dc.description.abstract |
Flavonoids are the most common group of polyphenolic compounds in the human
diet including fruits, vegetables, nuts and plant derived beverages, tea and wine. These
compounds have been reported to possess a wide range of bio-activities. Structural variations
of these flavonoids are associated with many different biological and pharmacological
activities including antioxidant, anticancer, antiinflamatory, antihyperglycemic, antidiabetic,
antibacterial, antifungal and antiviral activities. Antioxidant enzymes as well as non
enzymatic antioxidants are the first line of defense against oxidative stress. This oxidative
stress is the underline mechanism for diabetic complications. In recent years, the high
therapeutic properties of flavonoids and their analogues have brought attention of chemists to
synthesize various kinds of their derivatives by improving the existing synthetic
methodologies. It is therefore, the aim of present study was to synthesis and characterize the
novel flavonoids and their derivatives. These compounds were screened for their antioxidants
potential and evaluate their antihyperglycemic activity.
By using Claisen−Schmidt condensation, 2,5-dihydroxyacetophenone was allowed to
condense with different aromatic aldehydes. Four kinds of products were isolated; chalcones
(105, 106, 108, 110, 115, 119, 121), flavanones (107, 109, 111, 120, 123), Arylmethylidene
flavanone (112, 113, 114, 116, 117, 118, 122, 124, 127, 128) and 2-Arylmethylidene
indanones (125, 126). A series of chalcones (131-135) was also synthesized by reacting 2
hydroxy-5-nitro acetophenone with different aromatic aldehydes. The synthesized chalcones
134 underwent cyclization in the presence of iodine to obtain compound 136. Compound 105 was reacted with hydrazine hydrate to obtain 2-(5-(2-nitrophenyl)4,5-dihydro-1H-pyrazol-3
yl)benzene-1,4-diol (129) and compound 108 was reacted with hydrazine hydrate to form 2
(5-(4-nitrophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzene-1,4-diol (130). The
compound (125) was reacted with different N-substituted-2-bromoacetamide (137-139) to
form compound (144-146). After reacting 8-acetyl-7-hydroxy-4-methylcoumarin (142) with
2′-Bromo-N-benzylacetamide (137), the product 2-[(8-acetyl-4-methyl-2-oxo-2H-chromen
7-yl)-oxy]-N-phenylacetamide (143) was obtained. All the synthesized compounds were
characterized and confirmed through spectroscopic analysis i.e., Fourier-transform infrared
spectroscopy (FTIR), Nuclear magnetic resonance (NMR) spectroscopy and Electron
Ionization Mass Spectrometry (EIMS).
The compounds 105-126, 129, 130 and 131-135 were checked for their antioxidant
potential by α, α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging, Iron chelating
activity, Iron chloride (FeCl3) reducing power activity, Phosphomolybdinum assay and 2,2′
azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) activity. Among all the
synthesized compounds, the chalcones 105, 106, 108, 110, 115, 119, and 121 showed
excellent antioxidant activity. The chalcones 105, 110 and 115 exhibited better antioxidative
behavior than trolox and ascorbic acid. The Oral glucose tolerance test (OGTT) was
performed in normal hyperglycemic rats for compounds 105, 106, 107, 108 and 109. The
compound 109 exhibited good activity in normal hyperglycemic rats while the compound
105 showed significant activity in streptozotocin (STZ) induced diabetic rats as compared to
reference Glabenclamide. For in silico studies, Quantitative Structure-Activity Relationships
(QSAR) were performed for compounds 105-126 and 131-135. The comprehensive intra
molecular charge transfer has been perceived from the highest occupied molecular orbitals (HOMOs) to the lowest unoccupied molecular orbitals (LUMOs). The smaller ionization
potential (IP) and bond dissociation energy (BDE) values for compound 105, 106, 107, 108
and 109 revealed that these compounds would show proficient antioxidant behavior which is
in good agreement with the antioxidant experimental data. Experimental and computational
investigations concluded that compound 105 might be an effective antihyperglycemic agent
because of its antioxidative nature and smallest ionization potential. |
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