title: Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses.
abstract: A series of 15 novel compounds incorporating the thieno[2,3-b]thiophene moiety were synthesized. The chemical structures of these compounds were deduced from elemental analyses, (1)H NMR, (13)C NMR, and ESI-mass spectral data. The enzyme inhibition potential of these compounds was evaluated, in vitro, against β-glucuronidase, xanthine oxidase, and α-chymotrypsin enzymes. The cytotoxicity was evaluated by a cell viability assay utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Among the compounds tested, compound 3 was the most potent β-glucuronidase inhibitor with an IC50 value of 0.9 ± 0.0138 μM; it was much more active than the standard, d-saccharic acid 1,4-lactone (IC50=45.75 ± 2.16 μM). Compound 12, on the other hand, was the most potent as a xanthine oxidase inhibitor with an IC50 of 14.4 ± 1.2 μM. With the characterization of their mechanism of action and with further testing, these compounds could be useful candidates as anticancer drugs. In addition, the newly synthesized compounds were subjected to POM analyses to get insights about their degree of their toxicity.
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: Yahia@ksu.edu.sa.
authors.forename: Yahia Nasser
authors.initials: YN
authors.lastname: Mabkhot
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia; Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Ibrahimia, Alexandria 21321, Egypt. Electronic address: ambarakat@ksu.edu.sa.
authors.forename: Assem
authors.initials: A
authors.lastname: Barakat
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sammer
authors.initials: S
authors.lastname: Yousuf
authors.affiliation: Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
authors.affiliation: Institut für Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, Stuttgart 70569, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Frey
authors.affiliation: Laboratory of Chemical Material, FSO, University Mohammed Premier, Oujda 60000, Morocco.
authors.forename: Taibi
authors.initials: T
authors.lastname: Ben Hadda
authors.affiliation: Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Mubarak
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006023:Glycoproteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000601700:6,6'-(3-methyl-4-phenylthieno(2,3-b)thiophene-2,5-diyl)bis(2-ethoxynicotinonitrile); D006023:Glycoproteins; D011725:Pyridines; D013876:Thiophenes; C011473:beta-glucuronidase inhibitor; D005966:Glucuronidase
keywords: Cancer cell lines; Cytotoxicity; Petra/Osiris/Molinspiration (POM) analyses; Thienothiophene; α-Chymotrypsin inhibition; β-Glucuronidase inhibition