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Abstract
A series of 7-hydroxy or substituted benzoate flavones were prepared using the conventional Baker-Venkataraman method to prepare the selected flavones. The acid chloride was prepared using thionyl chloride. The benzoate was prepared using pyridine as a base and solvent (72%-81% yield). The dibenzoate was subjected to the rearrangement step using freshly ground KOH powder and pyridine as solvent; the reaction was completed in 30 min and the resulted diketone was used directly in next step. The cyclization step was achieved by dissolving the diketone in acetic acid and adding H2SO4 to get 1M concentration and was stirred at 80 C. A purified sample was obtained by silica gel column chromatography using 30% ethyl acetate/ hexane as a solvent system. The used acetophenone in this synthesis was 2, 4-dihydroxyacetophenone and thus both hydroxyl groups were bezoylated upon treatment with substituted benzoyl chloride. The produced 7-benzoate or (substituted benzoate) flavones (2-6) could be hydrolyzed in KOH to afford the 7-hydroxy flavones. A modified method was investigated and optimized using DBU to get the diketone intermediate without isolating the ester and Microwave irradiation to afford the cyclization step in short time. A series of eleven 6-bromo and 6-methoxy analogues was prepared in high yield and with environmentally friendly method. The synthesized compounds showed antifungal activity towards Fusarium oxysporum. Results showed that the activity of 6-bromoflavones were sensitive to the substituents in B ring where the order of effective substituents was 2(CF3) » Cl > F » OMe > H. In position 6, the bromo substituent was consistently more effective than the methoxy group. Results also indicated that esterification of
the hydroxyl group enhanced the toxicity from 622.9 ppm [1] to 277.5 ppm [2] and 103.4 ppm [4]. The order of the substituted benzoic acid affected the toxicity was p-OMe > p-Me > H > m-Me. The data and toxicity lines suggested that the flavone could be used as a core for anti Aspergillus niger activity with structural variations that gave toxicity range of 28.25 ppm- 177.64 ppm. The 7-methoxy-4’-bromo flavone [16] was the most active compound (IC50 28.25 ppm) followed by the 6-methoxy-4’-chloro flavone [14] (IC50 41.94 ppm). The study of the activity towards Monosporascus sp. showed that the free OH group substituent derivative [1] was less active IC50 64.58 ppm than the ester derivative [2] (35.22 ppm); in other words benzoylating the hydroxyl group increased the toxicity. In addition, compound [6] gave the least toxicity (IC50 90.75 ppm). 7-(p-Methoxy) benzoylate derivative [5] was very active (IC50 17.20 ppm). The antibacterial activity of the synthesized compounds towards some Gram positive and Gram negative bacteria were reported. All the synthesized compounds were inactive towards all Gram negative bacteria. Compounds [12] and [13] showed antibacterial activity against both examined Gram positive bacteria Staphylococcus aureus and Clavibacter Michigans. On the other hand, they were inactive against the tested Gram negative bacteria E. coli and Erwinia carotovora. This result suggests a relation between the cell wall structure of the bacteria and the activity of these two cyclohexyl derivatives. Compound [13] was effective against methicillin-resistant Staphylococcus aureus (IC50 69.6 ppm) comparing to Gentamycine 25.0 ppm. Only compounds [12] and [13] were active against the Culex pippins mosquito larvae (LC50 2.0 and 3.1 ppm), respectively. The toxicity regression lines for compounds [12] and [13] showed that the bromo derivative [12] was more active than the methoxy derivative [13]. The compounds also showed activity towards the plant pathogenic nematodes Meloidogyn sp. Most of the compounds were inactive except for the cyclohexyl
derivatives [12] and [13] which showed good activity (LC50 95.5 and 71.0 ppm), respectively. In contrary to their insecticidal activity, the methoxy derivative [13] was more active than the bromo derivative [12]. Also the regression lines showed similar slope values 1.7215 and 1.6794 for compounds [12] and [13] respectively which proposes that both compounds have the same dose response relationship. Moreover, First total synthesis of cis-Uvariamicin-I, a 37 carbon acetogenin with a mono cis-THF ring has been accomplished in 12 steps with 9 % overall yield.