title: Design, synthesis and biological evaluation of bivalent benzoxazolone and benzothiazolone ligands as potential anti-inflammatory/analgesic agents.
abstract: Benzoxazolone and benzothiazolone were used as template blocks to develop two series of dimers as anti-inflammatory and analgesic agents based on the concept of bivalent ligands. The first series (I) involved varying the carbon chain lengths extending from the piperazine core to the nitrogen atom of the dibenzo[d]oxazol-2(3H)-one or dibenzo[d]thiazol-2(3H)-one. The second series (II) was designed by changing the attachment point. All compounds were screened for their in vitro anti-inflammatory activity in terms of the inhibition of inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB). Seventeen compounds inhibited both targets. Eleven of them exhibited IC50 values below 3μM while five compounds showed IC50 values of 1μM or below. Most of the compounds were found to be devoid of cytotoxicity against mammalian kidney and solid tumors cell lines up to 25μg/mL. In vivo anti-inflammatory and antinociceptive studies revealed that compounds 3j, 5t and 8b have significant anti-inflammatory and analgesic activity comparable to that of indomethacin and ketorolac, respectively.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, MS 38677, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: Department of Psychology, College of Liberal Arts, The University of Mississippi, MS 38677, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: White
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, MS 38677, USA; Department of Psychology, College of Liberal Arts, The University of Mississippi, MS 38677, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Sufka
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, MS 38677, USA; Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, MS 38677, USA. Electronic address: cmccurdy@olemiss.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D019281:Dimerization; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D014709:Vero Cells
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052160:Benzothiazoles; D001583:Benzoxazoles; D016328:NF-kappa B; C017057:benzoxazolone; D002351:Carrageenan; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: Anti-inflammatory/analgesic; Benzothiazolone; Benzoxazolone; Dimers; NF-κB; Nociception; Piperazine; iNOS