Synthesis, characterization and antibacterial activity of curcumin and curcumin-like derivatives.

Abstract

This thesis consists of the synthesis, characterization and antibacterial activity of three series of curcumin and curcumin-like compounds. The curcumins were synthesised from acetylacetone and benzaldehydes whilst curcumin-like compounds were synthesised from acetone and either benzaldehydes or quinoline aldehydes. The curcumins were derivatised to pyrazolines and the curcumin-like compounds to ketopyrazoles with hydrazine hydrate and to spiro barbiturates with barbituric acid. The spiro barbiturates in turn were converted to oximes using hydroxylamine hydrochloride. A total of 52 new compounds were synthesised in this work. These compounds were characterized using 1H, 13C and 2D NMR spectroscopy and mass spectrometry. Both the ketopyrazoles and the spiro barbiturates contained sterogenic centers. Single crystal XRD was used to determine the configuration of these stereogenic centers, where the pyrazole was found to be in the 5S and the spiro barbiturates in the 7R,11R configuration. The three sets of synthesised compounds was tested for their antibacterial activity against two Gram +ve strains (Staphylococcus aureus and methicillin resistant S. aureus (MRSA)) and four Gram -ve strains (Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli). The best activity was seen by the 6-chloro, 6-bromo and 6- methyl derivatives of quinoline ketodienes, which were active against all six strains of Gram +ve and Gram -ve species at 0.98-31.3 g mL-1, with the exception of the 6-bromo derivative having lower activity against S. aureus at 250 g mL-1. This was followed by the curcumin pyrazolines where several compounds showed good antibacterial activity: the 3-Cl pyrazoline showed activity against both the Gram +ve MRSA (31.3 μg mL-1) and Gram –ve K. pneumonia (7.8 μg mL-1), the 2,4-difluoro pyrazoline showed activity against Gram –ve K. pneumonia (0.98 μg mL-1), and the 3-methoxy-4-(4-chlorobenzyloxy) curcumin derivativeand 3-methoxy-4-hydroxy pyrazoline showed activity against both S. aureus and MRSA at 31.3-62.5 μg mL-1. A further compound the 4-trifluoro curcumin pyrazoline was also active against the Gram –ve E. coli with a MBC of 31.3 μg mL-1. Amongst the ketopyrazoles, the chloro derivatives were active at low concentrations with MBC's between 15.6-62.5 g mL-1 against either S. aureus or MRSA. In addition, the 4- bromo derivative was also active against MRSA and the 2-chloro derivative against P. aeruginosa, both with a MBC value of 31.3 g mL-1. In contrast, the spiro barbiturates showed activity against the Gram –ve E. coli and P. aeruginosa with MBC values ranging from 0.98-125 g mL-1. In particular, the 4-bromo derivative showed excellent activity, better than the standards levofloxacin and ciprofloxacin with MBC values of 0.98 g mL-1. Conversion to the oximes resulted in loss of activity against all the Gram –ve bacteria. However the 4-trifluoro and 4-bromo spiro barbiturate oximes showed weak activity against MRSA.