Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Medicinal Chemistry
  4. Fast Track Articles
  5. Fast Track Article
image of Mechanochemical Synthesis of Diclofenac Conjugates with Glucosamine and Chitosan Exhibiting COX-2 Selective Ulcer Safe Anti-inflammatory Activity

Abstract

Introduction

Non-steroidal anti-inflammatory drugs are associated with severe gastrointestinal irritation upon prolonged use, largely due to their carboxylic (-COOH) functional group.

Aim

To address this issue, we aimed to synthesize diclofenac conjugates with glucosamine and chitosan, converting the -COOH group into an amide (-CONH-) a mechanochemical, environmentally friendly method.

Method

In this study, diclofenac acid was first converted to its acid chloride using thionyl chloride under mechanochemical conditions and subsequently reacted with glucosamine base and chitosan. The resulting conjugates were evaluated for anti-inflammatory activity through the rat-paw edema test, along with ulcerogenicity, COX inhibition assays, and cardiovascular assessment.

Result

The mechanochemical approach provided high yields (>90%) and resulted in conjugates that significantly reduced paw edema (62.3 ± 2.3% for diclofenac-glucosamine and 58.5 ± 1.6% for diclofenac-chitosan) compared to diclofenac sodium (49.0 ± 1.3%) after 5 h. Notably, the conjugates were ulcer-safe, as no gastric lesions were observed, unlike the multiple lesions detected in animals treated with diclofenac sodium. Both conjugates also demonstrated a high degree of COX-2 selectivity and cardiovascular safety.

Conclusion

This study highlights the potential of mechanochemical synthesis for efficient amide formation, avoiding the need for hydroxyl group protection.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673352652241217090558
2025-01-02
2025-04-25

