Letter pubs.acs.org/acsmedchemlett
2‑(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation Kapileswar Seth,† Sanjeev K. Garg,† Raj Kumar,† Priyank Purohit,† Vachan S. Meena,‡ Rohit Goyal,§,∥ Uttam C. Banerjee,‡ and Asit K. Chakraborti*,† †
Department of Medicinal Chemistry and ‡Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062 Punjab, India § Indo-Soviet Friendship (ISF) College of Pharmacy, Moga, 142 001 Punjab, India S Supporting Information *
ABSTRACT: The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a−m have been synthesized by Suzuki reaction of 2-(2bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs. KEYWORDS: 2-(2-Arylphenyl)benzoxazoles, novel anti-inflammatory scaffold, 3D QSAR, cyclooxygenase-2 selective, in vivo potency
I
uncontrolled inflammatory cascades is responsible for various diseases such as chronic asthma, rheumatoid and osteo-arthritis, multiple sclerosis, inflammatory bowl diseases and psoriasis,1 diabetic nephropathy,2 tumor initiation, and malignant progression.3 Pain is the most prevalent inflammatory symptom needing medical attention with an estimated amount of 105 million of affected people in the US amounting to the financial burden of US$ 100 billion per annum to the health care expenditure.4 Rheumatoid arthritis (RA) and osteoarthritis (OA) are the sever forms of inflammatory pain with a decade span of the disease shortening the life expectancy.5,6 The major complication of RA is its association with acceleration of cardiovascular diseases (CVDs).7 The nonsteroidal antiinflammatory drugs (NSAIDs) are used worldwide for therapeutic intervention of pain and inflammation. These exert their anti-inflammatory activity by inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes.8 The side effects such as gastric ulcer and gastrointestinal bleeding associated with the traditional NSAIDs (nonselective inhibitors of COX-1 and COX-2) led to the development of selective COX-2 inhibitors as a new class of NSAIDs generally recognized as coxibs.9 The recent withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib due to adverse cardiovascular side effects10 fuelled a debate about the increased cardiovascular risk associated with existing COX-2 inhibitors11 pressing the need for novel anti-inflammatory scaffold. The additional findings on therapeutic benefit of
nflammation is the natural defense mechanism of the body to deal with infection and tissue damage. However,
Figure 1. Topological model for selective COX-2 inhibition through scaffold-hopping.
Scheme 1. Synthesis of 3a−ma
a Reagents and conditions: (a) Pd(PPh3)4 (3 mol %), Na2CO3 (1.2 equiv), DMF, reflux, 2.5−6 h.
© 2014 American Chemical Society
Received: December 7, 2013 Accepted: February 17, 2014 Published: February 17, 2014 512
dx.doi.org/10.1021/ml400500e | ACS Med. Chem. Lett. 2014, 5, 512−516
ACS Medicinal Chemistry Letters
Letter
Table 1. In Vitro COX-1 and COX-2 Inhibitory Potency of 2-Benzoxazolyl Biarylsa % inhibitionb,c entry
compd
COX-1
COX-2
COX-2/COX-1
1 2 3 4 5 6 7
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n
15
3o
16
4
10.61 ± 1.41 14.85 ± 2.83 86.62 ± 1.41 59.85 ± 2.12 14.85 ± 3.54 43.45 ± 2.12 81.36 ± 2.83 0.67 ± 0.04e 33.94 ± 3.54 16.97 ± 2.12 8.46 ± 2.12 11.67 ± 3.54 57.95 ± 2.83 40.85 ± 2.83 94.90 ± 4.24 0.41 ± 0.02e 75.12 ± 2.12 1.34 ± 0.05e 100 0.29 ± 0.02e
0.44 ± 0.09 0.78 ± 0.24 1.49 ± 0.08 0.80 ± 0.07 0.87 ± 0.01 10.68 ± 6.07 12.61 ± 2.33
8 9 10 11 12 13 14
23.98 ± 1.41 19.08 ± 2.12 58.23 ± 4.24 74.87 ± 3.54 17.13 ± 4.24 4.07 ± 2.12 6.45 ± 1.41 46.78 ± 0.02e 2.19 ± 0.71 10.28 ± 2.12 1.65 ± 0.55 3.45 ± 1.41 6.58 ± 2.12 8.46 ± 2.12 7.56 ± 4.24 46.25 ± 0.04e 10.80 ± 2.12 45.06 ± 0.04e 26.68 ± 2.12 27.25 ± 0.04e
SId
69.82 ± 3.71 15.50 ± 6.65 1.65 ± 0.55 1.57 ± 0.42 3.38 ± 2.41 8.81 ± 2.43 4.83 ± 1.54 12.55 ± 7.57 112.80 ± 5.62 6.96 ± 1.17 33.62 ± 1.21 3.75 ± 0.30 92.87 ± 6.46
a
The enzyme inhibition studies were performed using COX inhibitor screening assay kit available commercially (catalog number 560131, Cayman chemical company) as per the manufacturer’s protocol (www.caymanchem.com). bResults are expressed as means of two determinations ± SD, and deviation from the mean is
