PMID: 3756135Jul 29, 1986Paper

Noncompetitive and irreversible inhibition of xanthine oxidase by benzimidazole analogues acting at the functional flavin adenine dinucleotide cofactor

Biochemistry
E B Skibo

Abstract

Benzimidazole derivatives possessing a leaving group in the 2 alpha-position and either 4,7-dione, 4,7-diol, or 4,7-dimethoxy substituents were examined as inhibitors of buttermilk xanthine oxidase. The quinone and hydroquinone derivatives are not inhibitors of xanthine-oxygen reductase activity, even though the latter is a powerful alkylating agent. The methoxylated hydroquinones are linear noncompetitive inhibitors, the best of which is the 2 alpha-bromo analogue (Ki = 46 microM). During xanthine-oxygen reductase activity, the 2 alpha-bromo analogue irreversibly traps the reduced enzyme. Formation of a C(4a) adduct of the reduced functional FAD cofactor is postulated on the basis of UV-visible spectral evidence and reconstitution of the enzyme after removal of the altered FAD. A probable sequence of events is reversible binding at or near the reduced cofactor followed by adduct formation. It is concluded that potent tight binding inhibitors could be designed that act at the FAD cofactor rather than the purine active site.

References

Sep 1, 1969·The Biochemical Journal·M A McGartoll, R C Bray
Jan 1, 1981·Medicinal Research Reviews·H W Moore, R Czerniak
Jan 1, 1981·Pharmacology & Therapeutics·R Hille, V Massey

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Citations

Dec 1, 1996·Journal of Computer-aided Molecular Design·B HernándezF J Luque
Aug 15, 2003·Preparative Biochemistry & Biotechnology·Hassan Y Aboul-EneinMagda Abd El-Aziz
Feb 12, 2019·ChemMedChem·Giuseppe LunaRicardo L Mancera
Feb 8, 2019·Current Topics in Medicinal Chemistry·Neelam MalikAnurag Khatkar
Aug 17, 2020·Expert Opinion on Therapeutic Patents·Jatinder Vir SinghSahil Sharma
Jun 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ferid AbdulhafizLebaka Veeranjaneya Reddy

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