Synthesis, biological evaluation, and pharmacokinetic profiling of benzophenone derivatives as tumor necrosis factor-alpha and interleukin-6 inhibitors

Article abstract of DOI:10.1007/s00044-011-9856-1

A new series of benzophenone derivatives are reported with comparative less toxicity with qualifying pharmacokinetic profiles. They were synthesized by Fridel- Craft acylation and evaluated for their anti-inflammatory activity (against Tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)) by LPS-induced cytokine production assay (phorbol myristate acetate stimulated human THP-1 cells in vitro). The screened compounds exhibited promising activity against IL-6 in a range of 63-82% at 10 μM concentration. Cytotoxicity was also determined by using CCK-8 cells at 10 μM. The synthesized benzophenone derivative 1c was not cytotoxic in CCK-8 cells up to the concentration of 100 μM and showed potent IL-6 inhibitory activity with IC₅₀ of 0.19 μM. With few exceptions, all other compounds were found to be moderate inhibitors of TNF-α. In silico, pre-lead prioritization of the leads was performed using QikProp 3.2, qualifying them for further study. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9856-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3177–3181
DOI 10.1007/s00044-011-9856-1
ORIGINAL RESEARCH
Synthesis, biological evaluation, and pharmacokinetic profiling
of benzophenone derivatives as tumor necrosis factor-alpha
and interleukin-6 inhibitors
•
Babasaheb Bandgar Baliram Hote
•
•
Rahul Gangwal Abhay Sangamwar
Received: 30 April 2011 / Accepted: 28 October 2011 / Published online: 11 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new series of benzophenone derivatives are
reported with comparative less toxicity with qualifying
pharmacokinetic profiles. They were synthesized by Fri-
del–Craft acylation and evaluated for their anti-inflamma-
tory activity (against Tumor necrosis factor-alpha (TNF-a)
and interleukin 6 (IL-6)) by LPS-induced cytokine pro-
duction assay (phorbol myristate acetate stimulated human
THP-1 cells in vitro). The screened compounds exhibited
promising activity against IL-6 in a range of 63–82% at
10 lM concentration. Cytotoxicity was also determined by
using CCK-8 cells at 10 lM. The synthesized benzophe-
none derivative 1c was not cytotoxic in CCK-8 cells up to
the concentration of 100 lM and showed potent IL-6
inhibitory activity with IC50 of 0.19 lM. With few
exceptions, all other compounds were found to be moderate
inhibitors of TNF-a. In silico, pre-lead prioritization of the
leads was performed using QikProp 3.2, qualifying them
for further study.
Keywords Benzophenone derivatives Á TNF-a Á
IL-6 Á Anti-inflammatory activity Á
Pharmacokinetic properties
Introduction
The rapid developments of biological agents targeting pro-
inflammatory cytokines have revolutionized the pattern of
treating chronic inflammation. The limitations of outburst
with immunosuppressive agents are minimized by current
cytokine targeted therapies by offering complete remission
of the inflammatory state. Tumor necrosis factor-alpha
(TNF-a) and interleukin 6 (IL-6) are principal pro-inflam-
matory cytokines implicated in many inflammatory dis-
eases such as rheumatoid arthritis (RA), inflammatory
bowel disease, osteoarthritis, psoriasis, endotoxemia, and
toxic shock syndrome (Dinarello, 1991; Arend and Dayer,
1990; Dayer and Demczuk, 1984; Barnes et al., 1998;
Loyau and Pujol, 1990; Kirkham, 1991; Nickoloff, 1991;
Saklatvala et al., 1996; Sacca et al., 1997).
Todate, antiTNF-abiologicsincludingetanercept(Enbrel;
Amgen/Wyeth), infliximab (Remicade; Centocor/Schering-
Plough/Tanabe Sieyaku), and adalimumab (Humira; Abbott)
have been approved by the FDA for use as anti-inflammatory
therapies (Taylor, 2003). Other protein-based therapeutics are
in various stages of clinical development and include PEG-
sTNFR1, sLTr, CDP-571, CDP-870, MAK-195F, and rTBP-1
(Palladino et al., 2003). Although the protein-based anti TNF-
a therapies prove promising, they have raised the potential for
adverse effects. The most prevalent concern has been an
increased incidence of re-exacerbation of latent tuberculosis.
Tuberculosis testing has been recommended for patients
commencing anti TNF-a therapies (Palladino et al., 2003).