  • From This Site

    /content/journals/cmc/10.2174/0109298673352652241217090558
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. LipinskiJ.R.A. ThillierY. MorisseauC. SebastianoC.S.Jr SmithB.C. HallC.D. KatritzkyA.R. Molecular docking-guided synthesis of NSAID–glucosamine bioconjugates and their evaluation as COX-1/COX-2 inhibitors with potentially reduced gastric toxicity.Chem. Biol. Drug Des.202198110211310.1111/cbdd.1385533955172
     [Google Scholar]
  2. UzzamanM. HasanM.K. MahmudS. FatemaK. MatinM.M. Structure-based design of new diclofenac: Physicochemical, spectral, molecular docking, dynamics simulation and ADMET studies.Inform. Med. Unlocked20212510067710.1016/j.imu.2021.100677
     [Google Scholar]
  3. HunterD.J. ZeinstraB.S. Osteoarthritis.Lancet2019393101821745175910.1016/S0140‑6736(19)30417‑931034380
     [Google Scholar]
  4. AltmanR. BoschB. BruneK. PatrignaniP. YoungC. Advances in NSAID development: Evolution of diclofenac products using pharmaceutical technology.Drugs201575885987710.1007/s40265‑015‑0392‑z25963327
     [Google Scholar]
  5. IbrahimM.M. ElsamanT. NourA.M.Y. Synthesis, anti-inflammatory activity, and in silico study of novel diclofenac and isatin conjugates.Int. J. Med. Chem.2018201811110.1155/2018/913978630009055
     [Google Scholar]
  6. UlubayM. YurtK.K. KaplanA.A. AtillaM.K. The use of diclofenac sodium in urological practice: A structural and neurochemical based review.J. Chem. Neuroanat.201887323610.1016/j.jchemneu.2017.02.00528179185
     [Google Scholar]
  7. NgoS.N.T. AddisonC.J. Are COX-2 selective NSAIDs associated with less GI, Renal, and cardiovascular side effects: Evidence from animals treated with NSAIDs.Annu. Res. Rev. Biol.20182961810.9734/ARRB/2018/45152
     [Google Scholar]
  8. GonzálezM.E.L. PatrignaniP. TacconelliS. RodríguezL.A.G. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding.Arthritis Rheum.20106261592160110.1002/art.2741220178131
     [Google Scholar]
  9. HladkykhF.V. ChyzhM.O. Characteristics of the mechanisms of anti-inflammatory action of cryopreserved placenta extract and diclofenac sodium by their threaded administration.Mod. Med. Technol.202134147
     [Google Scholar]
  10. SchmidtM. SørensenH.T. PedersenL. Diclofenac use and cardiovascular risks: Series of nationwide cohort studies.BMJ2018362k342610.1136/bmj.k342630181258
     [Google Scholar]
  11. ChengQ. LiR. HeY. ZhuY. KangY. JiX. Genetically engineered cellular nanovesicles: Theories, design and perspective.Adv. Funct. Mater.20243446240784210.1002/adfm.202407842
     [Google Scholar]
  12. YeJ. FanY. SheY. ShiJ. YangY. YuanX. LiR. HanJ. LiuL. KangY. JiX. Biomimetic self-propelled asymmetric nanomotors for cascade-targeted treatment of neurological inflammation.Adv. Sci.20241122231021110.1002/advs.202310211
     [Google Scholar]
  13. FanY. YeJ. KangY. NiuG. ShiJ. YuanX. LiR. HanJ. JiX. Biomimetic piezoelectric nanomaterial-modified oral microrobots for targeted catalytic and immunotherapy of colorectal cancer.Sci. Adv.20241019eadm956110.1126/sciadv.adm956138718119
     [Google Scholar]
  14. HiguchiK. UmegakiE. WatanabeT. YodaY. MoritaE. MuranoM. TokiokaS. ArakawaT. Present status and strategy of NSAIDs-induced small bowel injury.J. Gastroenterol.200944987988810.1007/s00535‑009‑0102‑219568687
     [Google Scholar]
  15. SuryawanshiS.B. Synthesis of various esters of diclofenac (NSAIDs) as pro-drugs and their biological evaluation.Chem. Sci. Trans.20143562565
     [Google Scholar]
  16. UllahN. HuangZ. SanaeeF. DimitrescuR.A. AldawsariF. JamaliF. BhardwajA. IslamN.U. MartínezV.C.A. NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect – why do we keep using it?J. Enzyme Inhib. Med. Chem.20163161018102810.3109/14756366.2015.108884026403939
     [Google Scholar]
  17. BosquesiP.L. MeloT.R.F. VizioliE.O. SantosJ.L. ChungM.C. Anti-inflammatory drug design using a molecular hybridization approach.Pharmaceuticals20114111450147410.3390/ph411145027721332
     [Google Scholar]
  18. ElsamanT. AldeebO.A.A. FadlA.T. HamedelneilE.I. Synthesis, characterization and pharmacological evaluation of certain enzymatically cleavable NSAIDs amide prodrugs.Bioorg. Chem.20177014415210.1016/j.bioorg.2016.12.00528040207
     [Google Scholar]
  19. HarmanC.A. TurmanM.V. KozakK.R. MarnettL.J. SmithW.L. GaravitoR.M. Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides.J. Biol. Chem.200728238280962810510.1074/jbc.M70133520017656360
     [Google Scholar]
  20. KalgutkarA.S. CrewsB.C. SalehS. PrudhommeD. MarnettL.J. Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors.Bioorg. Med. Chem.200513246810682210.1016/j.bmc.2005.07.07316169736
     [Google Scholar]
  21. RuberteA.C. AydilloC. SharmaA.K. SanmartínC. PlanoD. Vilsmeier reagent, NaHSe and diclofenac acid chloride: One-pot synthesis of a novel selenoindolinone with potent anticancer activity.RSC Advances20201063384043840810.1039/D0RA07332F35517563
     [Google Scholar]
  22. SaadiA.H.M. PangK.L. NirwanaI.S. ChinK-Y. Multifaceted protective role of glucosamine against osteoarthritis: Review of its molecular mechanisms.Sci. Pharm.20198743410.3390/scipharm87040034
