 17.7, 32.3, 40.0, 71.4, 98.4, 111.2,
114.7, 120.1, 121.0, 123.1, 125.9, 126.5, 128.3, 129.8,
130.8, 131.5, 135.9, 137.5, 138.7, 139.7, 140.3, 144.5,
161.3, 167.5, 194.3, 204.0. LC–MS m/z 528.2 (M + 1).
Anal. calcd. for C34H29N3O3: C, 77.40; H, 5.54; N, 7.96
Found: C, 77.45; H, 5.59; N, 8.01%.
[2-(4–4-Methylbenzoyl-2,6-dimethyl-phenoxy)]-1-[2-
(1-methyl-1H-indol-3-yl)methyl)-1H-benzo [d]imida-
zol-1-yl]ethanone (11g): White solid, yield 85%. mp
178–180 °C. FT-IR (KBr): 1655 (C=O),1685 (C=N),1725
1
1
cm−1. H NMR (DMSO-d6): δ 3.60 (s, 3H, N-CH3), 3.68
(N–C=O) cm−1. H NMR (DMSO-d6): δ 2.2 (s, 6H,
(s, 2H, CH2), 5.01 (s, 2H, OCH2), 6.3 (s, 1H, 2nd posi-
tion indole ring H), 6.95–7.70 (m, 15H, Ar–H). 13C NMR
(DMSO-d6):δ 32.4, 39.0, 76.1, 102.8, 112.6, 115.4, 116.5,
116.9, 120.1, 123.2, 125.5, 127.8, 128.5, 130.5, 131.5,
132.9, 134.3, 134.8, 135.9, 136.5, 137.5, 139.6, 140.3,
141.1, 142.1, 162.7, 171.2, 196.3, 204.0. LC–MS m/z
612.1 (M + 1), 614.1 (M + 2), 616.1 (M + 4). Anal. calcd.
for C32H23BrClN3O3: C, 66.71; H, 3.72; N, 6.86. Found: C,
66.80; H, 3.80; N, 6.90%.
2CH3),2.3 (s, 3H, CH3),3.50 (s, 3H, N-CH3), 3.69 (s, 2H,
CH2), 5.25 (s, 2H, OCH2), 6.25 (s, 1H, 2nd position indole
ring H), 6.9–7.75 (m, 15H, Ar–H). 13C NMR (DMSO-
d6):δ 16.7, 25.3, 32.3, 39.0, 78.4, 103.4, 111.2, 112.7,
116.1, 120.0, 122.1, 123.9, 126.5, 127.7, 129.9, 130.5,
130.7, 131.5, 131.7, 135.7, 137.9, 139.7, 141.3, 142.3,
165.4, 195.3, 201.8. LC–MS m/z 542.2 (M + 1). Anal.
calcd. for C35H31N3O3: C, 77.61; H, 5.77; N, 7.76. Found:
C, 77.65; H, 5.78; N, 7.74%.
[2-(4–4-Bromo-benzoyl-2-bromo-phenoxy)]-1-[2-(1-me-
thyl-1H-indol-3-yl)methyl)-1H-benzo [d]imidazol-1-yl]etha-
none (11d): White solid, yield 78%. mp 178–180 °C. FT-IR
(KBr): 1670 (C=O), 1685 (C=N),1740 (N–C=O) cm−1. 1H
NMR (DMSO-d6): δ 3.60 (s, 3H, N-CH3), 3.65 (s, 2H, CH2),
5.05 (s, 2H, OCH2), 6.3 (s, 1H, 2nd position indole ring H),
6.85–7.75 (m, 15H, Ar–H).13C NMR (DMSO-d6):δ 32.3,
37.0, 72.1, 103.4, 113.9, 114.2, 115.2, 116.7, 119.1, 121.0,
123.1, 128.9, 139.3, 130.1, 130.3, 131.3, 131.5, 134.1,
134.6, 134.8, 138.7, 139.9, 140.4, 143.5, 163.7, 194.3,
201.5. LC–MS m/z 656.0 (M + 1), 658.0 (M + 2), 660.0
(M+4). Anal. calcd. for C32H23Br2N3O3: C, 58.47; H, 3.53;
N, 6.39. Found: C, 58.45; H, 3.58; N, 6.41%.