Studies with infliximab and etanercept have also shown a
B. Bandgar
Organic Chemistry Research Laboratory,
School of Chemical Sciences, Solapur University,
Solapur 413 255, India
B. Bandgar Á B. Hote
Organic Chemistry Research Laboratory,
School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University,
Nanded 431 606, India
R. Gangwal Á A. Sangamwar (&)
Department of Pharmacoinformatics,
National Institute of Pharmaceutical Education and Research,
SAS Nagar, Mohali, Punjab 160 062, India
e-mail: abhays@niper.ac.in
123

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Med Chem Res (2012) 21:3177–3181
potential risk for worsening congestive heart failure and spe-
cific warnings are now placed on the FDA labels for these
products. In light of these FDA warnings, there are significant
advantages in developing orally active, small molecules
that target the specific signaling and synthesis pathways for
TNF-a.
Materials and methods
General
Melting points were recorded in open capillaries with super
fit melting point apparatus and were uncorrected. 1H NMR
spectra were recorded on 300/400 MHz Bruker FT-NMR
spectrometer using tetramethyl silane as internal standard
and chemical shifts are reported in d units and the coupling
constant (J) are reported in hertz. Mass spectra were
recorded on Bruker Daltonics Data Analysis 3.4. All
chromatographic purifications were performed using silica
gel (100–200 mesh), whereas all TLC (silica gel) devel-
opments were performed on silica gel (Merck Kiesel
60F254, 0.2 mm thickness) sheets. Commercial scale sol-
vents and reagents were used as supplied unless otherwise
stated. Yields reported are isolated yield of the compounds.
IL-6 is one of the key regulators of the inflammatory
responses (Ishihara and Hirano, 2002; Nishimoto and
Kishimoto, 2004), and it induces the final maturation of the
B cells into immunoglobulin-producing cells (Muraguchi
et al., 1981; Yoshizaki et al., 1982). Owing to these
properties, IL-6 is a pivotal molecule in the pathogenesis of
several chronic inflammatory diseases, which are often
refractory to conventional therapies such as corticosteroids
and immunosuppressants. IL-6 overproduction also plays
an important pathological role in several neoplasms,
including high grade multiple myelomas (Ludwig et al.,
1991) and malignant mesotheliomas (Nakano et al., 1998).
Therefore, the identification of inhibitory agents to target
IL-6 signaling is currently of interest in both anti-inflam-
matory and anti-cancer drug discovery. Actemra (toc-
ilizumab) is a recombinant humanized anti-human IL-6
receptor monoclonal antibody of the immunoglobulin
IgG1 k (gamma 1, kappa) subclass with a typical H2L2
polypeptide structure. It is indicated for the treatment of
adult patients with moderately to severely active RA who
have had an adequate response to one or more TNF
antagonist therapies (Scheinecker et al., 2009). However,
patients treated with Actemra are at increased risk for
developing serious infections that may lead to hospital-
ization or death. These findings have warranted the search
of orally active, small molecule therapies in the treatment
of chronic inflammatory disorders.
General procedure for the synthesis of 2-bromo-1,3,5-
trimethoxy benzene
1,3,5-trimethoxybenzene (0.2 gm, 1.02 mol) was dissolved
in glacial acetic acid (10 ml) and the solution was left in an
ice bath for 5 min and a solution of Br2 (0.3 gm, 1.57 mol)
in acetic acid was added slowly until the red color became
permanent indicating the excess of bromine. After 30 min,
the mixture was poured into ice water and the precipitate
was recrystallized from ethanol to give corresponding
product.
This compound was obtained as faint white solid in 60%
yield, mp 125°C, IR (KBr): 3129, 2997, 2964, 1674, 1591,
1410, 1030, 952, 804 cm-1 and 1H NMR (400 MHz
CDCl3) d: 6.1762 (s, 2H), 3.8782 (s, 6H), 3.8212 (s, 3H).
As part of our ongoing efforts toward discovering
orally active small molecule inhibitors of TNF-a and IL-6,
we have synthesized a new series of benzophenone
derivatives due to their therapeutic applications as an
anti-inflammatory (Palomer et al., 2000, 2002). Several
research groups have synthesized benzophenone analogues
and reported as potent anti-inflammatory agents (Brideau
et al., 1996; Williams et al., 1999). Venu et al. (2008)
reported benzophenone pyrimidine analogue as an anti-
inflammatory agent. Ottosen et al. (2003) have reported
aminobenzophenones, which is a novel class of p38 MAP
kinase inhibitors having high anti-inflammatory activity.
