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.

Electronic Fine‐Tuning of Oxygen Atom Transfer Reactivity of cis‐Dioxomolybdenum(VI) Complexes with Thiosemicarbazone Ligands

“…Selected bond lengths and angles and crystallographic data are summarized in Tables 1 and 2, respectively. The crystal structures confirmed that the thiosemicarb- [18,27,28,[37][38][39][40] The crystals consist of racemic mixtures of OC-6-24-Aand OC-6-24-C-configured [35,36] enantiomers. The complexes crystallize in centrosymmetric space groups…”

“…[24] In particular, thiosemicarbazones derived from salicylaldehydes allow a systematic investigation of the effect of electron-withdrawing groups (EWGs) or electron-donating groups (EDGs) on the electronic properties of a coordinated molybdenum center. It was found that these electronic trends are reflected in the spectroscopic properties of the molybdenum complexes formed, [18,25] and in their catalytic, [26] biological, [27,28] and pharmacological properties. [29,30] Here we present the synthesis, characterization and catalytic OAT activity of a series of cis-dioxomolybdenum(VI) complexes with structurally related tridentate thiosemicarbazone ligands (Scheme 2).…”

Randic Shape and Size Indices Account for the Variability in Xanthine Oxidase Inhibitory Activity of a Family of Fused Pyrans

“…These drawbacks have prompted the search for non-purine based XO inhibitors that lead to the discovery of recently approved drug Febuxostat 14 and its derivatives Piraxostat 15 and FYX-051 16 . Other classes of non-purine XO inhibitors reported in recent years include azaflavones 17 , pyrazolines 18 , acetamides 19 , naphthopyrans 20 , heteroaryl pyrimidinones 21 , isocytosines 22 , thiadiazolopyrimidones 23 , benzaldehydes 24 , and xanthones 25 .…”

RhII‐Catalyzed [3+2] Cycloaddition of 2 H‐Azirines with N‐Sulfonyl‐1,2,3‐Triazoles

“…In particular, thiosemicarbazones derived from salicylaldehydes allow a systematic investigation of the effect of electron‐withdrawing groups (EWGs) or electron‐donating groups (EDGs) on the electronic properties of a coordinated molybdenum center. It was found that these electronic trends are reflected in the spectroscopic properties of the molybdenum complexes formed,18,25 and in their catalytic,26 biological,27,28 and pharmacological properties 29,30…”