Design, Synthesis, Antimicrobial and Cytotoxicity of Curcumin Based Benzodiazepines, Diazepines, Diazoles and Amines
Date
2021-02-17
Authors
الكرم, رولا سلطان محمود
Journal Title
Journal ISSN
Volume Title
Publisher
An-Najah National University
Abstract
In this study novel sets of curcumin-based benzodiazepine, diazepine, diazoles and amines were prepared using simple and convenient condensation reaction; by reacting curcumin with various types of 1,2-diamino and hydrazine compounds. The prepared compounds were characterized using FT-IR, 1H NMR, and 13C NMR.
Several simple and convenient synthetic methods were employed in order to prepare the desired products. In the first method, curcumin-based benzodiazepine, diazepine, diazoles, and amines were prepared by condensation reaction of curcumin with various 1,2 diamino and hydrazine compounds in either ethanol which was used as a solvent and H2SO4 as a catalyst.
Another new set of curcumin-based benzodiazepine, diazepine, diazoles and amines were prepared using Knoevenagel Condensation that involves two-fold mechanism; The first step includes the formation of α,β-unsaturated intermediate 20 A using Knoevenagel condensation; by mixing curcumin with benzaldehyde in ethanol solvent, in the presence of catalytic amount of diisopropylamine (DIPA) base. Meanwhile, acid-catalyzed condensation cyclization reactions of the curcumin carbonyl groups of the synthesized intermediate with various 1,2-diamino or hydrazine compounds were involved in the second step to produce the desired products. The Knoevenagel condensation was employed in this work to prevent keto-enol tautomerization, which expected to enhance the yield.
H-Curcumin-based amine was prepared by condensation reaction of H-curcumin with ammonium acetate in two steps; the first step involved heating the resulting mixture at 60 °C until complete solvent evaporation. Followed by heating the resulted compound again at 60 °C for an hour.
Then a selected set of the prepared curcumin-based compounds was functionalized with methoxy group. Where; the phenolic groups of the selected compounds were alkylated by reacting with iodomethane in the presence of sodium hydroxide. Functionalization of the prepared curcumin-based compounds with alkyl groups was employed in this work in order to determine the effect of the hydroxyl group on the antimicrobial activity.
Antibacterial activities of selected set of the prepared curcumin-based heterocycles were evaluated against four types of bacteria strains: S. aureus, MRSA, E. coli and K. pneumoniae.
The antimicrobial activity occurred by inhibition of growth of the tested strains with MIC values ranging between 1.56-200 μg/mL. In general, the potency against S. aureus and Klebsiella is greater than that against MRSA and E. coli.
However, the highest activity was shown by compound 9 as it showed MIC of (1.56, 1.56, 50 μg/ mL) against S. aureus, MRSA, and Klebsiella respectively. And it is the only compound that showed activity against MRSA with MIC of (1.56 μg/ mL).
Moreover, the prepared curcumin-based heterocycle diazepines (compounds 2, 4, 10, 35) showed synergistic effects with ampicillin antibiotics. Furthermore, the Genotoxicity test was performed on compound 8. Results showed that compound 8 did not interact with the DNA molecule in E. coli strains. Thus, it is considered as a non-mutagenic or non-genotoxic agent. This study revealed that, the prepared curcumin-based diazepine could be a promising design for a potentially active antibacterial synergized agent with conventional antibiotics.