Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors.

AIMS AND OBJECTIVE: Alzheimer's disease is now a most prevalent neurodegenerative disease of central nervous system leading to dementia in elderly population. Numerous pathological changes have been associated in the progression of Alzheimer's disease. One of such pathological hypotheses is declined cholinergic activity which eventually leads to cognitive and memory deficits. Inhibition o f cholinesterases will apparently elevate acetyl choline levels which is benefactor on cognitive symptoms of the disease. This manuscript describes the new tacrine derivatives tethered to isatin Schiff bases through alkanoyl linker and screened for cholinesterase inhibitory activity. MATERIALS AND METHODS: Tacrine and two more cycloalkyl ring fused quinolones were synthesized and converted to N-cycloalkyl fused quinoline chloroamides. Isatin Schiff bases were also synthesized by the reaction between isatin and substituted aromatic anilines and in subsequent reaction, isatin Schiff bases were reacted with cycloalkyl fused quinolones to afford anticipated compounds 10a-i, 11a-i and 12a-i. All the compounds have been screened for acetyl- and butyrylcholinesterase inhibitory activity and in vivo behavioral studies. Binding interactions of the desired compounds have also been studied by docking them in active site of both cholinesterases. RESULTS: Three compounds 12d, 12e and 12h with propionyl and butyroyl linker between amine and isatin Schiff base scaffold have shown potent acetyl- and butyrylcholinesterase inhibitory activity. However most potent cholinesterase inhibitor was 13d with IC50 value of 0.71±0.004 and 1.08±0.02 µM against acetyl- and butyrylcholinesterases respectively. The hepatotoxicity of potent compounds revealed that the tested compounds were less hepatotoxic than tacrine and also exhibited encouraging in vivo behavioral studies in test animals. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site of both cholinesterases. CONCLUSION: New cycloalkyl fused quinolones tethered with alkanoyl linker to isatin Schiff bases endowed significant and potent cholinesterase inhibitory activities. Few of the compounds have also exhibited lesser hepatotoxicity and all the synthesized compounds were good in behavioral studies. Molecular docking studies also indicated close interactions in active site of cholinesterases.

Structural Characterisation and Assessment of the Novel Bacillus amyloliquefaciens RK3 Exopolysaccharide on the Improvement of Cognitive Function in Alzheimer's Disease Mice.

In this study Bacillus amyloliquefaciens RK3 was isolated from a sugar mill effluent-contaminated soil and utilised to generate a potential polysaccharide with anti-Alzheimer's activity. Traditional and molecular methods were used to validate the strain. The polysaccharide produced by B. amyloliquefaciens RK3 was purified, and the yield was estimated to be 10.35 gL-1. Following purification, the polysaccharide was structurally and chemically analysed. The structural analysis revealed the polysaccharide consists of α-d-mannopyranose (α-d-Manp) and ß-d-galactopyranose (ß-d-Galp) monosaccharide units connected through glycosidic linkages (i.e., ß-d-Galp(1→6)ß-d-Galp (1→6)ß-d-Galp(1→2)ß-d-Galp(1→2)[ß-d-Galp(1→6)]ß-d-Galp(1→2)α-d-Manp(1→6)α-d-Manp (1→6)α-d-Manp(1→6)α-d-Manp(1→6)α-d-Manp). The scanning electron microscopy and energy-dispersive X-ray spectroscopy imaging of polysaccharides emphasise their compactness and branching in the usual tubular heteropolysaccharide structure. The purified exopolysaccharide significantly impacted the plaques formed by the amyloid proteins during Alzheimer's disease. Further, the results also highlighted the potential applicability of exopolysaccharide in various industrial and pharmaceutical applications.