Preliminary Study On Synthesis And In Vitro Antibacterial Activity Of Canthin-6-one And Their Derivatives

Canthin-6-one alkaloids are an important subclass of natural products, which attract peoples’ attention by their good and wide range of biological activities. In this paper, we conducted a systematic review for canthin-6-one alkaloids from three aspects that consist of isolation and extraction, synthesis, and biological activities. The literature review shows that, in recent years, the main research of canthin-6-one focused on synthetic methods, antitumor activity, anti-inflammatory, anti-proliferative, anti-parasitic and anti-fungal activity, etc., and there are not comprehensive and systematic study for antibacterial avtivity. In order to study the antibacterial activity of these compounds, we have synthesized series of canthin-6-one derivatives which begin efforts from tryptamine, and tested their inhibitory activity against several common bacteria. The results are as follows:1. Successively through a reductive amination reaction, Pictet-Spengler reaction, amidation reaction, catalytic hydrogen transfer reaction and the oxidation reaction, canthin-6-one was synthesized which begin efforts from tryptamine. And this synthetic route has not been reported. Two series of 3-N-alkylated and 3-N-benzylated canthin-6-one derivatives were obtained by quaternization reaction, including of 20 novel compounds in all of 22 derivatives. Canthin-6-one-3-N-oxide was obtained by oxidation reaction. All structures of the compounds were confirmed by 1H NMR, 13 C NMR and ESI-MS.2. Derivatives and intermediates of canthin-6-one were tested for their in vitro antibacterial activity. Disk diffusion antibiotic testing was utilized to evaluate the inhibitory activity of 27 compounds against tested bacteria. And the results show that there are good activities for compounds against S. aureus, B. cereus, R. solanacearum and P. solanacearum, poor activities against E. coli, P. aeruginosa, P. syringae pv. actinidiae and B. subtilis. Microdilution antibiotic testing was utilized to evaluate the minimum inhibitory concentration values of 27 compounds against four tested bacteria that activities are relatively good.3. Through analyzing the chemical structure and in vitro antibacterial activity of these compounds, we have found that: 1) The in vitro antibacterial activity gradually increases with the increasing of the 3-N-alkyl chain length for all tested bacteria. Unfortunately, the side alkyl chain group is not conducive to improve the in vitro antibacterial activity; 2) Compared the MICs of derivatives with Ampicillin Sodium, Fosfomycin Sodium and the parent compound canthin-6-one, 3-N-benzylated canthin-6-ones generally show good in vitro antibacterial activity, especially for S. aureus and P. solanacearum; 3) Comparing the MICs of the compound D5 b with D4 and D5 a, the unsaturated bonds could improve their antibacterial activity; 4) The halogen of these compounds has some effect on the in vitro antibacterial activity while the clear relationship has not been investigated due to the limitation of the number of samples; 5) The in vitro antibacterial activity of canthin-6-one-3-N-oxide D7 is weaken than canthin-6-one D5 b with a little change; 6) Compounds D6i-r and D6 t are the significantly potential compounds with MICs lower than 1.95 μg/mL against S. aureus, while the positive controls are just 3.91 μg/mL. Compounds D6i-o, D6 q, D6 r, D6 t and D7 are also found to be the most potential compounds with MICs lower than 7.81 μg/mL against P. solanacearum, compared with the positive control values 7.81 μg/mL. The in vitro antibacterial activity data revealed that canthin-6-one derivatives have the potentiality to be developed into new anti-bacterial drugs.