Abstract
In order to develop new selective COX-2 inhibitors, a new series of 2-phenyl-4H-chromen-4-one derivatives possessing a methylsulfonyl pharmacophore group at the para position of the C-4 phenyl ring were designed, synthesized, and evaluated for cyclooxygenase-2 inhibitory activity. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) as a potent COX-2 inhibitor (IC50 = 0.07 μM) with a high COX-2 selectivity index (SI = 287.1) comparable to the reference drug celecoxib (COX-2 IC50 = 0.06 μM; COX-2 SI = 405). A molecular modeling study where 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) was docked into the active site of COX-2 showed that the p-MeSO2 substituent on the C-4 phenyl ring was well-oriented in the vicinity of the COX-2 secondary pocket (Arg513, Val523, and His90) and the carbonyl group of the chromene ring could interact with Ser530. The structure-activity data acquired indicated that the nature and size of the substituent on the C-3 chromene scaffold are important for COX-2 inhibitory activity. Our results also indicated that the chromene moiety constitutes a suitable template to design new COX-2 inhibitors.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs that provide analgesic, antipyretic, and anti-inflammatory effects. Their pharmacological effects arise from the non-selective inhibition of the cyclooxygenase (COX) enzyme, a key enzyme in the arachidonic acid pathway that leads to the biosynthesis of prostaglandins
The selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders when compared with NSAIDs
As part of our continuing program to discover selective COX-2 inhibitors, we describe the synthesis and biological evaluation of a group of 2-phenyl4H-chromen-4-one derivatives possessing a methylsulfonyl pharmacophore at the para position of the C-4 phenyl ring in conjunction with various substitutes at the C-3 chromene moiety
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are an important class of drugs that provide analgesic, antipyretic, and anti-inflammatory effects. In order to obtain new COX-2 inhibitors with better safety and more efficacy, there is still a need to do new investigations on the development of new scaffolds as COX-2 inhibitors In this regard, we reported several investigations describing the design, synthesis, and COX inhibitory activities of a novel class of compounds possessing an acyclic 1,3-diarylprop-2-en-1-one structural template [16]. We reported several investigations describing the design, synthesis, and molecular modeling studies for a group of 2-phenyl-4-carboxylquinolines possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring in conjunction with various substituents at the C-7 and C-8 quinoline ring [17] In this group, 2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (see Structure B), having lipophilic substituents at the C-7 and C-8 positions, exhibited higher selectivity for COX-2 inhibition than the reference drug celecoxib. The acyclic 1,3-diarylprop-2-en-1-one structural template (A) as a lead compound was converted to a cyclic ring (chromene) similar to 2-aryl quinolines (B) to fulfill the goals of better COX-2 inhibitory potency and selectivity
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