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Title: Novel analogues of isoflavones as potential anti-inflammatory drugs for the treatment of neurodegenerative disorders
Author: Mengheres, Gabriel
ISNI:       0000 0005 0287 3689
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2019
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In an effort to discover novel isoflavones with potential anti-inflammatory and neuroprotective activities, this thesis reports the synthesis and biological activity of some simple isoflavones and their hybrids. The hybrids contain 1,2,4-oxadiazole, 1,2,3-triazole, benzodiazepine, β-sultam or benzosultam side-chains, well known pharmacophores with a range of biological applications. A total of 152 compounds were synthesised and screened. Simple isoflavones with a variety of functional groups were synthesised using the deoxybenzoin route and the Suzuki-Miyaura cross-coupling reaction. Further functionalisation involved the synthesis of amines and azides. Next to 3-halochromones synthesised for the cross coupling reaction, some other chromones were obtained containing a 3-alkyne or 3-formyl groups. The synthesis of the hybrids was achieved using a Williamson ether synthesis for isoflavone/1,2,4-oxadiazole and isoflavone/β-sultam hybrids, click chemistry for isoflavone/1,2,3-triazole hybrids, and a cascade of cross-coupling and 6-endodig cyclisation for isoflavone/benzo-δ-sultam hybrids. Subsequent deprotection, esterification and/or other transformations on simple isoflavones and hybrids led to synthesis of supplementary isoflavone analogues. Screening of the compounds on LPS-activated BV2 microglia cells showed a decrease in nitrite production and good cell viability for most of the compounds. Subsequent TNF-α inhibitory activity for the most active compounds with cell viability ≥80%, and NO production ≤40% revealed a triazole derivative as the most active compound with a TNF-α production of 18% at 20 μM. The structure-activity relationship suggests that the presence of a hydroxyl and/or chloroalkyl group is beneficial for the anti-inflammatory activity.
Supervisor: Hemming, Karl ; Olajide, Olumayokun Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; RM Therapeutics. Pharmacology