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

Abstract：

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.

journal_name

Comb Chem High Throughput Screen

journal_title

Combinatorial chemistry & high throughput screening

authors

Macha B,Kulkarni R,Garige AK,Palabindala R,Akkinepally R,Garlapati A

doi

10.2174/1386207323666201211092138

subject

Has Abstract

pub_date

2020-12-10 00:00:00

eissn

1386-2073

issn

1875-5402

pii

CCHTS-EPUB-112337

pub_type

杂志文章

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