[2-(4–2-Chlorobenzoyl-2,6-dimethyl-phenoxy)]-1-[2-
(1-methyl-1H-indol-3-yl)methyl)-1H-benzo [d]imida-
zol-1-yl]ethanone (11h): White solid, yield 88%. mp
165–169 °C. FT-IR (KBr): 1660 (C=O), 1685 (C=N),1740
1
(N–C=O) cm−1. H NMR (DMSO-d6): δ 2.25 (s, 6H,
2CH3), 3.55 (s, 3H, N-CH3), 3.55 (s, 2H, CH2), 5.15
(s, 2H, OCH2), 6.3 (s, 1H, 2nd position indole ring H),
6.8–7.65 (m, 14H, Ar–H).13C NMR (DMSO-d6):δ 16.7,
32.3, 36.0, 75.4, 97.4, 111.2, 114.7, 114.1, 120.0, 121.1,
123.8, 126.5, 127.9, 129.7, 130.2, 131.9, 132.2, 133.4,
134.0, 135.9, 138.5, 139.7, 140.9, 143.5, 158.4, 193.3,
206.1. LC–MS m/z 562.1 (M + 1), 564.1 (M + 2). Anal.
1 3

Journal of the Iranian Chemical Society
calcd. for C34H28ClN3O3: C, 72.66; H, 5.02; N, 7.48.
Found: C, 72.45.68; H, 5.06; N, 7.52%.
Ketoconazole and fuconazole (Himedia, Mumbai) were
used as positive control against fungi.
[2-(4–4-Bromobenzoyl-2,6-dimethyl-phenoxy)]-1-[2-
(1-methyl-1H-indol-3-yl)methyl)-1H -benzo [d]imida-
zol-1-yl]ethanone (11i): White solid, yield 74%. mp
190–195 °C. FT-IR (KBr): 1675 (C=O), 1680 (C=N),1730
Tested microbes
The following gram-positive bacteria were used for
the experiments: S.aureus, S.aureus (MRSA), M.luteus
and E.erogenes. The gram-negative bacteria included
K.pneumonia, S.typhimurium, P.Vulgaris and S.Paratyphi-
B. In addition, fungi C.albicans, B.cinerea, C.Krusei and
M.pachydermatis were also used for the experiments. All
cultures were obtained from the Department of Microbiol-
ogy, Manasagangotri, Mysuru.
1
(N–C=O) cm−1. H NMR (DMSO-d6): δ 2.30 (s, 6H,
2CH3), 3.58 (s, 3H, N-CH3), 3.59 (s, 2H, CH2), 5.25 (s, 2H,
OCH2), 6.25 (s, 1H, 2nd position indole ring H), 6.95–7.75
(m, 14H, Ar–H). 13C NMR (DMSO-d6):δ 19.1, 32.1, 40.0,
71.4, 103.4, 114.2, 117.7, 118.1, 122.0, 123.1, 124.8, 125.5,
129.7, 130.8, 131.1, 131.5, 132.1,134.5, 137.8, 138.1, 139.7,
140.5, 141.1, 162.4, 195.3, 198.0. LC–MS m/z 606.1.
(M+1), 608.1 (M+2). Anal. calcd. for C34H28BrN3O3: C,
67.33; H, 4.65; N, 6.93. Found: C, 67.38; H, 4.68; N, 6.98%.
[2-(4–4-Fluorobenzoyl-2,6-dimethyl-phenoxy)]-1-[2-
(1-methyl-1H-indol-3-yl)methyl)-1H -benzo [d]imida-
zol-1-yl]ethanone (11j): White solid, yield 69%. mp
218–220 °C. FT-IR (KBr): 1680 (C=O),1675 (C=N),1745
Preparation of inoculums
Bacterial inoculums were prepared by growing cells in
Mueller Hinton Broth (MHA, Himedia Mumbai) for 24 h
at 37 °C. These cell suspensions were diluted with sterile
MHB to provide initial cell counts of about 104 CFU/mL.
