title: Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: Synthesis, biological evaluation and molecular modeling studies.
abstract: 3-Substituted-1,2,4-triazole-5-thiones are versatile synthetic intermediates for the preparation of several biologically active N-bridged heterocyclic compounds, given that they have two reactive sites, thiocarbonyl and an amine nitrogen (N1/N4). For several years, our interest has focused on the synthesis of novel heterocyclic systems derived from 3-substituted-1,2,4-triazole-5-thiones having analgesic/anti-inflammatory activity. In this study, a series of novel thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives bearing naproxen was synthesized and evaluated for their in vivo analgesic and anti-inflammatory properties in acute experimental pain and inflammation models. The compounds were also tested for their ulcerogenic potential. Our findings showed that all the newly synthesized derivatives attenuate nociception and inflammation compared with a control. All the synthesized compounds exhibited much lower ulcerogenic risk than the standard drugs indomethacin and naproxen. Some compounds with significant analgesic and/or anti-inflammatory activities as well as low ulcer scores were further evaluated for in vitro COX-1 and COX-2 inhibitory potential in a COX-catalyzed prostaglandin biosynthesis assay. Among the tested compounds, compound 1q showed the highest selectivity index (SI) of 4.87. The binding mode for some of the tested compounds to the cyclooxygenase (COX) enzymes was predicted using docking studies.
authors: Hacettepe University, Faculty of Science, Department of Chemistry, 06800 Ankara, Turkey.
authors: Deniz
authors: D
authors: Sarigol
authors: Hacettepe University, Faculty of Science, Department of Chemistry, 06800 Ankara, Turkey.
authors: Ayse
authors: A
authors: Uzgoren-Baran
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100 Ankara, Turkey.
authors: Banu Cahide
authors: BC
authors: Tel
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100 Ankara, Turkey.
authors: Elif Inci
authors: EI
authors: Somuncuoglu
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100 Ankara, Turkey.
authors: Inci
authors: I
authors: Kazkayasi
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey.
authors: Keriman
authors: K
authors: Ozadali-Sari
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey.
authors: Oya
authors: O
authors: Unsal-Tan
authors: Sirnak University, Faculty of Engineering, Department of Renewable Energy Systems, 73100 Sırnak, Turkey.
authors: Gurol
authors: G
authors: Okay
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey.
authors: Mevlut
authors: M
authors: Ertan
authors: Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey. Electronic address: tbirsen@hacettepe.edu.tr.
authors: Birsen
authors: B
authors: Tozkoparan
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D004195:Disease Models, Animal; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007249:Inflammation; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009288:Naproxen / Q000737:chemistry / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013871:Thiones / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D013844:Thiazoles; D013871:Thiones; D014230:Triazoles; D009288:Naproxen; D002351:Carrageenan
keywords: Analgesic/anti-inflammatory activity; Molecular modeling; Naproxen derivatives; Thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one; Ulcerogenic risk