Synthesis, Characterization And In Silico Studies Of Piperidone Derivatives: Dengue Protease Inhibitory Studies On Selected Compounds
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Date
2016-02
Authors
Idris, Nor Hashima
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
New biologically active compounds 26(a-j) and 27(a-j) comprising
piperidone derivatives were synthesized by incorporating acetophenone derivatives
with varies of 3,5-bis(arylidenepiperidine)-4-one derivatives in the presence of
K2CO3 as catalyst under nucleophilic substitution reaction. The synthesized
compounds were obtained in the range of 58.0-89.9 % yields and were fully
characterized by IR, 1H NMR, 13C NMR, DEPT and elemental analysis. The
structures of some compounds were further confirmed by 2D NMR (COSY, HSQC
and HMBC) spectroscopic techniques as well as X-ray crystallography. The
synthesized compounds were virtually screened using Wilchapong homology model
structure through molecular docking study by AutoDock 4.2.5 to disclose the binding
interaction mechanism and orientation of the compounds towards DENV2 NS2BNS3
protease. Compounds 26h and 27h were observed to have the highest binding
affinity towards the protease while having interaction with the essential amino acid
residues, His51 and Ser135 in the catalytic triad with -11.06 kcal/mol and -11.36
kcal/mol, respectively. The rest of the compounds exhibit good energy binding
compared to the crystal structure of the model. The selected compounds, 26h and
27h then underwent inhibition activity assays toward DENV2 NS2B-NS3 protease
by using fluorogenic substrate Boc-Gly-Arg-Arg-MCA. Both compounds which
bearing p-NO2 at the aromatic ring showed high inhibition activity against the
protease with IC50 value of 15.13 μM ±1.05 and 16.14 μM ±1.23, respectively.
Description
Keywords
Piperidone