The flamentous fungi were grown on sabouraud dextrose
agar (SDA) slants at 28 °C for 10 days, and the spores
were collected using sterile doubled distilled water and
homogenized.
1
(N–C=O) cm−1. H NMR (DMSO-d6): δ 2.25 (s, 6H,
2CH3), 3.55 (s, 3H, N–CH3), 3.69 (s, 2H, CH2), 5.25 (s, 2H,
OCH2), 6.2 (s, 1H, 2nd position indole ring H), 6.85–7.75
(m, 14H, Ar–H). 13C NMR (DMSO-d6):δ 16.4, 36.3, 37.0,
73.1, 98.4, 112.2, 114.7, 116.1, 119.0, 120.1, 122.9, 124.5,
128.7, 129.9, 130.9, 132.3, 133.2, 135.9, 139.7, 140.9,
141.5, 160.4, 161.6, 165.6, 193.3, 205.1. LC–MS m/z 546.2
(M+1). Anal. calcd. for C34H28FN3O3: C, 74.85; H, 5.17;
N, 7.70. Found: C, 74.88; H, 5.19; N, 7.75%.
Disk difusion assay
Antibacterial activity was carried out using a disk difu-
sion method [54]. Petri plates were prepared with 20 mL of
sterile (MHA). The test cultures were swabbed on the top
of the solidifed media and allowed to dry for 10 min. The
tests were conducted at 1000 μg/disc. The loaded discs were
placed on the surface of the medium and left for 30 min at
room temperature for compound difusion. Negative control
was prepared using respective solvent. Streptomycin (10 μg/
disc) was used as positive control. The plates were incubated
for 24 h at 37 °C for bacteria and 48 h at 27 °C for fungi.
A zone of inhibition was recorded in millimeters, and the
experiment was repeated thrice.
[2-(4–4-Methoxybenzoyl-2,6-dimethyl-phenoxy)]-
1-[2-(1-methyl-1H-indol-3-yl)methyl)-1H-benzo [d]imi-
dazol-1-yl]ethanone (11k): White solid, yield 75%. mp
201–204 °C. FT-IR (KBr): 1675 (C=O), 1680 (C=N),1730
(N–C=O)cm−1. 1H NMR (DMSO-d6): δ 2.25 (s, 6H, 2CH3),
3.65 (s, 3H, N-CH3), 3.69 (s, 2H, CH2), 3.80 (s, 3H, OCH3),
5.02 (s, 2H, OCH2), 6.3 (s, 1H, 2nd position indole ring
H), 6.75–7.76 (m, 14H, Ar–H). 13C NMR (DMSO-d6):δ
16.1, 33.1, 40.0, 58.8, 76.4, 102.4, 113.2, 114.7, 114.9,
116.1, 120.0, 123.1, 123.1, 125.8, 126.3, 126.8, 128.1,
129.7, 131.1, 131.5, 135.3, 140.7, 143.5, 158.4, 161.3,
195.3, 204.0. LC–MS m/z 558.2 (M+ 1). Anal. calcd. for
C35H31N3O4: C, 75.38; H, 5.60; N, 7.54. Found: C, 75.40;
H, 5.63; N, 7.56%.
Minimum inhibitory concentration (MIC)
MIC study of synthesized compounds (11a–k) was per-
formed according to the standard reference method [55] for
bacteria and flamentous fungi by serial dilution method
(compounds were dissolved in DMSO). An inoculum of
100 µL from each well was inoculated. The antifungal agents
ketoconazole, fuconazole for fungi and streptomycin and
ciprofoxacin for bacteria were included in the assays as
positive controls. For fungi, the plates were incubated for
48–72 h at 28 °C, and for bacteria, the plates were incubated
for 24 h at 37 °C. The MIC for fungi was defned as the low-
est extract concentration, showing no visible fungal growth
Biology
Antimicrobial activity
Compounds (6a–l) were tested for their antimicrobial activ-
ity by disk difusion assay and minimum inhibitory con-
centration (MIC) methods. Ampicillin and ciprofoxacin
(Sigma) were used as positive control against bacteria.