     [Google Scholar]
  23. WalyN.E. RefaiyA. AborehabN.M. IL-10 and TGF-β: Roles in chondroprotective effects of glucosamine in experimental osteoarthritis?Pathophysiology2017241454910.1016/j.pathophys.2017.02.00528214084
     [Google Scholar]
  24. CapomacchiaA. GarnerS. BeachJ. Beach, glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods.Patent: US,8,361,990,B22005
  25. AdhikariH.S. YadavP.N. Anticancer activity of chitosan, chitosan derivatives, and their mechanism of action.Int J Biomater20182018295208510.1155/2018/2952085
     [Google Scholar]
  26. SahariahP. MássonM. Antimicrobial chitosan and chitosan derivatives: A review of the structure–activity relationship.Biomacromolecules201718113846386810.1021/acs.biomac.7b0105828933147
     [Google Scholar]
  27. DuttaP.K. DutaJ. TripathiV.S. Chitin and chitosan: Chemistry, properties and applications.J. Sci. Ind. Res.2004632031
     [Google Scholar]
  28. BhartiD. PradhanB. VermaS. KunduS.C. OliveiraJ.M. BanerjeeI. PalK. Chitosan-Based Gels for Regenerative Medicine ApplicationsPolysaccharides of Microbial Origin: Biomedical Applications202012510.1007/978‑3‑030‑42215‑8_65
     [Google Scholar]
  29. DreveS. KacsoI. BratuI. IndreaE. Chitosan-based delivery systems for diclofenac delivery: Preparation and characterization.J. Phys.: Conf. Ser.200918201206510.1088/1742‑6596/182/1/012065
     [Google Scholar]
  30. GhodeswarB.C. PophalikarR.N. BhojaniM.R. NagpalD. DhaneshwarS.S. Synthesis and pharmacological evaluation of mutual prodrugs of some nonsteroidal antiinflammatory drugs with glucosamine.Indian J. Pharm. Sci.200466773777
     [Google Scholar]
  31. KazimiS.G.T. IqbalM.S. MulliganC.C. BaseerM. RehmanA.U. FarooqiF. PersonJ.R. Mechanochemical synthesis of six Cu(II) complexes with selected thiols, their physicochemical characterization and interaction with DNA.J. Mol. Struct.2022126513343610.1016/j.molstruc.2022.133436
     [Google Scholar]
  32. GoodyearM.D.E. JericK.K. LemmensT. The declaration of Helsinki.Bmj20073357621624625
     [Google Scholar]
  33. WhiteleyP.E. DalrympleS.A. Models of inflammation: Carrageenan-induced paw edema in the rat.Curr. Protocols Pharmacol.199815610.1002/0471141755.ph0504s00
     [Google Scholar]
  34. SavjaniJ.K. MulamkattilS. VariyaB. PatelS. Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents.Eur. J. Pharmacol.2017801283410.1016/j.ejphar.2017.02.05128259712
     [Google Scholar]
  35. BhandariS.V. BotharaK.G. RautM.K. PatilA.A. SarkateA.P. MokaleV.J. Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives.Bioorg. Med. Chem.20081641822183110.1016/j.bmc.2007.11.01418248993
     [Google Scholar]
  36. KonopelskiP. UfnalM. Electrocardiography in rats: A comparison to human.Physiol. Res.201665571772510.33549/physiolres.933270
     [Google Scholar]
  37. JonesR.N. The infrared absorption spectra of deuterated esters: Iii. Methyl laurate.Can. J. Chem.196240230132010.1139/v62‑049
     [Google Scholar]
  38. NandiyantoA.B.D. OktianiR. RagadhitaR. How to read and interpret ftir spectroscope of organic material.Ind. J. Sci. Technol.2019419711810.17509/ijost.v4i1.15806
     [Google Scholar]
  39. TumerT.B. OnderF.C. IpekH. GungorT. SavranogluS. TokT.T. CelikA. AyM. Biological evaluation and molecular docking studies of nitro benzamide derivatives with respect to in vitro anti-inflammatory activity.Int. Immunopharmacol.20174312913910.1016/j.intimp.2016.12.00927988460
     [Google Scholar]
  40. HixsonA.W. CrowellJ.H. Dependence of reaction velocity upon surface and agitation.Ind. Eng. Chem.193123892393110.1021/ie50260a018
     [Google Scholar]
  41. DalirfardoueiR. KarimiG. JamialahmadiK. Molecular mechanisms and biomedical applications of glucosamine as a potential multifunctional therapeutic agent.Life Sci.2016152212910.1016/j.lfs.2016.03.02827012765
     [Google Scholar]
  42. NarsinghaniT. SharmaR. Synthesis, anti-inflammatory activities and docking studies of amide derivatives of meclofenamic acid.Chem. Pap.201771485786810.1007/s11696‑016‑0102‑7
     [Google Scholar]
  43. CoccoT.M. CongiuC. OnnisV. MorelliM. CauliO. Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties.Eur. J. Med. Chem.200338551351810.1016/S0223‑5234(03)00074‑612767601
     [Google Scholar]
  44. JüniP. NarteyL. ReichenbachS. SterchiR. DieppeP.A. EggerM. Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis.Lancet200436494502021202910.1016/S0140‑6736(04)17514‑415582059
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673352652241217090558
Loading
Mechanochemical Synthesis of Diclofenac Conjugates with Glucosamine and Chitosan Exhibiting COX-2 Selective Ulcer Safe Anti-inflammatory Activity
Bentham Science Publishers ; https://doi.org/10.2174/0109298673352652241217090558
/content/journals/cmc/10.2174/0109298673352652241217090558
/content/journals/cmc/10.2174/0109298673352652241217090558
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: glucosamine ; conjugates ; chitosan ; bio-conjugates ; Diclofenac sodium ; NSAIDs

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test