Design, synthesis, and biological evaluation of tyrcinnamine derivatives as bactericides

Structural modification of bioactive natural products plays a vital role in the development of new drugs. Herein, we report the design and synthesis of twelve new tyrcinnamin derivatives (6a-8a, 6b-7b, 6c-8c, 10, and 13–15) using tyrcinnamin methyl ester (2) as a lead. In vitro biological investigation indicated that, unlike the lead (2), which is a bacteriostat, 14 exhibited significant bactericidal activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic studies indicated that the bactericidal effect of 14 might induced by the membrane-disrupting and reactive oxygen species (ROS) generation. In vivo investigation with a Galleria mellonella larvae infection model revealed that 14 significantly inhibited the growth of MRSA, therefore enhancing the survival rate of the MRSA-infected G. mellonella larvae. The strong antibacterial activity, excellent safety profile, and good solubility of 14 make it a promising candidate for the development of new bactericides.