1 3

Journal of the Iranian Chemical Society
after incubation time. Further, 5 mL of testing broth was
placed on the sterile MHA plates for bacteria and incubated
at respective temperatures. The MIC for bacteria was deter-
mined as the lowest concentration of the compound inhibit-
ing the visual growth of the test cultures on the agar plate.
spectral data. The benzoylated products 3a–k were synthe-
sized by the benzoylation of substituted phenols 1a–b with
substituted benzoyl chlorides 2a–f under low temperature
and confrmed by the appearance of the carbonyl stretching
band (1705–1735 cm−1) for the ester group in the IR spectra
and the disappearance of broad singlet of the OH proton of
substituted phenols 1a–b in proton NMR spectra. Fries rear-
rangement of compounds 3a–k using anhydrous aluminum
chloride as a catalyst under neat condition gave hydroxy
benzophenones 4a–k, which were established by the dis-
appearance of carbonyl stretching of compounds 3a–k and
appearance of OH stretching bands around 3505-3635 cm−1
in IR spectra also by the appearance of broad singlet for
OH proton around4.22–4.6 ppm and decrease in one aro-
matic proton in proton NMR spectra. Compounds 4a-k on
etherifcation with ethyl chloroacetate using dry acetone as
a solvent gave substituted (4-benzoyl-phenoxy)-acetic acid
ethyl esters5a-k, which were confrmed by the disappear-
ance of the OH stretching of compounds 4a-k and appear-
ance of carbonyl stretching band around 1760-1779 cm−1
for the ester group in the IR absorption spectra. The proton
NMR observations revealed that broad singlet for the OH
proton of compounds 4a-k was disappeared and a triplet
and quartet for CH3(1.2–1.6 ppm) and CH2(4.1–4.6 ppm)
protons were appeared, respectively. The compounds 5a–k
on refuxing with aqueous sodium hydroxide in ethanol gave
(4-benzoyl-phenoxy)-acetic acids 6a–k, which was clearly
evident with the appearance of carbonyl (1715–1740 cm−1)
and OH (3400–3560 cm−1) groups stretching bands of car-
boxylic group in the IR spectra. In proton NMR, the appear-
ance of COOH proton (9.0–9.5 ppm) and disappearance of
triplet and quartet peaks for CH3 and CH2 protons, respec-
tively, of compounds 5a-k has confrmed the formation of
the products 6a-k. Besides, N-(2-aminophenyl)-2-(1-methyl-
1H-indol-3-yl)acetamide (9) was obtained by the reaction of
2-(1-methyl-1H-indol-3-yl)acetic acid (7) and 1,2-diamino
benzene (8) in the presence of lutidine as a base and dichlo-
romethane as a solvent. This compound 9 was established by
the disappearance of O–H stretching of compound 7and NH2
stretching of compound 8 in the IR spectrum. Besides, an
appearance of NH (9.8 ppm) proton and the disappearance
of one -COOH proton and NH2 proton of compound 7 and 8,
respectively, in the NMR spectrum was also observed. Com-
pound 9 on refuxing with acetic acid undergoes cyclization
to give 2-((1-methyl-1H-indol-3-yl)methyl)-1H-benzo[d]
imidazole (10) which was confrmed by the appearance of
C = N stretching at 1680 cm−1 and disappearance of NH2
stretching band in the IR spectrum. Further, in NMR spec-
trum of compound 10 there is a disappearance of NH2 proton
of compound 8. Finally, substituted (4-benzoyl-phenoxy)-
acetic acids (6a–k), on treatment with 2-((1-methyl-1H-in-
dol-3-yl)methyl)-1H-benzo[d]imidazole (10) in the presence
of lutidine and TBTU as a coupling reagent, delivered the
Docking studies
The molecular interaction between protein and ligand can
virtually be studied by subjecting the input fles for molecu-
lar docking study. The docking operations can be performed
by several algorithms, of which SURFLEX DOCK being
such a program as available with SYBYL-X 2.1.1 soft-
ware package (Tripos Inc., USA). The algorithm can read-
