LAUSR

To develop new antibiotics owning a special mechanism, we used the molecular assembly method to synthesize a series of novel pleuromutilin derivatives containing a cinnamic acid scaffold at the C‐14 side chain. We evaluated their antibacterial activity and used in silico molecular docking to study their binding mode with the target. The structure–activity relationship (SAR) study suggested that compounds with NO2 (13e), OH (13u), and NH2 (13y) appeared more active (0.0625–2 µg/mL) in vitro against several penicillin‐resistant Gram‐positive bacteria and the position of the substituent on the benzene ring would affect the activity. The in vivo efficacy investigation of 13e, 13u, and 13y with once daily intragastric (i.g.) administration at 40 mg/kg for 3 consecutive days in a mouse systemic infection model showed that 13u had equal activity as valnemulin providing the mice with 60% survival, while 13e and 13y gave 30 and 40% survival, respectively. The molecular docking studies indicated that π–π stacking and hydrogen bond formation played important roles in improving the antibacterial activity.