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Title: Non purine inhibitors of xanthine oxidase
Author: Leigh, Maria
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2011
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Abstract:
The increase in the occurrence of hyperuricemia and gout in recent years, coupled with side- effects associated with use of the main anti-gout therapeutic, allopurinol, have triggered the search for non-purine alternatives. The first such inhibitor to be made available is Adenurlc", 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid. The aim of this work was to synthesise a small library of non-purine compounds and evaluate their inhibitory activity against the enzyme, xanthine oxidase. Successful inhibitors are marked as those that gave a comparable or lower ICso value than allopurinol (3 ± 0 J.1M), under conditions employed in this work. A range of five-membered heterocyclic compounds, including 1,2,4-triazole-3-thiones, 2- amino-1,3,4-thiadiazoles and 1,3-thiazoles were synthesised. On testing, the heterocyciic compounds did not reveal significant inhibition of XO. SAR analysis marked the presence of alkyl chains and para-cyano substituents as contributors to inhibition. The most successful heterocyciics investigated were highlighted as [17b), 4-(4-cyanophenyl)-1,3-thiazole-2- carboxylic acid, (ICso= 150 ± 14 J.1M) and [15), [4-(4-bromophenyl)-1,3-thiazole-2- sulfanyl]acetonitrile, (ICso= 29 ± 4 J.1M). A concise library of Schiff base compounds was then investigated, incorporating thiosemicarbazones, dithiocarbazates and hydrazones, with varied number and positioning of aromatic substituents. SAR analysis revealed important structural features affecting inhibition, such as a para-hydroxyl benzaldehyde substituent and a para-hydroxyl/cyano substituent on hydrazide/thiosemicarbazide rings. The position rather than the number of hydroxyl substituents proved significant for inhibition. The most potent compounds were thiosemicarbazones 8-Tz3 (0.6 ± 0.2 IlM), 10-Tz2 (0.5 ± 0 ~LM), 10-Tz3 (0.6 ± 0.1 IlM), 11- Tz2 (O.B ± 0.1 J.1M), 11-Tz3 (0.6 ± 0 J.1M) and 11•DTz1 (0.7 ± 0.1 J.1M), giving four times lower ICso than allopurinol. Potent uncomplexed Schiff bases as XO inhibitors have not been previously reported. Steady-state kinetic studies on 8-Tz3, 11-Tz3, 8-DTz1 and 11•DTz1 revealed mixed-type inhibition. As 11•DTz1 gave the lowest Kj value (0.4 ± 0 IlM), coupled with its low ICso value, highlight it as a promising lead compound. Upon reduction of the imine bond, 11•DTz1 reduced retained improved activity over allopurinol, though less potent than its parent Schiff base. Complexation to Mo{VI) and Cu{lI) centres occurred, with the ligands acting as tridentate ONS/ONO donors. The distorted octahedral coordination geometry of Mo(Vl) complexes was confirmed via crystal structure determination. The Cu(lI) complexes, [Cun(l10-TZ2)n) and [Cun(L S-HS)n), revealed a 3-fold increase in potency over their free ligands. The presence of Cu(lI) therefore appears to have a cooperative effect and warrants further investigation as means of improving potency and hydrolytic stability.
Supervisor: Not available Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.550273  DOI: Not available
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