ily be applied to rigid to fexible type docking. The input
fles as PDB fle of protein and virtually sketched fles of
synthesized compounds showing best biological activity
were either collected from online server or drawn by using
Chemdraw 15.0., and all other necessary calculations were
performed as per default protocol [56]. Preamble to docking
protocol, all the required input fles were prepared, hydrogen
atoms were added, water was removed, ionization state of
C-terminal and N-terminal was fxed and fnally energy min-
imized by steepest descent method applying Gasteiger–Mar-
sili charges and MMFF94s forcefeld to the protein fle with
100 iterations of conjugate gradient method with 1.0 kcal/
mol as the convergence criteria fxing to 0.5 dielectric con-
stant, whereas ligand fles were converted to 3D forms and
energy minimized by applying Gasteiger–Huckel charges.
The Geom mode of Surfex dock allows the ligand fles to
fexibly interact with rigid protein fles. The binding site
of the protein fle was abstracted from co-crystal ligand
bound information and protomol generation program uses
such information to fnd suitable cavity for docking. The
adopted docking protocol was validated using a comparison
of the binding modes of co-crystalized ligand of the target
protein FtsZ (PDB: 3VOB) before and after the docking
study. Highlighting feature of Geom mode is generation of
20 conformers for each ligand which interacts to the protein
individually in order to identify the most stable conformer
having best binding pose and binding energy. The respec-
tive ligand poses and docking scores in terms of Total score,
Crash score and Polar score were obtained and represented
accordingly.
Result and discussion
Chemistry
Synthesis of the title compounds 10a–k was accomplished
by a synthetic procedure as shown in Scheme 1. All the syn-
thesized compounds were established by IR, NMR and mass
1 3

Journal of the Iranian Chemical Society
expected final products 2-(4-benzoylphenoxy)-1-(2-((1-
methyl-1H-indol-3-yl)methyl)-1H-benzo [d]imidazol-1-yl)
ethanones (11a–k) in a good yield (75–85%). This was
supported by the disappearance of NH proton of com-
pound 10and COOH proton of compound 9 and also by the
increase in number of aromatic protons in NMR spectra and
by appearance of amide carbonyl stretching around 1725-
1745 cm−1 in the IR spectra.
with two methyl groups at the ortho positions of phenoxy
ring and a methoxy group at the para position of benzoyl
ring exhibited weak activity towards most of the bacterial
strains. Moreover, compounds 11a with a bromo group at
the ortho position of the phenoxy ring and 11g with two
methyl groups at the ortho positions of phenoxy ring and a
third methyl group at the para position of the benzoyl ring
displayed moderate antibacterial activity towards most of
the strains.
Interestingly, in antifungal assay the same compounds
11b, 11e, 11f and 11h exhibited broad activity with MIC
values in the range 15.62–250 μg/mL against C.albicans,
B.cinerea, C.Krusei and M.pachydermatis fungal strains.
On the contrary, the MIC values for the remaining com-
pounds are 250 μg/ mL and above. The enhanced activity
of the compounds 11b, 11e, 11f and 11h is due to various
substituents at diferent positions of the benzophenone ring.
On the other hand, compounds 11d, 11g, 11j and 11k dis-
played very weak antifungal activity. The structural activ-
ity relationship revealed that the synthesized compounds
with electron withdrawing groups at the ortho position of
the phenoxy and benzoyl ring were more bioactive while
the compounds with electron-donating groups at the ortho
position of the phenoxy ring were also more bioactive than
other compounds in the series (Tables 1, 2).
