Synthesis of some newer analogues of substituted dibenzoyl
phenol as potent anti-inflammatory agents
Shaukath Ara. Khanum,
a
Venu T. D,
a
Sheena Shashikanth
a,
*
and Aiysha Firdouse
b
a
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
b
Department of Biochemistry, Farooqia Dental College, Mysore 570 001, India
Received 23 April2004; revised 6 August 2004; accepted 7 August 2004
Available online 9 September 2004
Abstract—Benzoylation of hydroxybenzophenones 1a–f affords substituted benzoylphenylbenzoates 3a–f, which on Fries rear-
rangement using microwave irradiation led to a facile synthesis of solely dibenzoyl phenols 4a–f in excellent yield. The newly syn-
thesized compounds were screened for their anti-inflammatory activity and were compared with standard drugs. Out of the
compounds studied, the compound 4e showed more potent activity than the standard drugs at all doses tested.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Nonsteroidalanti-inflammatory drugs (NSAIDs) are
therapeutic agents usefulin the treatment of inflamma-
tion, pain and pyresis.
1,2
Inflammatory responses are
considered to be mediated in part by the prostaglandins
(PGs). PGs are produced by the action of cyclooxyge-
nase (COX) enzyme, which is also referred as prosta-
glandin H synthase on arachidonic acid.
3,4
Recent
studies have shown that COX exists in two isoforms
COX-1 and COX-2. Both COX are constitutively ex-
pressed in most tissues, but COX-2, in contrast to
COX-1, is the mitogen inducible isoform. The inducing
stimuli for COX-2 include pro-inflammatory cytokines
and growth factors, implying a role for COX-2 in both
inflammation and controlof cellgrowth.
5–7
COX iso-
forms are almost identical in structure but have impor-
tant differences in substrate and inhibitor selectivity
and in their intracellular locations.
8
NSAIDs block the
formation of PGs and have anti-inflammatory, analgesic
and anti-pyretic activities.
1,2
The discovery of COX-2
9
isoform has made possible the design of drugs that re-
duce inflammation without removing the protective
PGs in the stomach and kidney made by COX-1. In
addition, its discovery has opened the possibility of
developing COX-2 selective inhibitors to act as an effec-
tive NSAIDs without the gastrotoxic effect.
6
The competence of benzophenone analogues as chemo-
therapeutic agent especially as anti-inflammatory is well
recognized.
1,2
Some of these analogues were synthesized
by severalscientists of the world and have been reported
as potent anti-inflammatory agents.
10–12
Recently Otto-
sen et al. have reported synthesis and structural activity
relationship of benzophenones as novel class of p38
MAP kinase inhibitors with high anti-inflammatory
activity.
13
Our search for new molecules with anti-
inflammatory activity
14
encouraged us to synthesize
some newer more potent analogues of hydroxybenzo-
phenones by modifying the aromatic moiety with the
introduction of second benzoylgroup at 2- and 6-posi-
tions. We have focused our interest on the synthesis
and biological evaluation of substituted dibenzoyl phen-
ols for a rational study of the structural activity
relationships.
2. Chemistry
The synthetic sequence is outlined in Scheme 1. Benzoyl-
ation of substituted hydroxybenzophenones 1a–f with
respective benzoylchlorides 2a–d affords substituted
benzoylphenylbenzoate 3a–f.
15
Compounds 3a–f on
thoroughly mixing with an equal amount of montmor-
rillonite k 10 clay in the solid state using vortex mixer
and on subjecting to microwave irradiation for 10–
13 min afforded substituted dibenzoylphenols 4a–f in
excellent yield compared to one pot conventional meth-
od.
16
The newly synthesized compounds 3a–f
17
and
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.014
Keywords: Synthesis; Dibenzoylphenols; Anti-inflammatory activity.
*
Corresponding author. Fax: +91 0821 2518358; e-mail: shashi56_
2000@yahoo.com
Bioorganic & MedicinalChemistry Letters 14 (2004) 5351–5355