Synthesis and evaluation for antimicrobial activity of curcumin derivatives and related compounds

According to the World Health Organisation antimicrobial resistance (AMR) is one of the top 10 world health threats. In 2019 an estimated 4.95 million deaths were caused by AMR. With the spread of resistance, common antibiotics have stopped being effective and in addition, new antibiotics are increasingly becoming ineffective. Therefore, there is a need for new alternatives.

Turmeric, a diarylheptanoid from the Curcuma longa species contains the bioactive compound Curcumin. Dating back 4000 years turmeric has been used for its range of medicinal properties as well as flavour profile and is of interest for this project. Curcumin has shown potential as an antimicrobial, a cytotoxic agent and as an anti-Alzheimer drug. However, due to its unfavourable physiochemical and pharmacokinetic profiles curcumin has limited therapeutic potential. Therefore, a range of curcumin derivatives (CDs) have been synthesised using the Claisen Schmidt reaction to address these issues. In this project 11 curcumin derivatives were synthesized, and the two Suzuki reactions were investigated as a potential method to extend the carbon side arms of the curcumin derivatives. The Suzuki coupling reaction is a palladium catalysed coupling reaction where a new carbon to carbon bond is formed. This reaction is versatile for making drug molecules with milder reaction conditions. The curcumin derivatives were chosen based upon previous work in the group, literature and modelling conducted in SWISSADME. SWISSADME isa online website that predict properties of small drug molecules. Once synthesised the derivatives were fully characterised using NMR, IR, and mass spectrometry.

The microbiological evaluation was assessed with two assays. The disk diffusion assay and MIC determination assay. Two Gram-positive and two Gram-negative bacteria were tested. The diffusion assay showed that eight out of thirteen curcumin derivatives have inhibitory activity against both Gram-positive and Gram-negative bacteria (zone of inhibition range: 1.7 mm-6.3mm at 10ug/ml). Curcumin derivatives that showed inhibitory activity via disk diffusion assay were selected for MIC determination. Eight out of eight compounds assessed showed MIC values of 10 μg/ml against Pseudomonas aeruginosa (Gram-negative) and seven out of eight showed MIC values of 2.5 μg/ml against MRSA (Gram-positive). The structure activity relationship (SAR) showed derivatives with a substituted central ring also posed activity as well as compounds with halogen substituents. Furthermore, compounds that have bulky side groups also show activity. Further work would involve formulation studies to improve the solubility of the derivatives as well as work on the optimisation of the Suzuki reaction conditions to produce potential intercalating agents.