dc.description.abstract |
Oxidative-stress, inflammation and glycation processes cause cell damages in the human
body and may lead to aging and different disease conditions. Drugs that ameliorate oxidative
stress can solve several disease pathologies. Drug development experiments in the early
stages are expensive and time-consuming. These constraints could be minimised through
computational approach. A 4-aminoantipyrine possesses biological properties including
antioxidant and anti-inflammatory activities. However, information on its application as
antiglycating agent is sparse. Therefore, this study was aimed at synthesising 4-
aminoantipyrine derivatives and evaluating their antioxidant, anti-inflammatory,
antiglycation and toxicity potentials using experimental, docking and ADMET profiling.
Synthesis of Schiff bases was carried out by condensation of 4-aminoantipyrine with
different substituted benzaldehydes. Ether derivatives were prepared from 4-
aminoantipyrine Schiff bases via Williamson ether synthesis. The compounds were purified
by solvent extraction and characterised using Fourier Transform Infra-Red (FTIR)
spectroscopy, 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy, Mass
Spectrometry (MS) and X-ray Diffraction (XRD) analysis. Cytotoxicity analysis was
carried out using brine shrimps and 3T3 mouse fibroblast cell lines. The antioxidant, antiinflammatory and antiglycating activities were evaluated in vitro using 2,2-diphenyl-1-
picrylhydrazyl radical, oxidative burst assay and human serum albumin solution; and
compared with gallic acid, ibuprofen and rutin (standards), respectively. Molecular
descriptors were obtained from Density Functional Theory (DFT) calculations and the
binding affinity determined by molecular docking. Quantitative Structure-Activity
Relationship (QSAR) model was used to predict the bioactivity of the compounds. A
detailed ADMET (adsorption, distribution, metabolism, excretion, and toxicity) screening
was done in-silico. Data were analysed by descriptive statistics.
Fifty-eight compounds (thirty Schiff bases and twenty-eight ether derivatives) were
synthesised out of which 24 were new. A newly synthesised 4-((2-chloro-4-
fluorobenzylidene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, had
characteristic FTIR ῡmax at 1593 cm-1 for C=N (azomethine bond). The 1H-NMR spectrum
showed seven methine signals at 9.91, 8.22, 7.55, 7.49, 7.40, 7.36 and 7.34 and two methylvi
signals at 3.21and 2.47 ppm. The 13C NMR displayed seven quaternary, nine methine and
two methyl carbons. The MS showed the molecular ion at 343 m/z corresponding to
C18H15ClFN3O. The XRD showed a monoclinic unit cell and theta of 66.66o. None of the
compounds was cytotoxic against normal cell lines (Cytotoxicity (3T3Cell-line) %
inhibition ≤ 25%). Five of the compounds possessed antioxidant activity, with 4-((4-
hydroxy-3-methoxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyraz-ol-3-
one having similar activity (IC50 =111.10±1.80 µM) as gallic acid (IC50 = 111.60±2.40
µM). Four of the compounds exhibited anti-inflammatory activities with 4-((2,3-
dihydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
having a lower IC50 (0.01±0.02 µM) than that of ibuprofen (11.20±1.90µM). Eight of the
compounds possessed moderate antiglycation activity (IC50 = 321.16±5.70-
856.80±2.80µM) when compared to standard (IC50 = 282.40±0.80 µM). The DFT
calculations and molecular docking confirmed compounds 4-((3,4-
dihydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3 one and 4-
((2,3-dihydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one
with best activities among the tested compounds. The molecular descriptors (EHOMO,
ELUMO, polarisability, dipole moment and polar surface area) were responsible for the
biological activities of the compounds. All the synthesised compounds demonstrated
acceptable outcome in oral bioavailability, lipophilicity, pharmacokinetics, and toxicity
prediction.
The synthesised 4-aminoantipyrine derivatives were non-toxic and some possessed antiinflammatory, antioxidant and antiglycation properties making them potential drug
candidates. |
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