Biology
As per the literature, the biological activities of indole, ben-
zimidazole, benzophenone and their derivatives have been
recognized for a long time. Based on this in the present
investigation, the combination of above three molecules was
chosen for the synthesis of novel molecules as antimicro-
bial agents. The title compounds were designed to achieve
a wide range of potential microbial inhibitors by replacing
the hydrogen at various positions of the benzophenone ring
with diferent groups. All the synthesized compounds 11a–k
were evaluated for antimicrobial activity by disk difusion
method and compared with the activity of the standard drugs
(ampicillin, ciprofoxacin, ketoconazole and fuconazole).
The synthesized analog was tested for in vitro antibacterial
activity against gram-positive (S.aureus, S.aureus (MRSA),
M.luteus and E.erogenes) and gram-negative (K.pneumo-
nia, S.typhimurium, P.Vulgaris and S.Paratyphi-B) bacteria.
Also, these compounds were tested with fungal strains like
C.albicans, B.cinerea, C.Krusei and M.pachydermatis.
The antibacterial results displayed that compounds 11b
with a methyl group at the para position of benzoyl ring
and bromo group at the ortho position of the phenoxy ring,
11e with fuoro group at para position of benzoyl ring and
a bromo group at the ortho position of the phenoxy ring,
11f with two methyl groups at the ortho positions of phe-
noxy ring, and 11h with a chloro group at the ortho position
of benzoyl ring and two methyl groups at ortho positions
of phenoxy ring were found to be more active towards all
the tested strains. Consequently, these compounds were
subjected to MIC assay by broth dilution method. In this
screening compounds, 11b and 11f were shown the least
MIC value against gram-negative bacteria and compounds
11f and 11h shown the least MIC value against gram-posi-
tive bacteria. Incontrast, compounds 11c with a chloro group
at the ortho position of benzoyl ring and bromo group at the
ortho position of the phenoxy ring, 11d with a bromo group
at para position of benzoyl ring and another bromo group at
the ortho position of the phenoxy ring, 11i with two methyl
groups at the ortho positions of phenoxy ring and abromo
group at the para position of benzoyl ring, 11j with two
methyl groups at the ortho positions of phenoxy ring and
a fuoro group at the para position of benzoyl ring and 11k
Docking studies
A molecular docking study fundamentally defnes the bind-
ing modes of ligand interaction at the active site of the recep-
tor [56]. In our study, the four compounds with notable anti-
bacterial activity were subjected for docking studies against
FtsZ protein and the results are shown in Table 3. The inhi-
bition of FtsZ (flamentous temperature-sensitive protein
Z) protein prevents the formation of divisome, and hence,
it is proven to be a striking target for antibiotic research
[57]. Present docking study tries to provide with an insight
to the protein binding of biologically active potent ligands,
and the rationale of selecting only four ligands for dock-
ing study was based on antibacterial biological activity data
which then subjected to bind the active site of FtsZ protein.