Khanum et al. (2009) identified benzophenone N-ethyl
piperidine ether analogues and benzophenone (Khanum
et al., 2004) analogues as anti-inflammatory agents.
Murari et al. (2004) reported benzophenone oxime ana-
logues as inhibitors of phospholipase A2 with anti-
inflammatory activity. Revesz et al. (2004) described
benzoylpyridines and benzophenones as p38 MAP kinase
inhibitors with oral activity.
General procedure for the synthesis of (3-bromo-2-
hydroxy-4,6-dimethoxy)(phenyl) methanone (1a–1g)
A solution of 2-bromo-1,3,5-trimethoxy benzene (5 gm,
0.03 mol) was added to a cooled solution of anhydrous
AlCl3 (9 g, 0.067 mol) in dry ether (50 ml). The mixture
was cooled at 0°C and stirred vigorously. A solution of
distilled substituted benzoyl chloride (4.5 ml, 5.45 g,
0.03 mol) in dry ether (20 ml) was added drop wise during
1 h. The stirring was continued for 6 h more at 0°C and the
mixture was left at room temperature for 48 h. Ice 100 g
and conc. HCl (15 ml) were added to the reaction mixture.
It was heated on water bath for 30 min, ether being allowed
to distil away. The hot mixture was extracted with benzene/
diethyl ether (200 ml). The extracted organic layer was
washed with sodium carbonate (Na2CO3) solution (5%,
150 ml) and extracted with NaOH (5%, 150 ml). The
cooled clear alkaline solution was acidified with HCl. The
separated product was filtered and washed with water. It
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Med Chem Res (2012) 21:3177–3181
3179
1
was recrystallized from ethanol to obtain corresponding
933, 844 cm-1; H NMR (300 MHz CDCl3) d: 11.82 (s,
1H), 7.64 (dd, 2H, J = 2.1 Hz), 6.91 (dd, 2H, J = 2.1 Hz),
6.09 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.62 (s, 3H).
products (1a–1g).
(3-Bromo-2-hydroxy-4,6-
dimethoxyphenyl)(phenyl)methanone (1a)
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(3-
chlorophenyl)methanone (1g)
Green crystal, yield 42%, mp 142°C; IR (KBr):3360, 2956,
1
1690, 1585, 1477, 1031, 806 cm-1; H NMR (200 MHz
Faint green crystal, yield 43%, mp 125°C; IR (KBr): 3560,
3021, 2060, 2876, 1630, 1597, 1567, 1460, 1408, 1020,
956, 840 cm-1; 1H NMR (400 MHz CDCl3) d: 14.2431 (s,
1H, bs), 7.8924 (d, 1H, J = 1.4 Hz), 7.741 (dd, 1H,
J = 2.2 Hz), 7.612 (d, 1H, J = 2.2 Hz), 7.402 (m, 1H),
6.021 (s, 1H), 3.942 (s, 3H), 3.324 (s, 3H).
CDCl3) d: 12.32 (s, 1H, bs), 7.54 (dd, 2H, J = 2 Hz), 7.34
(dd, 1H, J = 2 Hz), 7.12 (dd, 2H, J = 2 Hz), 6.04 (s, 1H),
3.99 (s, 3H), 3.53 (s, 3H).
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(2-
flurophenyl)methanone (1b)
Assay for TNF-a and IL-6 inhibition
Faint green crystal, yield 68%, mp 122°C; IR (KBr):3400,
1
1620, 1577, 1402, 1030, 834 cm-1; H NMR (400 MHz
Pro-inflammatory cytokines production by lipopolysac-
charides in THP-1 cells was measured according to the
method described by Hwang et al. (1993). In brief, THP-1
cells were cultured in RPMI 1,640 culture medium (Gibco
BRL, Pasley, UK) containing 100 U/ml penicillin and
100 lg/ml streptomycin (1009 solution sigma chemical
Co. St. Louis.MO) containing 10% fetal bovine serum (FB,
JRH). Cells were differentiated with phorbol myristate
acetate (PMA, Sigma) following cells plating. The test
compound or vehicle (0.5% DMSO) was added to each
well and the plate was incubated for 30 min) was added at
a final concentration at 1 lg/ml. Plates were incubated at
37°C for 24 h. 5% CO2 supernate were harvested and
assayed for TNF-a and IL-6 by ELISA as described by the
manufacturer (BD. Biosciences). The cells were simulta-
neously evaluated for cytotoxicity using CCK-8 cell from
Dojindo laboratories. Percent inhibition of cytokine release
compared to the control was calculated.
