title: Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen-Antioxidant Mutual Prodrugs.
abstract: Dexibuprofen-antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen5a-cwere obtained by reacting its -COOH group with chloroacetyl derivatives3a-c. The in vitro hydrolysis data confirmed that synthesized prodrugs5a-cwere stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of5c(p< 0.001) is more significant than the parent dexibuprofen. The prodrug5cproduced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs5aand5bshowed significant inhibition of pyrexia (p< 0.001). The analgesic activity of5ais more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug5awas more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs5a-cinteracts with the residues present in active binding sites of target protein. The stability of drug-target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan. mzchem@yahoo.com.
authors.forename: Zaman
authors.initials: Z
authors.lastname: Ashraf
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy University of Sargodha, Sargodha 40100, Pakistan. alam_yuchi@yahoo.com.
authors.lastname: Alamgeer
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan. raqiqa_chem@yahoo.com.
authors.forename: Raqiqatur
authors.initials: R
authors.lastname: Rasool
authors.affiliation: Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314701, Korea. mubashirhassan_gcul@yahoo.com.
authors.forename: Mubashir
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy University of Sargodha, Sargodha 40100, Pakistan. haseebahsan110@yahoo.com.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Ahsan
authors.affiliation: Faculty of Pharmacy, BahauddinZakria University, Multan 60800, Pakistan. samina.afzal@bzu.edu.pk.
authors.forename: Samina
authors.initials: S
authors.lastname: Afzal
authors.affiliation: Faculty of Pharmacy, BahauddinZakria University, Multan 60800, Pakistan. khurram.afzal@bzu.edu.pk.
authors.forename: Khurram
authors.initials: K
authors.lastname: Afzal
authors.affiliation: Department of Orthopaedic Surgery & Biomedical Engineering, University of Tennessee Health Science Center-Campbell Clinic, Memphis, TN 38104, USA. hcho4@uthsc.edu.|Research 151, Veterans Affairs Medical Center, Memphis, TN 38104, USA. hcho4@uthsc.edu.
authors.forename: Hongsik
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Biology, College of Natural Sciences, Kongju National University, Gongju 314701, Korea. ksj85@kongju.ac.kr.
authors.forename: Song Ja
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011355:Prodrugs; C539402:dexibuprofen; D051546:Cyclooxygenase 2; D007052:Ibuprofen
keywords: antioxidants; dexibuprofen; in vitro hydrolysis; molecular dynamics simulation; mutual prodrugs; nonsteroidal anti-inflammatory drugs (NSAIDs); pharmacological activity