Synthesis, Cytotoxic, and Antibacterial Evaluation of C-12 Substituted Ocotillol-type Derivatives

A novel series of ocotillol-type triterpenoid derivatives have been synthesized to evaluate for their antibacterial activity, structure-activity relationships (SARs), and antibacterial mechanism. Compound ( Vl ), which were found to be the most active one, displayed good antibacterial activity with minimum inhibitory concentrations (MICs) of 2–8 μg/mL against Gram+ bacteria and 8–32 μg/mL against Gram– bacteria. Further testing against drug-resistant bacteria also showed that ( Vk ) and ( Vl ) exhibited potent antibacterial activity with MICs of 4–32 μg/mL against MRSA and K. pneumonia . The following synergistic antibacterial activity revealed that compound ( Vl ) significantly improved the susceptibility of MRSA USA300 and E.coli DH5α to kanamycin and chloramphenicol. Further research suggested that ( Vl ) displayed obvious bactericidal activity against MRSA at 2 MIC while it only showed bacteriostatic effects at MIC. This active molecule ( Vl ) also induced bacterial resistance more slowly than norfloxacin and chloramphenicol. Moreover, compound ( Vl ) not only had low toxicity, but also could rapidly inhibit the growth of drug-resistant bacteria by damaging cell membranes, and the incidence of drug resistance was obviously lower than that of positive control group. Additionally, the properties of absorption, distribution, metabolism, and excretion (ADME) of these compounds demonstrated their drug-likeness with moderate oral absorption and blood-brain barrier permeability. Preliminary in vivo results also confirmed that ( Vl ) could reduce the number of viable colonies in the infected cornea at a high concentration (3.2 mg/mL). These results suggested that ocotillol-type triterpenoid derivatives represent as potential leads for the development of antibacterial agents against antibiotic-resistant superbugs and deserve further attention.