CDCl3) d: 13.45 (s, 1H, bs), 7.43 (m, 2H, J = 4.5 Hz,
J = 4.3 Hz), 7.21 (m, 1H), 7.05 (t, 1H, J = 1.2 Hz,
J = 8 Hz), 5.9 (s, 1H), 3.98 (s, 3H), 3.54 (s, 3H).
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(4-
flurophenyl)methanone (1c)
Green crystal, yield 40%, mp 118°C; IR (KBr):3360, 3074,
1
2951, 1591, 1482, 1020, 952 cm-1; H NMR (300 MHz
CDCl3) d: 13.45 (s, 1H, bs), 7.43 (m, 2H, J = 4.5 Hz,
J = 4.3 Hz), 7.21 (m, 1H), 7.05 (t, 1H, J = 1.2 Hz,
J = 8 Hz), 5.9 (s, 1H), 3.98 (s, 3H), 3.54 (s, 3H).
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(O-
tolyl)methanone (1d)
Green crystal, yield 38%, mp 127°C; IR (KBr): 3674,
2949, 2918, 1606, 1591, 1465, 1435, 1402, 956, 871 cm-1
;
1H NMR (300 MHz CDCl3) d: 13.87 (s, 1H, bs), 7.2 (m,
4H), 5.98 (s, 1H), 3.95 (s, 3H), 3.31 (s, 3H), 2.3 (s, 3H).
Results and discussion
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(m-
tolyl)methanone (1e)
Chemistry
The synthesis of benzophenone derivatives is outlined in
Scheme 1. 2-Bromo-1,3,5-trimethoxy benzene was syn-
thesized from 1,3,5-trimethoxy benzene by bromination
using bromine in glacial acetic acid. The benzophenone
derivatives (1a–1g) were synthesized by acylating
2-bromo-1,3,5-trimethoxy benzene with substituted ben-
zoyl chlorides in dry ether via Fridel–Craft acylation
(Chiche et al., 1986).
Faint green crystal, yield 30%, mp 143°C; IR (KBr): 3590,
1
2980, 2887, 1620, 1573, 1471, 1402, 970, 846 cm-1; H
NMR (400 MHz CDCl3) d: 13.456 (s, 1H, bs), 7.674 (d,
1H, J = 2.3 Hz), 7.621 (dd, 1H, J = 2.3 Hz), 7.521 (dd,
1H, J = 2.1 Hz), 7.321 (m, 1H), 5.972 (s, 1H), 3.972 (s,
3H), 3.821 (s, 3H), 2.321 (s, 3H).
(3-Bromo-2-hydroxy-4,6-dimethoxyphenyl)(4-
methoxyphenyl)methanone (1f)
Biological evaluation
Faint green crystal, yield 23%, mp 124°C; IR (KBr): 3360,
3190, 3001, 2943, 1630, 1599, 1566, 1483, 1369, 1030,
All synthesized compounds were evaluated for anti-
inflammatory activity against TNF-a and IL-6 at 10 lM
123

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Med Chem Res (2012) 21:3177–3181
Scheme 1 Reagent and
O
O
O
O
O
conditions: (a) glacial acetic
acid, Br2, 0°C-rt, 1 h, (b) anhy.
AlCl3, dry ether, substituted
benzoyl chlorides, 0°C-rt, 48 h
a
b
Cl
R
R
O
O
O
OH
O
O
Br
Br
4
1
2
3
R = 1a = H, 1b = 2-F, 1c = 4-F, 1d = 2-CH3, 1e = 3-CH3, 1f = 4-OCH3, 1g = 3-Cl
Table 1 Anti-inflammatory activity against TNF-a and IL-6
exhibited very promising activity 63–82% inhibition
against IL-6. The derivative 1c having significant IL-6
inhibitory activity was not cytotoxic in CCK-8 cells even at
concentrations [100 lM with IC50 of 0.19 lM. Therefore,
compound 1c can be use as lead for designing new anti-
inflammatory agents.
Compounds
% Inhibition at 10 lM
TNF-a
IL-6
Toxicity
1a
19
00
00
00
04
06
10
72
80
76
63
70
76
82
78
94
38
46
19
40
32
34
33
0
1b
1c
Pharmacokinetic evaluation
1d
1e
All synthesized compounds were evaluated for their drug
like behavior through analysis of pharmacokinetic param-
eters required for absorption, distribution, metabolism,
excretion, and toxicity (ADMET) by use of QikProp 3.2.
