Synthesis and biological evaluation of fluorinated derivatives of 2-styrylchromones and 2-thioxo imidazole dicarboxylate esters.

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.