title: Structure-activity relationship of novel series of 1,5-disubstituted tetrazoles as cyclooxygenase-2 inhibitors: Design, synthesis, bioassay screening and molecular docking studies.
abstract: A novel class of modified 1,5-disubstituted tetrazoles was designed and synthesized, their biological activity as cyclooxygenases inhibitors was screened, and their molecular docking studies were performed. The structural modifications of the first category included the 4-methylsulfonyl phenyl at C-1 of the central moiety and the linkers (-OH, -CH2OH, -CH2CH2OH) with different lengths at the para position of the N-1 phenyl group. For the second category, the 4-methylsulfonyl phenyl group at C-1 was replaced with 4-aminosulfonyl phenyl. While for the third category, a methylene unit was inserted between the C-1 of the tetrazole central ring and the 4-(methylsulfonyl)phenyl group, keeping the same linkers of various extensions at the para position of the N-1 phenyl group. Among the screened compounds, tetrazole 4i showed the best inhibition potency and selectivity values for both COX-2 enzyme (IC50=3μM, SI>67) and COX-1 isoenzyme (IC50>200μM). Compounds 4e, 4h, and 4i, which have the highest inhibition potency toward COX-2 were selected for the molecular docking studies to verify their inhibition and selectivity for COX-2 over COX-1 with their modified structure. The obtained theoretical studies are in agreement with the in vitro bioassay screening results, which supports the importance of the structural modifications for our studied compounds.
authors: Faculty of Science, American University of Madaba, PO Box 2882, Amman 11821, Madaba, Jordan. Electronic address: b.jawabrah@aum.edu.jo.
authors: Baker
authors: B
authors: Jawabrah Al-Hourani
authors: Faculty of Science, American University of Madaba, PO Box 2882, Amman 11821, Madaba, Jordan.
authors: Wajdy
authors: W
authors: Al-Awaida
authors: Faculty of Health Sciences, American University of Madaba, Madaba, Jordan.
authors: Khalid Z
authors: KZ
authors: Matalka
authors: Department of Chemistry, The Hashemite University, Zarqa, Jordan.
authors: Musa I
authors: MI
authors: El-Barghouthi
authors: Department of Chemistry, The Hashemite University, Zarqa, Jordan.
authors: Fatima
authors: F
authors: Alsoubani
authors: Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
authors: Frank
authors: F
authors: Wuest
mesh_terms: D001681:Biological Assay; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D013777:Tetrazoles
keywords: 1,5-Disubstituted tetrazoles; Aminosulfonyl; COX-1 inhibitors; COX-2 inhibitors; Methylsulfonyl; Molecular docking; Structure–activity relationship