The best binding pose for docked ligands was identifed and
visualized based on binding afnities. The binding interac-
tions of protein with the compounds revealed that almost all
the compounds were interacting similarly to the identifed
binding site and valine 297, leucine 200, isoleucine 226, iso-
leucine 228, threonine 265, valine 307 and methionine 226
(Fig. 1–4), with diferent H-bond and hydrophobic interac-
tions showing distances ranging between 2.117 and 3.786 Å,
docking result included with several scores as Total score,
Crash score and Polar score, where Total score being repre-
senting the binding afnities. The docking outcome provides
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Journal of the Iranian Chemical Society
Table 1 In vitro antibacterial
and antifungal activity of
compounds 11a-k
Compounds
Zone of inhibition in mm
Gram-positive bacteria
Gram-negative bacteria
Fungi
C.a
S.a
S.a-M
M.l
E.e
K.p
S.t
P.v
Sp.B
B.c
C.k
M.p
11a
11b
11c
11d
11e
11f
11g
11h
16
23
9
12
17
11
9
20
14
13
11
8
9
8
21
–
14
21
11
11
15
17
16
21
12
10
11
23
–
15
18
12
9
25
19
14
20
9
10
16
12
9
22
15
15
15
11
12
11
23
–
15
23
9
12
19
9
11
11
8
8
24
9
11
13
8
14
22
12
10
22
21
12
20
12
9
10
9
10
8
13
10
8
13
10
10
9
16
15
13
14
17
15
13
11
16
8
23
12
16
12
21
12
8
23
13
8
10
23
22
17
22
11
11
10
24
–
11
13
24
17
24
10
11
12
25
–
8
18
18
10
17
9
13
11
19
–
11i
11j
9
9
11k
Streptomycin
Ketoconazole
10
26
–
10
25
–
9
–
23
9
–
18
10
–
24
–
14
Gram-positive bacteria—S.a S. aureus, S.aM S. aureus (MRSA), M.l M. luteus, E.e E. erogenes
Gram-negative bacteria—K.p K. pneumonia, S.t S. typhimurium, P.v P. vulgaris, Sp.B S. Paratyphi−B
Fungi—C.a C. albicans, B.c B. cinerea, C.k C. krusei, M.p M. pachydermatis
Table 2 MIC (μg/mL) of potent
compounds against tested
bacteria and fungi
Compounds Minimum inhibitory concentration (μg/ mL)
Gram-positive bacteria
S.a S.aM M.l
15.62 31.25 15.62 62.5 125
31.25 250 250
31.25 15.62 15.62 15.62 15.62 125
Gram-negative bacteria
K.p S.t P.v
62.5 125
31.25 62.5 250
Fungi
Sp.B C.a
500
E.e
B.c
C.k M.p
11b
11e
11f
11 h
62.5 15.62 250 125
125 62.5 250 250
31.5 125 31.5 500
15.62 15.62 250 250
31.25 62.5
15.62 250
15.62 125
6.25 >100
62.5 62.5 550
6.25 25 6.25
31.25 125
30 ni
500
Streptomycin
6.25
-
-
-
-
Ciprofoxacin <0.78 >100 <0.78 >100 <0.78 >100 6.25 <0.78
-
25
>100 ni
-
25
-
15
-
15
Ketoconazole
Fluconazole
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
12.5 12.5
Gram-positive bacteria—S.a S. aureus, S.aM S. aureus (MRSA), M.l M. luteus, E.e E. erogenes
Gram-negative bacteria—K.p K. pneumonia, S.t S. typhimurium, P.v P. vulgaris, Sp.B S. Paratyphi−B
Fungi—C.a C. albicans, B.c B. cinerea, C.k C. krusei, M.p M. pachydermatis
ni no inhibition
Table 3 Docking scores of compounds with respect to FtsZ protein
understanding of ligand interaction and ofers a support to
the hypothesis.
Sl. No
Compounds
Total score
Crash score
Polar score
Binding pose with the maximum binding afnity for
docked conformation of compounds 11b, 11e, 11f and 11h
is shown in Fig. 1–4. Figure 1–4 reveals that various inter-
actions in terms of hydrogen bonding, π—donor hydrogen
bonding, π—alkyl and π–π interactions are mainly respon-
sible for anchoring of the compounds 11b, 11e, 11f and 11h
in the active site of FtsZ protein. Compound 11f interacts
with FtsZ protein with the docking score of 9.5396 and the
1
2
3
4
11b
11e
11f
9.5396
8.9102
8.1618
6.4529
− 2.5956
− 1.564
− 1.5306
− 2.4048
0
1.1547
0
0.0159
11h
*Crash score: revealing the inappropriate penetration into the binding
site
^Polar score: reports the polar region of the ligands
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Journal of the Iranian Chemical Society
Fig. 1 Binding pose of compound 11b with FtsZ protein (2D) and (3D) after docking studies
π-electrons of benzophenone phenyl ring interacts with Leu-
261 by π-sigma interactions. Meanwhile, the same Leu-261
interacts with the halogen/bromine which is present at the
ortho/2nd position of the phenyl ring. Further, the benzoyl
ring π-electrons interact with Ile-197 and Ile-311. Simul-
taneously, the methyl group present at para position in the
benzoyl ring interacts with Ile-311and Met-226. In the same
vicinity, the π-electrons of indole benzene ring having pi-
alkyl interacts with Ile-228 (Fig. 1).
