Novel Analogues of Isoflavones as Potential Anti-Inflammatory Drugs for the Treatment of Neurodegenerative Disorders

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.