Synthesis and biological evaluation of fluorinated derivatives of 2-styrylchromones and 2-thioxo imidazole dicarboxylate esters.
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Date
2012
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Abstract
Two classes of fluorinated derivatives were synthesized in this work to test the effects of the
fluorinated drugs in antibacterial, antioxidant and anti-platelet activity. These two classes
were the 2-styrylchromones and the 2-thioimidazoles. The 2-styrylchromones were tested for
their antibacterial activity and the 3-hydroxypentadien-1one intermediates were tested for
their antioxidant activity. The 2-thioimidazoles were tested for the ability to inhibit platelet
aggregation in vitro.
A total of ten 2-styrylchromones together with their intermediates were synthesized of which
six were new(A5a-A5f). The two intermediates to each of the six compounds were also new
and together with the 2-styrylchromones resulted in thirty compounds being synthesised and
characterised. The synthesis was based on the Baker-Venkataraman rearrangement using
substituted cinnamic acids and hydroxyacetophenones.All the 2-styrylchromones were
screened for their antibacterial activity using Gram-positive bacteria (Staphylococcus
aureus,scuii and xylosus and Bacillussubtilis) and Gram-negative bacteria (Escherichia coli,
Pseudomonas aeruginosaand Klebsiella pneumonia). The compounds were most effective
against B. subtilis followed by S. aureus and a single strain of E. coli (ATCC 25922).
Difluorination on the phenyl ring was shown to enhance antibacterial activity and fluorine
substitution at the 6-position was shown to be far superior to substitution at the 7-position. In
comparison to tetracycline, the activity indices of the fluorinated styrylchromones ranged
from 0.50 to 0.75 against B. subtilis.
The fluoro and methoxy analogues of (2Z, 4E)-3-hydroxy-1-(2-hydroxyphenyl)-5-(phenyl)
penta-2, 4-dien-1-one, the intermediates to the 2-styrylchromones were tested for their ability
to act as antioxidants since they contained a 3-hydroxy group in the backbone of their
structure. They were screened by the 2, 2-diphenyl-1-pycryl-hydrazyl (DPPH) radical
scavenging assay and Ferric Reducing Power assay (FRAP).All the methoxylated analogues
showedbetter activity thanthe fluorinated analogues and comparable to that of ascorbic acid.
Seven fluorinated derivatives of diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-
dicarboxylate (B6a-B6g) as well as a nitro and chloro derivative (B6h-B6i) also known as 2-
thiomidazole derivativeswere prepared in five steps from glycine, ethyl formate, diethyl
oxalate, potassium thiocyanate and substituted benzyl bromides. The synthesized compounds
exhibited concentration dependent anti-platelet aggregation activity on both the thrombin and
ADP induced platelet aggregation. The 4-nitro and 4-fluoro compounds exhibited the highest
activity from the compounds tested, with estimatedIC₅₀ values of 1.05 and 0.99 mM for the
thrombin-induced and ADP-induced platelet aggregation respectively. Three of the
compounds, the 3,4-difluoro(B6c), 4-nitro(B6h) and 3-chloro(B6i) derivatives have
reasonable activity in both of the assays and could have potential as broad spectrum
antiplatelet inhibitors. With the exception of B6c, the fluoro derivatives were not as active as
the nitro and chloro compounds.
All the reactions in this work were monitored by ¹H and ¹³C NMR at each step and all
compounds were characterized using 1D and 2D NMR as well as MS, IR and UV data. All
the synthesised compounds were fully characterised unambiguously and the respective
carbon and proton resonances were assigned with the aid of HSQC, HMBC and NOESY
data. In addition, crystal structures of two 2-styrylchromones and three of its cinnamate ester
intermediates as well as the 2-thioimidazole provide a full structural analysis of the
compounds synthesised.
Description
Ph. D. University of KwaZulu-Natal, Durban 2012.
Keywords
Esters., Organic compounds--Synthesis., Oxidation., Chemistry, Organic., Antioxidants., Theses--Chemistry.