Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of 2-aroylbenzofurans,
rugchalcones A, B and their derivatives as potent anti-inflammatory
agents
Young Hwa Seo a, Kongara Damodar a, Jin-Kyung Kim b, Jong-Gab Jun a,
⇑
a Department of Chemistry and Institute of Natural Medicine, Hallym University, Chuncheon 200-702, Republic of Korea
b Department of Biomedical Science, College of Natural Science, Catholic University of Daegu, Gyeungsan-Si 700-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 2-aroylbenzofurans, rugchalcones A, B and their derivatives was accomplished in
excellent yields by the Rap–Stoermer reaction between substituted salicylaldehydes and phenacyl bro-
mides. Later their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-induced RAW-
264.7 macrophages. The compounds were exhibited exceptional potency against inflammatory mediated
Received 24 October 2015
Revised 28 January 2016
Accepted 10 February 2016
Available online 10 February 2016
NO production with no cytotoxicity at 10
lM concentration and IC50 values are found in the range from
0.75 to 13.27 M. Among the 2-aroylbenzofurans prepared in this study, compounds
l
4
(99.6%;
Keywords:
2-Aroylbenzofuran
Rugchalcones
Rap–Stoermer reaction
Nitric oxide
anti-Inflammatory
IC50 = 0.57), rugchalcone B (2) (99.3%; IC50 = 4.13), 7 (96.8%; IC50 = 1.90) and 8 (74.3%; IC50 = 0.99) were
showed the maximum inhibitory activity. This study suggests that compounds 2, 4, 7 and 8 which are
having 4-hydroxyphenyl group and/or hydroxy (–OH) group at 5- and/or 6-position of benzofuran motif
could be considered as a promising scaffolds for the further development of iNOS inhibitors for potential
anti-inflammatory applications.
Ó 2016 Elsevier Ltd. All rights reserved.
In multi-cellular organisms, inflammation is a cardinal host
defense response to tissue damage, injury, infectious agents or
autoimmune responses and is an integral part of the immune
response.1 Symptoms of inflammation include swelling, redness
of the area, pain, and sometimes loss of function.2 Based on time
and pathological features, it can be either acute or chronic. Inflam-
mation is present in several disorders and diseases like atheroscle-
rosis, diabetes and cancer. Increased blood supply, enhanced
vascular permeability and migration of immune cells occur at
damaged sites. In this process, activated inflammatory cells (neu-
trophils, eosinophils, mononuclear phagocytes and macrophages)
secrete increased amounts of nitric oxide (NO), prostaglandins
(PGs) and cytokines, such as interleukin (IL)-1b, IL-6, and tumor
necrosis factor (TNF). Among these, two of the most prominent
are PGs and NO. PGs are produced by cyclooxygenase (COX, which
mainly having two forms COX-1 and COX-2) by arachidonic acid
pathway. NO is a small, lipophilic, diffusible and transient free-rad-
including vasodilatation, thermoregulation, and neuromodulation.
High levels of NO is produced ‘on-demand’ by the inducible (iNOS)
enzyme, to help kill tumors, viruses and bacteria. Both underpro-
duction and overproduction of NO have been linked to various
human pathologies. Insufficient NO production from eNOS and
nNOS can lead to hypertension, atherosclerosis, and cardiovascular
disease, whereas excess NO production by iNOS can cause inflam-
mation, inflammatory bowel disease (IBD), rheumatoid arthritis,
asthma, diabetes, stroke, cancer and neurodegenerative disorders.3
Therefore, control of the excess NO production by inhibition of
iNOS may exert anti-inflammatory effects.
Traditional non-steroidal anti-inflammatory drugs (tNSAIDs)
and aspirin usage is general practice in the therapeutic approach
to alleviate the symptoms associated with both acute and chronic
inflammatory diseases. Their activity is most likely mediated
through their ability to inhibit COX enzymes. However, their
long-term oral administration is restricted because of the high inci-
dence of side effects, particularly those relating to the gastroin-
testinal (GI) tract, renal and cardiovascular systems due to the
inhibition of the housekeeping enzyme COX-1 along with COX-
2.4 Later, selective COX-2 inhibitors (COXIBs) were introduced to
reduce the risks. While these COXIBs did reduce the risk of GI
injury, like the tNSAIDs, they are also appeared to increase the risk
of cardiovascular events, such as heart attack and stroke. Hence,
ical species generated from L-arginine by three types of nitric oxide
synthase (NOS) enzymes. It acts as a double-edged sword. Physio-
logically vital amount of NO produced by the endothelial (eNOS)
and neuronal (nNOS) enzymes which is crucial for signaling,
⇑
Corresponding author. Tel.: +82 33 248 2075; fax: +82 33 256 3421.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.