Design and Synthesis of Celecoxib and Rofecoxib Analogues as Selective Cyclooxygenase-2 (COX-2) Inhibitors:  Replacement of Sulfonamide and Methylsulfonyl Pharmacophores by an Azido Bioisostere

Habeeb, Amgad G.; Rao, P Narasimha; Knaus, Edward E.

doi:10.1021/jm010153c

Cited by 209 publications

(106 citation statements)

References 13 publications

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“…The smaller valin residue at COX-2 forms a hydrophobic area and secondary pocket, due to pharmacophore SO2Me and SO2NH2 [39]. This secondary pocket in the COX-2 receptor is absent in COX-1, and become a target for the COX-2 selective inhibitor [40].…”

Section: Resultsmentioning

confidence: 99%

In Silico Molecular Docking of Xanthone Derivatives as Cyclooxygenase-2 Inhibitor Agents

Miladiyah

Jumina

Haryana

et al. 2017

Int J Pharm Pharm Sci

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Objective: To demonstrate the potential ofdifferent xanthone derivatives as cyclooxygenase-2 (COX-2) inhibitor agents and their selectivity against cycloooxygenase-1 (COX-1) and COX-2 using molecular simulation. Methods:Nine novel xanthone derivatives (compounds A-I) were employed to dock against protein COX-2 (Protein Data Bank/PDB ID: 1CX2) and COX-1 (PDB ID: 3N8Z). Celecoxib, a selective COX-2 inhibitor, was chosen as a control compound. The free binding energy produced by the docking was scored using Protein-Ligand Ant System (PLANTS) and the hydrogen bonds (H-bonds) between ligands and enzymes were visualised using Pymol.Results: Molecular docking studies revealed that celecoxib docked to the active site of COX-2 enzyme, but not to COX-1; where as xanthone derivatives docked to the active site of both COX-2 and COX-1. Free binding energy of xanthone derivatives ranged between-73, 57 to-79,18 and between-73,06 to-79,25 against COX-2 and COX-1, respectively, and-78,13 against celecoxib. H-bonds in the molecule of xanthone derivatives and COX-2 protein were found in amino acid residues Arg 120 , Tyr 355 , Tyr 385 , and Ser 353 . There was an insignificant difference between the free binding energyof xanthone derivatives against COX-2 and against COX-1, suggesting that their inhibition was non-selective. Conclusion:In conclusion, in silico studies showed that xanthone derivatives could be effective as potential inhibitors against COX-2, although they are not selective.

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Section: Resultsmentioning

confidence: 99%

In Silico Molecular Docking of Xanthone Derivatives as Cyclooxygenase-2 Inhibitor Agents

Miladiyah

Jumina

Haryana

et al. 2017

Int J Pharm Pharm Sci

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“…In an elegant study, Knaus and coworkers showed that the para-SO 2 NH 2 pharmacophore in celecoxib and the para-SO 2 Me pharmacophore in rofecoxib can be replaced by a linear azide (N 3 ) or a sulfonyl azido group. This was the first example where a crucial binding site structural difference in COX-1 and COX-2 was exploited (95,96). Replacement of His513 in COX-1 by Arg513 in COX-2 has been reported to play a key role in the hydrogen-bond network of the COX active site (97).…”

Section: Diarylheterocycles As Selective Cox-2 Inhibitorsmentioning

confidence: 99%

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Rao

Knaus²

2008

J Pharm Pharm Sci

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598

391

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ABSTRACT. Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

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“…20 The other derivatives display antidepressant, 21 antiarthritic 22 and cerebroprotecting 23 properties. Some aryl pyrazoles were reported to be non-nucleoside human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, 24 COX-2 inhibitor, [25][26][27] activator of the nitric oxide receptor and to have soluble guanylate cyclase activity. 28 Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invansion by secondary pathogens.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

Srinivas

Sunitha²,

Karthik³

et al. 2017

ACSi

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Design and Synthesis of Celecoxib and Rofecoxib Analogues as Selective Cyclooxygenase-2 (COX-2) Inhibitors: Replacement of Sulfonamide and Methylsulfonyl Pharmacophores by an Azido Bioisostere

Cited by 209 publications

References 13 publications

In Silico Molecular Docking of Xanthone Derivatives as Cyclooxygenase-2 Inhibitor Agents

In Silico Molecular Docking of Xanthone Derivatives as Cyclooxygenase-2 Inhibitor Agents

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

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