Semisynthesis, Structure Elucidation and Anti- Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups.

The incidence of infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti- drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5' and C-6', exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5' and C-6' on this compound's activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5' and C-6'. The / configuration of the diastereoisomer at C-13' was further determined through an NOE correlation analysis of CH or CH at the derivative C-13' position and the H-5' and H-6' by means of a 1D NOE experiment. Further comparative H NMR analysis of diastereoisomers showed the difference in the chemical shift () value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds - and - demonstrated promising activity against , with MIC values ranging from 70 to 90 μM, closely approaching the MIC of isoniazid. The preliminary structure-activity relationships showed that the ketal groups with aromatic rings at C-5' and C-6' could enhance the inhibition of . Further study demonstrated that compounds , , , and had significant inhibitory effects on and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting resistance.