(QikProp 2010) The partition coefficient (QPlog Po/w) and
water solubility (QPlogS) were critical for estimation of
absorption and distribution of drugs within the body. The
partition coefficient and water solubility for synthesized
compounds ranged from 3.769 to 4.274 and -4.72 to
-5.877, respectively. Cell permeability (QPPCaco), a key
factor governing drug metabolism and its access to bio-
logical membranes, ranges from 861 to 2083.643, while the
toxicity of all synthesized compounds in terms of predicted
IC50 value for blockage of HERG K? channels ranges
from -5.407 to –5.87 which are below the acceptable
range but do not violate 95% range. Overall, the human
oral absorption for the compounds is moderate. All the
synthesized compounds show pharmacokinetic parameter
1f
1g
Dexamethasone(1 lM)
The results summarized are the mean values of n = 2
concentration, whereas cytotoxicity was determined by
using CCK-8 cells at 10 lM concentration. Results are
shown in Table 1. Dexamethasone was used as reference
standard for the assay. The activity results indicated the
effect of substitution. About TNF-a activity, the unsubsti-
tuted derivative 1a was more active of the tested lot of
compounds with percentage inhibition of 19. The com-
pounds 1e and 1f having electron donating substituents at
meta and para position exhibited percentage inhibition of 4
and 6, respectively, while the meta chloro substituted
derivative 1g exhibited percentage inhibition of 10;
derivatives 1b, 1c, and 1d were inactive. Derivatives 1a–1g
Table 2 QikProp(3.2) properties of the all synthesized compounds
Lead
molecules
QPlogPo/wa
QPlogSb
QPPCacoc
QPlogHERGd
Human oral
absorptione
1a
1b
1c
1d
1e
1f
1g
a
3.769
3.94
-4.72
1329.263
948.038
884.325
2083.643
1840.75
939.061
861.485
-5.63
2
2
2
2
2
2
2
-5.302
-5.457
-5.293
-5.441
-5.582
-5.877
-5.633
-5.671
-5.407
-5.491
-5.87
3.986
4.176
4.164
4.01
4.274
-5.721
Predicted octanol/water partition coefficient log p (acceptable range: -2.0 to 6.5)
b
c
d
e
Predicted aqueous solubility; S in mol/l (acceptable range: -6.5 to 0.5)
Predicted Caco-2 cell permeability in nm/s (acceptable range: \25 is poor and [500 is great)
Predicted IC50 value for blockage of HERG K? channels (concern below -5.0)
Predicted human oral absorption (0 (Very Good), 1(Good), 2(Moderate), 3(poor), 4(very poor))
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Med Chem Res (2012) 21:3177–3181
3181
Loyau G, Pujol JP (1990) The role of cytokines in the development of
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Conclusions
This article presents synthesis of new analogues of ben-
zophenone and their in vitro anti-inflammatory activity.
Although most of the analogues have not shown promising
TNF-a inhibitory activity, analogue 1c has promising IL-6
inhibition (IC50 0.19 lM). IL-6 is a pro-inflammatory and
anti-inflammatory cytokine, which expresses indepen-
dently of TNF-a. In this context, the inhibition of IL-6
satisfies the aims of researchers in design of anti-inflam-
matory agents. Structure activity relationship of these
analogues will help in design of more potent analogues.
Nishimoto N, Kishimoto T (2004) Inhibition of IL-6 for the treatment
of inflammatory diseases. Curr Opin Pharmacol 4:386–391
¨
Ottosen ER, Sørensen MD, Bjorkling F, Skak-Nielsen T, Fjording
Acknowledgments BH is thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award of SRF as well as
to Mr. Mahesh Nambiar and Mrs. Asha Almeida, Piramal life Sciences
Ltd., Mumbai for screening of the compounds against TNF-a and IL-6
human cancer lines. RG is thankful to the Department of Science and
Technology (DST), New Delhi for the award of JRF.
MS, Aaes H, Binderup L (2003) Synthesis and structure- activity
relationship of aminobenzophenones. A novel Class of p38 MAP
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Anti-TNF- therapies: the next generation. Nat Rev Drug Discov
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Mauleon D (2000) Modeling cyclooxygenase inhibition. Impli-
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