2-(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation

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-(2-bromophenyl)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 nflammation is the natural defense mechanism of the body to deal with infection and tissue damage. However, 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 effects 10 fuelled a debate about the increased cardiovascular risk associated with existing COX-2 inhibitors 11 pressing the need for novel anti-inflammatory scaffold. The additional findings on therapeutic benefit of

Design, Synthesis and Biological Evaluation of 2 (((5‐aryl‐1,2,4‐oxadiazol‐3‐yl)methyl)thio)benzo[d]oxazoles: New Antiinflammatory and Antioxidant Agents

“…The benzoxazoles were reported to have good anti‐inflammatory activity by targeting COX‐2 isoenzyme . The, 2‐(((5‐aryl‐1,2,4‐oxadiazol‐3‐yl)methyl)this)benzo[ d ]oxazoles ( 5 a‐5 o ) reported herein in this paper was designed by scaffold hopping approach ( Figure ).…”

“…Shafi et al ., reported, 2‐((1‐(4‐Fluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methylthio)benzothiazole ( IV ) selective COX‐2 inhibitor (COX‐2/COX‐1=0.44) in which benzthiazole nucleus was attached to aryl linked triazole through the methylthio (‐SCH 2 ‐) linkage . Similarly Seth et al ., reported, 2′‐benzoxazol‐2‐yl‐3‐chlorobiphenyl‐4‐ol, selective COX‐2 inhibitor (IC 50 =0.41±0.02 μM) ( V ) . Earlier our research group reported the (4‐(3‐((benzo[d]thiazol‐2‐ylthio)methyl)‐1,2,4‐oxadiazol‐5‐yl)phenyl) (morpholino)methanone ( VI ) as selective COX‐2 inhibitor (IC 50 =5.0 μM) .…”

Mechanistic Study on the Formation of Compounds from Thioureas

“…Benzoxazoles are a class of heterocyclic compounds exhibiting therapeutical activities (Figure 2), such as, antifungal agents [38][39][40], cytotoxic compounds [41], as anti-inflammatory agents [42], as HIV-1 protease inhibitor [43], as an antibiotic [44], as CpIMPDH inhibitors [45], nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTI) [46], and antitumour agents [47].…”

Recent Advances in the Development of Pharmacologically Active Compounds that Contain a Benzoxazole Scaffold

“…[121] Recently,C hakrabortia nd co-workers synthesized some benzoxazole-based compounds that demonstratedp otentialC OX inhibition, and three of them (i.e., 95, 96,a nd 97)h avee merged as selective in vitro COX-2 inhibitors with in vivo anti-inflammatory potencyt hat is better than that of the standard anti-inflammatory drugs diclofenac and celecoxib ( Figure 39). [122] Inducible microsomal prostaglandin E 2 synthase-1 (mPGES-1), which is involvedi nC OX-2-mediated PGE2 production, has also become an ew therapeutic target of considerable interest for the treatment of inflammation and pain. [123] Compound 98 was found to be ap otent inhibitor of mPGES-1 and demonstratedg ood in vivo pharmacokinetic properties when studied in rats (Figure 40).…”