Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses

Yahia Nasser Mabkhot; Assem Barakat; Sammer Yousuf; M Iqbal Choudhary; Wolfgang Frey; Taibi Ben Hadda; Mohammad S Mubarak

doi:10.1016/j.bmc.2014.08.014

Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, β-glucuronidase inhibition activity, crystal structure, and POM analyses

Bioorg Med Chem. 2014 Dec 1;22(23):6715-6725. doi: 10.1016/j.bmc.2014.08.014. Epub 2014 Aug 20.

Authors

Yahia Nasser Mabkhot¹, Assem Barakat², Sammer Yousuf³, M Iqbal Choudhary⁴, Wolfgang Frey⁵, Taibi Ben Hadda⁶, Mohammad S Mubarak⁷

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: Yahia@ksu.edu.sa.
² 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.
³ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁴ 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.
⁵ Institut für Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, Stuttgart 70569, Germany.
⁶ Laboratory of Chemical Material, FSO, University Mohammed Premier, Oujda 60000, Morocco.
⁷ Department of Chemistry, The University of Jordan, Amman 11942, Jordan.

PMID: 25245672
DOI: 10.1016/j.bmc.2014.08.014

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.

Keywords: Cancer cell lines; Cytotoxicity; Petra/Osiris/Molinspiration (POM) analyses; Thienothiophene; α-Chymotrypsin inhibition; β-Glucuronidase inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Glucuronidase / antagonists & inhibitors*
Glucuronidase / metabolism
Glycoproteins / chemical synthesis*
Glycoproteins / chemistry
Glycoproteins / pharmacology*
Humans
Models, Molecular
Molecular Structure
Pyridines / chemistry*
Pyridines / pharmacology*
Structure-Activity Relationship
Thiophenes / chemistry*
Thiophenes / pharmacology*

Substances

6,6'-(3-methyl-4-phenylthieno(2,3-b)thiophene-2,5-diyl)bis(2-ethoxynicotinonitrile)
Glycoproteins
Pyridines
Thiophenes
beta-glucuronidase inhibitor
Glucuronidase