title: Aryl/heteroaryl Substituted Celecoxib Derivatives as COX-2 Inhibitors: Synthesis, Anti-inflammatory Activity and Molecular Docking Studies.
abstract: BACKGROUND
  Cyclooxygenase (COX-2) inhibitors have been developed to provide better anti-inflammatory and analgesic efficacy than those of traditional NSAIDs. Several compounds having selective COX-2 inhibitors such as SC-558, Celecoxib, Rofecoxib, Valdecoxib and Etoricoxib are marketed as new generation NSAIDs and block the production of prostaglandins (PGs) in inflammatory cells. New anti-inflammatory agents with improved potency and safety profile are still needed.
  
  
  OBJECTIVE
  As a part of our continuation research work towards new anti-inflammatory agents, the synthesis of N-substituted aryl/heteroaryl-pyrazole-1yl benzene sulfonamide (Celecoxib) derivatives, their anti-inflammatory activity in both methods in vitro and in vivo and molecular docking study on COX-2 enzyme will be discussed in this study.
  
  
  METHODS
  A series of N-substituted (aryl/heteroarylpyrazol-1-yl)benzenesulfonamide (Celecoxib) derivatives was synthesized and characterized them using IR, NMR (1H and 13C), mass and elemental analyses. Anti-inflammatory activity of the title compounds was evaluated by in vitro initially using albumin denaturation and membrane stabilization methods, enzymatic activity against COX-2 enzyme using colorimetric assay and then in vivo by carrageenan induced paw oedema and cotton pellet induced granuloma methods. The docking study was performed, to find the binding mode of the title compounds with the binding site of the COX-2 enzyme.
  
  
  RESULTS
  The biological activity screening data disclosed that some of the compounds 5b, 5e, 5f and 5i exhibited potent anti-inflammatory activity in both methods, in vitro and in vivo. The enzymatic assay on COX-2 enzyme demonstrated that few compounds potently inhibit COX-2 enzyme activity with IC50 of &lt;0.89 &#956;M. Unexpectedly, compound 5e (IC50, 0.62±0.17 &#956;M) showed more potent COX-2 inhibited activity than that of parent drug, celecoxib (IC50, 0.62±0.25 &#956;M) and the standard, flufenamic acid (IC50, 0.71±0.12 &#956;M).
  
  
  CONCLUSIONS
  The bio-screening data, in vitro and in vivo anti-inflammatory activity and COX-2 enzymatic assay revealed that few N-substituteed aryl/heteroaryl-pyrazol-1-yl) benzene sulfonamides showed potent activity and compound 5e showed more potent COX-2 inhibit activity than that of parent drug, celecoxib and the standard, flufenamic acid. Moreover, all the newly synthesized title products were bonded well with good binding energies in the sight of COX-2 enzyme. Therefore, the described study might provide sustained information to the development of new series of derivatives with potent drug like activity.
authors.affiliation: Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India.
authors.forename: Golla
authors.initials: G
authors.lastname: Madhava
authors.affiliation: Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India.
authors.forename: Katla V
authors.initials: KV
authors.lastname: Ramana
authors.affiliation: Department of Zoology, Sri Venkateswara University, Tirupati-517502, Andhra Pradesh, India.
authors.forename: Saddala M
authors.initials: SM
authors.lastname: Sudhana
authors.affiliation: Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India.
authors.forename: Devineni S
authors.initials: DS
authors.lastname: Rao
authors.affiliation: Aptus Bio Sciences Private Limited, Yenugonda, Mahaboobnagar-509 002, Telangana, India.
authors.forename: Kuntrapakam H
authors.initials: KH
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, Dravidian University, Kuppam, Chittoor-517 426, Andhra Pradesh, India.
authors.forename: Valluru
authors.initials: V
authors.lastname: Lokanatha
authors.affiliation: Department of Zoology, Sri Venkateswara University, Tirupati-517502, Andhra Pradesh, India.
authors.forename: Asupatri U
authors.initials: AU
authors.lastname: Rani
authors.affiliation: Department of Chemistry, Sri Venkateswara University, Tirupati-517502, Andhra Pradesh, India.
authors.forename: Chamarthi N
authors.initials: CN
authors.lastname: Raju
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D000068579:Celecoxib / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D005439:Flufenamic Acid; D000068579:Celecoxib
keywords: Albumin; NSAIDs; anti-inflammatory activity; celecoxib derivatives; cyclooxygenase-2; molecular docking study