Characterizing fibril morphological changes by spirooxindoles for neurodegenerative disease application.

Fibrillation of proteins and polypeptides, which leads to the deposition of plaques in cells and tissues has been widely associated with many neuropathological diseases. Inhibition of protein misfolding and aggregation is crucial for the prevention and treatment of these conditions. The growing interest in identifying inhibitor molecules to prevent the formation of fibrils in vivo has led to the results highlighted in this study. Due to their hydrophobic structure and potential to readily cross the blood brain barrier, a library of spirooxindole compounds were synthesized with those labelled Hd-63, Hd-66 and Hd-74 proving to be the most potent against fibril formation. Our spectroscopic analysis provides detailed insight, that the introduction of these spirooxindole compounds leads to morphological changes in the mechanism of fibril formation which prevent the formation of highly ordered fibrils, instead results in the formation of disordered aggregates which are not fibrillar in nature.

Regioselective pyrrolizidine bis-spirooxindoles as efficient anti-amyloidogenic agents.

Here, we report a microwave-assisted, one-pot, three-component, 1,3-dipolar cycloaddition reaction to produce highly regioselective and stereoselective bis-spirooxindoles as potential inhibitors against amyloid-ß fibrillation. Ease of synthesis, promising anti-amyloidogenic activity, low toxicity, and in vitro blood brain barrier permeability makes these compounds attractive therapeutic leads to treat Alzheimer's disease.

Microwave-assisted rapid synthesis of spirooxindole-pyrrolizidine analogues and their activity as anti-amyloidogenic agents.

A library of Sox-pyrrolizidines was rapidly prepared by microwave-assisted, one-pot, three-component, 1,3-dipolar cycloaddition of azomethine ylides from l-proline and isatin, with various ß-nitrostyrenes. Nitro-Sox compounds, 4b, 4d and 4e inhibit HEWL amyloid fibril formation by ThT studies with percentages of fluorescence intensity of 55.4, 42.9 and 40.3%, respectively. Further studies with MTT assay, Raman spectroscopy, TEM and molecular docking supported these promising candidates for activity against amyloid misfolding, a phenomenon leading to Alzheimer's disease pathology.

Natural spirocyclic alkaloids and polyphenols as multi target dementia leads.

The U rhynchophylla, U tomentosa, Isatis indigotica Fortune, Voacanga Africana, herbal constituents, fungal extracts from Aspergillus duricaulis culture media, include spirooxindoles, polyphenols or bridged spirocyclic alkaloids. Their constituents exhibit specific and synergistic multiple neuroprotective properties including inhibiting of Aß fibril induced cytotoxicity, NMDA receptor inhibition in mice models of Alzheimer's disease (AD). The pioneering research from Woodward to Waldmann has advanced the synthesis of spirocyclic alkaloids. Furthermore, the elucidation of the genetic analysis, biochemical pathways that links strictosidine to the alkaloids akuammicine, stemmadenine, tabersonine, catharanthine, will now enable the biotechnological generation, also stimulate synthesis of related bridged spirocyclic alkaloids for medicinal investigations. From the value of spirocyclic structures as multi target dementia leads, we hypothesise that simpler Lipinski-like natural/synthetic alkaloid analogues may likewise be discovered that provide neurocognitive enhancing activities against dementia and AD.