Novel fluorine-containing chiral hydrazide-hydrazones: Design, synthesis, structural elucidation, antioxidant and anticholinesterase activity, and in silico studies.

Abstract

In this study, a series of fluorine-containing chiral hydrazide-hydrazone derivatives [III-XII] from ʟ-cysteine ethyl ester hydrochloride was synthesized as new antioxidant and anticholinesterase agents. The antioxidant activity of these derivatives was evaluated by ABTS and DPPH scavenging and CUPRAC assays and the anticholinesterase activity by the Ellman method spectrophotometrically. The results of the antioxidant assay showed that compounds V, IX, and X exhibited higher activity than BHT and α-tocopherol used as positive standards. Among the synthesized derivatives, compound IX (IC : 2.3 ± 1.6 μM) exhibited higher acetylcholinesterase inhibitory activity than galantamine (IC : 4.5 ± 0.8 μM). Compounds XI (IC : 9.6 ± 1.0 μM), IX (IC : 12.5 ± 1.6 μM), III (IC : 16.0 ± 1.6 μM), X (IC : 17.2 ± 1.8 μM), VI (IC : 20.2 ± 0.8 μM), XII (IC : 21.5 ± 1.0 μM), and VII (IC : 24.6 ± 0.6 μM) displayed better butyrylcholinesterase inhibitory activity than galantamine (IC : 46.03 ± 0.14 μM). ADME-Tox analysis was used to probe the drug-like properties of the compounds. Molecular docking studies were also applied to understand the interactions between compounds and targets. The docking calculations were supported by the experimental data. In particular, compound IX, having better activity than galantamine against acetylcholinesterase and butyrylcholinesterase enzymes, was visualized using molecular docking.