title: Inhibition of xanthine oxidase by thiosemicarbazones, hydrazones and dithiocarbazates derived from hydroxy-substituted benzaldehydes.
abstract: Nonpurine xanthine oxidoreductase (XOR) inhibitors represent important alternatives to the purine analogue allopurinol, which is still the most widely used drug in the treatment of conditions associated with elevated uric acid levels in the blood. By condensing mono-, di- and trihydroxybenzaldehydes with aromatic thiosemicarbazides, aryl hydrazides and dithiocarbazates, three series of structurally related Schiff bases were synthesised, characterised and tested for XOR inhibitory activity. Hydroxy substitution in the para-position of the benzaldehyde component was found to confer high inhibitory activities. Acyl hydrazones were generally less potent than thiocarbonyl-containing Schiff bases. Within the thiosemicarbazone series, chloro and cyano substituents in the para-position of the thiosemicarbazide unit increased activities further, up to potencies approximately four-times higher than that of the benchmark allopurinol, as measured under the same assay conditions. In order to illustrate the potential of the Schiff bases to bind directly to the molybdenum centre in the active site of the enzyme, a representative example (H₂L) of each inhibitor series was co-ordinated to a cis-dioxomolybdenum(VI) unit, and the resulting complexes, [MoO₂(L)MeOH], were structurally characterised. Subsequent steady-state kinetic investigations, however, indicated mixed-type inhibition, similar to that observed for inhibitors known to bind within the substrate access channel of the enzyme, remote from the Mo centre. Enzyme co-crystallisation studies are thus required to determine the exact binding mode. Finally, the coordination of representative inhibitors to copper(II) gave rise to significantly decreased IC₅₀ values, revealing an additive effect that merits further investigation.
authors.affiliation: Department of Chemistry, University of York, Heslington, York YO105DD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Leigh
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Raines
authors.forename: Carmen E
authors.initials: CE
authors.lastname: Castillo
authors.forename: Anne K
authors.initials: AK
authors.lastname: Duhme-Klair
mesh_terms: D001547:Benzaldehydes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008982:Molybdenum / Q000737:chemistry; D012545:Schiff Bases / Q000737:chemistry; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D006834:Hydrazines; D006835:Hydrazones; D012545:Schiff Bases; D013882:Thiosemicarbazones; C010877:carbazic acid; D003300:Copper; D008982:Molybdenum; D014969:Xanthine Oxidase