Abstract
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.
| Date of Award | 15 Apr 2020 |
|---|---|
| Original language | English |
| Supervisor | Karl Hemming (Main Supervisor) & Olumayokun Olajide (Co-Supervisor) |