Aims and Objective: Alzheimer’s disease is now a most prevalent neuro degenerative disease of central nervous
system leading to dementia in elderly aged population. Numerous pathological changes have been associated in the
progression of Alzheimer’s disease. One of such pathological hypothesis is declined cholinergic activity which eventually
affects cognitive and memory deficits. Inhibition 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 Ncycloalkyl 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 butyryl
cholinesterase 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 butyryl cholinesterase 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 butyryl cholinesterases 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 alkoyl 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.