of phenyl ring. In the same path, Leu-302 having a π-alkyl
group interacts with the π-electrons of benzoyl ring; in addi-
tion the same benzoyl ring having a π-lone pair interacts
with Glu-301 amino acid. In continuation, compound 11e
correspondingly interacts with Ile-228, Leu-200 and Val-
297 amino acids with benzimidazole and indole by alkyl,
π-sigma and π-alkyl groups, respectively (Fig. 2).
Likewise, compound 11f having a total docking score of
8.1618 interacts or forming a bond with FtsZ protein by
carbon-hydrogen bonding, π-lone pair and π-alkyl interac-
tion with Val-203—indole and benzimidazole ring systems,
Asp-199—phenyl ring of benzophenone and Ile-228—ben-
zoyl ring, Leu -200—benzene ring of indole and Val—297
-imidazole ring of benzimidazole, respectively (Fig. 3).
Similarly, compound 11e has a docking score of 8.9102.
The formation of conventional hydrogen bond with Thr-265
amino acid and oxygen of benzophenone C=O is clearly
visible, whereas Val-307 having alkyl group interacts with
this compound through the bromine present at 2nd position
Fig. 2 Binding pose of compound 11e with FtsZ protein (2D) and (3D) after docking studies
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Journal of the Iranian Chemical Society
Fig. 3 Binding pose of compound 11f with FtsZ protein (2D) and (3D) after docking studies
Fig. 4 Binding pose of compound 11 h with FtsZ protein (2D) and (3D) after docking studies
Finally compound 11 h, scoring 6.4529 in docking with
FtsZ protein, forms a conventional hydrogen bond between
benzophenone oxygen—Val -203, carbon hydrogen bond for-
mation with Gln—192 and hydrogen of indole N–H. Further,
compound 11 h has an alkyl interaction between Val—307—
imidazole, and Leu—209, Val—297, Leu—200 with the ben-
zoyl ring system. Similarly, Val—297 having a π-alkyl group
interacts with the phenyl ring of benzophenone ring system
(Fig. 4).
Conclusion
In conclusion, the synthesis of various indole and benzimi-
dazole containing benzophenone derivatives was achieved
by multi step synthesis. All the synthesized compounds
11a–k were subjected for the antimicrobial activity and
compared with the activity of standard drugs. In the
series of 11a–k, the compounds 11b, 11e, 11f and 11h
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Journal of the Iranian Chemical Society
20. B.G. Mohamed, M.A. Hussein, A.-A.M. Abdel-Alim, M. Hashem,
Arch. Pharm. Res. 29, 26–33 (2006)
were publicized as potent compounds among the tested
strains. Further, results obtained from docking studies
were accordance with in vitro results. Finally, the struc-
tural activity relationalship revealed that substitution of
electron withdrawing and donating groups in the proper
position and the combination of two heterocyclic moie-
ties, with benzophenone nucleus leads to the enhanced
bioactivity of the synthesized compounds.
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Acknowledgments Dr. Shaukath Ara Khanum, Dr. Prashanth T and
Dr.Lakshmi Ranganatha V are grateful to UGC New Delhi for the
grant of Major Research Project [UGC No. F.39-737/2010 (SR) dated
06/01/2010]. Further, Dr. Prashanth T gratefully acknowledge Principal
and VVIET Management for their encouragement and constant support
to carry out the research work.
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Compliance with ethical standards
Conflict of interest Authors declare that we don’t have any confict of
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S.A. Khanum, Biochem. Pharmacol. 125, 26–40 (2017)
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