Title:Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors
Volume: 25
Issue: 1
Author(s): Baswaraju Macha, Ravindra Kulkarni, Anil Kumar Garige, Rambabu Palabindala, Raghuramrao Akkinepally and Achaiah Garlapati*
Affiliation:
- Medicinal Chemistry Division, University College of Pharmaceutical Sciences, University, Warangal, Telangana- 506009,India
Keywords:
Alzheimer's disease, cholinesterase inhibitors, synthesis, behavioral studies, docking, hepatotoxicity.
Abstract:
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.
