Acute and 28-Day Toxicity Evaluation of New Pleuromutilin Derivative 4g

A novel pleuromutilin derivative, compound 4g with a cyclobutyl side chain, was identified and found to have good antibacterial activity, including methicillin-resistant Staphylococcus aureus (MRSA) and Mycoplasma. In order to evaluate its safety profile, acute and 28-day oral toxicity studies were carried out. An acute toxicity study in rats revealed that the oral LD₅₀ of 4g exceeded 5000 mg/kg, indicating that the compound had low acute toxicity. In a 28-day oral toxicity test, the rats were repeatedly administered 0, 300, 1000, and 3000 mg/kg doses and showed no adverse clinical symptoms or death. Although 4g did not affect body weight, hematological findings indicated dose-dependent inflammatory changes at 1000 and 3000 mg/kg. Serum biochemistry showed decreases in alanine aminotransferase (ALT) and alkaline phosphatase (ALP), suggesting adaptive metabolic responses rather than classic hepatocellular injury. Significantly, dose-dependent increases in relative liver weight were observed at all dose levels, accompanied by minimal hepatocyte steatosis and altered serum lipid profiles, identifying the liver as a primary target organ. Based on the totality of findings, the no-observed-adverse-effect level (NOAEL) was determined to be 300 mg/kg. In conclusion, pleuromutilin derivative 4g has low toxicity, which provides the theoretical basis to further investigate for a new candidate drug.